Inhibition of 11β-HSD

5697-56-3

OBZHEBDUNPOCJG-WBXJDKIVSA-N

Carbenoxolone

DTXSID4022733

1405-86-3

LPLVUJXQOOQHMX-QWBHMCJMSA-N

Glycyrrhizin

α-D-Glucopyranosiduronic acid, (3β,20β)-20-carboxy-11-oxo-30-norolean-12-en-3-yl 2-O-β-D-glucopyranuronosyl- 18β-Glycyrrhizic acid Acide glycyrrhizique acido glicirricico Glycyron Glycyrrhetinic acid glycoside glycyrrhizic acid Glycyrrhizinic acid Glycyrrhizinsaure NSC 167409 NSC 234419 Potenlini β-Glycyrrhizin

DTXSID8047006

83-46-5

KZJWDPNRJALLNS-VJSFXXLFSA-N

beta-Sitosterol

Stigmast-5-en-3-ol, (3β)- (-)-β-Sitosterol (24R)-Ethylcholest-5-en-3β-ol (24R)-Stigmast-5-en-3β-ol 22,23-Dihydrostigmasterol 24α-Ethylcholesterol Angelicin Azuprostat Betaprost Cinchol Cupreol estigmast-5-en-3-β-ol Nimbosterol NSC 18173 NSC 49083 NSC 8096 Prostasal Quebrachol Rhammol Rhamnol Sito-Lande Sitosterol Sobatum stigmast-5-en-3-β-ol Stigmast-5-en-3β-ol stigmast-5-ene-3-β-ol Stigmasterol, 22,23-dihydro- α-Dihydrofucosterol α-Phytosterol β-Sitosterin β-Sitosterol Δ5-Stigmasten-3β-ol

DTXSID5022481

41859-67-0

IIBYAHWJQTYFKB-UHFFFAOYSA-N

Bezafibrate

Propanoic acid, 2-[4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy]-2-methyl- Befizal Benzofibrate Bezafibrat bezafibrato Bezalip Bezatol Difaterol

DTXSID3029869

25812-30-0

HEMJJKBWTPKOJG-UHFFFAOYSA-N

Gemfibrozil

Pentanoic acid, 5-(2,5-dimethylphenoxy)-2,2-dimethyl- 2,2-Dimethyl-5-(2,5-xylyloxy)valeric acid 5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic acid Decrelip gemfibrozilo Gevilon Lopizid Trialmin 900 Valeric acid, 2,2-dimethyl-5-(2,5-xylyloxy)-

DTXSID0020652

117-81-7

BJQHLKABXJIVAM-UHFFFAOYNA-N

BJQHLKABXJIVAM-UHFFFAOYSA-N

Di(2-ethylhexyl) phthalate

1,2-Benzenedicarboxylic acid, bis(2-ethylhexyl) ester DEHP 1,2-Benzedicarboxylic acid, bis(2-ethyl-hexyl) ester 1,2-Benzenedicarboxylic acid bis(2-ethylhexyl) ester 1,2-Benzenedicarboxylic acid, 1,2-bis(2-ethylhexyl) ester 1,2-Benzenedicarboxylic acid,bis(2-ethylhexylester) Bis(2-ethylhexyl) 1,2-benzenedicarboxylate Bis(2-ethylhexyl) o-phthalate bis(2-ethylhexyl) phthalate Bis(2-ethylhexyl)phthalat Bis(2-ethylhexyl)phthalate Bisoflex 81 Bisoflex DOP Corflex 400 Di(2-ethylhexyl)phthalate Di(isooctyl) phthalate Di-2-ethylhexlphthalate Di-2-ethylhexyl phthalate DI-2-ETHYLHEXYL-PHTHALATE Diacizer DOP Diethylhexyl phthalate Dioctylphthalate DOF Ergoplast FDO Ergoplast FDO-S ETHYLHEXYL PHTHALATE Eviplast 80 Eviplast 81 Fleximel Flexol DOD Flexol DOP ftlalato de bis(2-etilhexilo) Garbeflex DOP-D 40 Good-rite GP 264 Hatco DOP Jayflex DOP Kodaflex DEHP Kodaflex DOP Monocizer DOP NSC 17069 Palatinol AH Palatinol AH-L Phtalate de Bis (Ethyle-2-Hexyle) Phtalate de bis(2-ethylhexyle) PHTHALATE, BIS(2-ETHYLHEXYL) Phthalic acid di(2-ethylhexyl) ester Phthalic acid, bis(2-ethylhexyl) ester PHTHALIC ACID, BIS(2-ETHYLHEXYL)ESTER PHTHALSAEURE-BIS-(2-AETHYLHEXYL)-ESTER Pittsburgh PX 138 Plasthall DOP Reomol D 79P Sansocizer DOP Sansocizer R 8000 Sconamoll DOP Staflex DOP Truflex DOP Vestinol AH Vinycizer 80 Vinycizer 80K Witcizer 312

DTXSID5020607

52315-07-8

KAATUXNTWXVJKI-UHFFFAOYNA-N

KAATUXNTWXVJKI-UHFFFAOYSA-N

Cypermethrin

3-(2,2-Dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid, cyano (3-phenoxyphenyl)methyl ester Zeta-cypermethrin (ECL) Cyclopropanecarboxylic acid, 3-(2,2-dichloroethenyl)-2,2-dimethyl-, cyano(3-phenoxyphenyl)methyl ester (RS)-alpha-Cyano-3-phenoxybenzyl (1RS)-cis-trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (S)-α-Cyano-3-phenoxybenzyl(1RS,3RS;1RS,3SR)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-carboxylate 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate de α-cyano-3-phenoxybenzyle 3-(2,2-diclorovinil)-2,2-dimetilciclopropanocarboxilato de α-ciano-3-fenoxibencilo Agrometrin Agrothrin Almetrin Ambush C Ambush CY Antiborer 3767 Asymmethrin Barrage Barricade Barricade 10EC Basathrin Chinimix Chinmix Cilcord cis-Cypermethrin Creokhin Cyano(3-phenoxyphenyl)methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate Cymbush Cympa-Ti Cymperator Cyperco Cyperil Cyperkill Demon TC Ecofleece Sheep Dip (Non-OP) Ectomin Ectopor Flytick Hilcyperin Kreokhin Leptocide Luseweilei Neramethrin Neramethrin EC 50 Nurse Green Peststop B Peststop B 5SC Polytrin Prevail Prevail FT PYR-VU-TO 2 Ralothrin Ripcord Ronatak Summerin Supercypermethrin Supercypermethrin forte Supermethrin Supersect alpha-Cyan-3-phenoxybenzyl-3-(2,2-dichlorvinyl)-2,2-dimethylcyclopropancarboxylat alpha-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate alpha-Cyano-m-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate

DTXSID1023998

298-46-4

FFGPTBGBLSHEPO-UHFFFAOYSA-N

Carbamazepine

Carbazepine 5H-Dibenz[b,f]azepine-5-carboxamide 5-Carbamoyl-5H-dibenz[b,f]azepine 5H-Dibenzo [b,f] azepine-5-carboxamide Amizepin Calepsin Carbamazepen Carbamazepin carbamazepina Carbatrol Carbelan Finlepsin Geigy 32883 Karbamazepin Karbelex Karberol Neurotol Neurotop NSC 169864 Stazepine Tegretal Tegretol Tegretol XR Telesmin Timonil

DTXSID4022731

13311-84-7

MKXKFYHWDHIYRV-UHFFFAOYSA-N

Flutamide

Propanamide, 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]- 4-Nitro-3-(trifluoromethyl)isobutyranilide 4'-Nitro-3'-trifluoromethylisobutyranilide Eulexin Flucinom Flutamid flutamida m-Propionotoluidide, α,α,α-trifluoro-2-methyl-4'-nitro- N-(Isopropylcarbonyl)-4-nitro-3-trifluoromethylaniline Niftholide Niftolide NSC 147834 NSC 215876

DTXSID7032004

50471-44-8

FSCWZHGZWWDELK-UHFFFAOYNA-N

FSCWZHGZWWDELK-UHFFFAOYSA-N

Vinclozolin

2,4-Oxazolidinedione, 3-(3,5-dichlorophenyl)-5-ethenyl-5-methyl- (.+-.)-Vinclozolin BAS 352-04F N-3,5-Dichlorophenyl-5-methyl-5-vinyl-1,3-oxazolidine-2,4-dione N-3,5-Dichlorophenyl-5-methyl-5-vinyloxazolidine-2,4-dione N-3,5-Dichlorphenyl-5-methyl-5-vinyl-1,3-oxazolidin-2,4-dion N-3,5-diclorofenil-5-metil-5-vinil-1,3-oxazolidina-2,4-diona Ornalin Ranilan Ronilan Ronilan 50WP

DTXSID4022361

CHEBI:34133

CHEBI 11-Keto-testosterone

FMA:67338

FMA Mature sperm cell

PCO:0000001

PCO population of organisms

GO:0006702

GO androgen biosynthetic process

HP:0008669

HP Abnormal spermatogenesis

PCO:0000008

PCO population growth rate

D005298

MESH fertility

WIKI decreased

WIKI abnormal

N-(5-Hydroxytricyclo[3.3.1.13,7]dec-2-yl)-α,α-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-1-piperazineacetamide

2020-07-05T11:13:05

Carbenoxolone

2020-03-30T15:25:49

Glycyrrhizin

2020-07-13T10:41:04

PF915275

2020-07-13T10:42:07

beta-Sitosterol

2020-03-23T14:04:49

Bezafibrate

2016-11-29T18:42:27

Gemfibrozil Fibrate drug

2016-11-29T18:42:27

2020-03-31T10:24:40

Bis(2-ethylhexyl) phthalate

2016-11-29T18:42:08

Cypermethrin

2016-11-29T18:42:27

Carbamazepine

2016-11-29T18:42:27

Flutamide

2016-11-29T18:42:27

Vinclozolin

2020-05-14T11:28:31

70862

NCBI teleost fish

30483

NCBI Order carcharhiniformes

WikiUser_17

mammals

WikiUser_28

Vertebrates

WikiUser_22

all species

10116

NCBI rat

10090

NCBI mouse

WCS_9606

common toxicological species human

WikiUser_6

ApacheUser fish

WikiUser_26

ApacheUser rodents

Inhibition of 11β-HSD

Molecular

AOPWiki 2020-07-13T09:23:54

2020-07-13T09:23:54

Decreased, plasma 11-ketotestosterone level

Decreased, 11KT

Tissue

11-ketotestosterone (11KT; CAS 564-35-2 | DTXSID8036499) is an oxygenated steroidal androgen with a keto group at the C11 position (Pretorius et al. 2017).  11-ketotestosterone is a dominant androgen in teleost fish (Borg 1994). It is synthesized from testosterone using the enzymes CYP11b1 and HSD11b (Yazawa et al., 2008; Swart et al., 2013). Zebrafish studies also show that cyp17a1 and cyp11c1 knockouts have dramatically reduced levels of 11KT (Shu et al., 2020; Zhang et al., 2020) 11KT is also produced by other vertebrates, although the site of its biosynthesis and physiological signficance in different taxa can vary widely. In humans, 11KT is primarily synthesized in the adrenal glands (Pretorius et al. 2017; Turcu et al. 2018).    Although mutations in the mettl3 gene usually cause embryonic lethality, one particular mutation in non-lethal and causes significantly reduced 11KT levels in zebrafish (Xia et al., 2018)

11KT production can be measured in an ex vivo steroidogenesis assay using the organism's gonad after it has been exposed to a compound. The concentration of 11KT can be measured in a radioimmunoassay or enzyme-linked immunosorbent assay (ELISA).  Several papers show that in fish, 11KT is correlated with testosterone levels (Spanò et al., 2004; Maclatchy & Vanderkraak, 1995; Lorenzi et al., 2008).

Taxanomic Applicability: Most understand of 11KT comes from studies involving teleost fish as it is their dominant androgen. Some studies have measured 11KT in sharks of the order carcharhiniformes, but there is less research in this area (Manire et al., 1999; Garnier et al. 1999; Mills et al. 2010). Many mammals possess the genes necessary to produce 11KT (NCBI), but 11KT may not be as relevant when it’s not the dominant androgen. Sex Applicability: Males and females use the same biological processes to produce steroids. However, sexual dimorphism in 11KT production varies between species. In humans, plasma levels of 11KT do not differ between sexes (Imamichi et al., 2016). In Zebrafish, gonad levels of 11KT are approximately two magnitudes higher in males than females (Wang & Orban, 2007). Of the 30 other fish species sampled by Lokman et al. (2002), 11KT levels are typically dramatically lower in females than in males, but a few species of the order Perciformes show no sexual dimorphism. Life Stage Applicability: 11KT can be measured in fish larvae however individuals must be pooled for sufficient sample size (Hattori et al., 2009). Lokman et al. (2002) measured plasma levels of 11-KT in several species of juvenile and adult fish. 11KT levels tend to be higher in males although some fish species don’t show sexual dimorphism. Levels of 11KT in juveniles are similar to levels in females regardless of if the species shows sexual dimorphism in 11KT levels. In males, 11KT increases for spawning and decreases afterwards (Kindler et al., 1989; Páll et al., 2002). Because of it’s involvement in reproduction, 11KT levels may not be meaningful in juveniles.

UBERON:0001969

UBERON blood plasma

High Male High Female

Moderate

Juvenile

High

Adult, reproductively mature

Moderate

Larvae

High Moderate Low

Borg, B. (1994). Androgens in teleost fishes. Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology, 109(3), 219-245. Fraz, S. et al. (2018) “Gemfibrozil and carbamazepine decrease steroid production in zebrafish testes (Danio rerio)”, Aquatic Toxicology, Vol. 198, Elsevier, pp. 1-9. https://doi.org/10.1016/j.aquatox.2018.02.006  Golshan, M. & S.M.H. Alvai (2019) “Androgen signaling in male fishes: Examples of anti-androgenic chemicals that cause reproductive disorders”, Theriogenology, Vol. 139, Elsevier, pp. 58-71. https://doi.org/10.1016/j.theriogenology.2019.07.020  Hattori, R.S. et al. (2009) “Cortisol-induced masculinization: Does thermal stress affect gonadal fate in pejerrey, a teleost fish with temperature-dependent sex determination?”, PLoS ONE, Vol. 4(8), pp. 1-7. doi:10.1371/journal.pone.0006548 Imamichi, Y. et al. (2016) “11-Ketotestosterone is a major androgen produced in human gonads”, The Journal of Clinical Endocrinology & Metabolism, Vol. 101(10), Oxford Academic, pp. 3582-3591. https://doi.org/10.1210/jc.2016-2311 Kindler, P. M. et al. (1989) “Serum 11-ketotestosterone and testosterone concentrations associated with reproduction in male bluegill (Lepomis macrochirus: Centrarchidae)”, General and Comparative Endocrinology, Vol. 75(3), Elsevier, pp. 446-453. https://doi.org/10.1016/0016-6480(89)90180-9 Lee, G. et al. (2019) “Effects of gemfibrozil on sex hormones and reproduction related performances of Oryzias latipes following long-term (155 d) and short-term (21 d) exposure”, Ecotoxicology and Environmental Safety, Vol. 173, Elsevier, pp. 174-181. https://doi.org/10.1016/j.ecoenv.2019.02.015 Lokman, P.M. et al. (2002) “11-Oxygenated androgens in female teleosts: prevalence, abundance, and life history implications”, General and Comparative Endocrinology, Vol. 129, Academic Press, pp. 1-12. doi: 10.1016/s0016-6480(02)00562-2 Lorenzi, V. et al. (2008) “Diurnal patterns and sex differences in cortisol, 11-ketotestosterone, testosterone, and 17β-estradiol in the bluebanded goby (Lythrypnus dalli)”, General and Comparative Endocrinology, Vol. 155(2)., Elsevier, pp. 438-446. https://doi.org/10.1016/j.ygcen.2007.07.010 MacLatchy, D.L. and G.J. Vanderkraak (1995) “The phytoestrogen β-sitosterol alters the reproductive endocrine status of goldfish”, Toxicology and Applied Pharmacology, Vol. 134(2), Elsevier, pp. 305-312. https://doi.org/10.1006/taap.1995.1196 Manire, C.A., L.E. Rasmussen & T.S. Gross (1999) “Serum steroid hormones including 11-ketotestosterone, 11-ketoandrostenedione, and dihydroprogesterone in juvenile and adult bonnethead sharks, Sphyrna tiburo”, Journal of Experimental Zoology, Vol. 284(5), Wiley-Blackwell, pp. 595-603. DOI: 10.1002/(sici)1097-010x(19991001)284:5<595::aid-jez15>3.0.co  Páll, M. K., I. Mayer and B. Borg (2002) “Androgen and behavior in the male three-spined stickleback, Gasterosteus aculeatus I. – Changes in 11-ketotestosterone levels during nesting cycle”, Hormones and Behavior, Vol. 41(4), Elsevier, pp. 377-383. https://doi.org/10.1006/hbeh.2002.1777 Pretorius, E, Arlt, W & Storbeck, K-H 2016, 'A new dawn for androgens: novel lessons from 11-oxygenated C19 steroids', Molecular and Cellular Endocrinology. https://doi.org/10.1016/j.mce.2016.08.014 Shu, T. et al. (2020) “Zebrafish cyp17a1 knockout reveals that androgen-mediated signaling is important for male brain sex differentiation”, General and Comparative Endocrinology, Vol. 295. doi:10.1016/j.ygcen.2020.113490  Singh, P.B. & V. Singh (2008) “Cypermethrin induced histological changes in gonadotrophic cells, liver, gonads, plasma levels of estradiol-17beta and 11-ketotestosterone, and sperm motility in Heteropneustes fossilis (Bloch)”, Chemosphere, Vol. 72(3), Elsevier, pp. 422-431. DOI: 10.1016/j.chemosphere.2008.02.026  Spanó, L. et al. (2004) “Effects of atrazine on sex steroid dynamics, plasma vitellogenin concentration and gonad development in adult goldfish (Carassius auratus)”, Aquatic Toxicology, Vol. 66(4), Elsevier, pp. 369-379. https://doi.org/10.1016/j.aquatox.2003.10.009 Swart, A.C. et al. (2013) “11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione”, The Journal of Steroid Biochemistry and Molecular Biology, Vol 138, Elsevier, pp. 132-142. https://doi.org/10.1016/j.jsbmb.2013.04.010 Turcu AF, Nanba AT, Auchus RJ. The Rise, Fall, and Resurrection of 11-Oxygenated Androgens in Human Physiology and Disease. Horm Res Paediatr. 2018;89(5):284-291. doi: 10.1159/000486036. Epub 2018 May 9. PMID: 29742491; PMCID: PMC6031471. Velasco-Santamaría, Y.M. et al. (2011) “Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (Danio rerio)”, Aquatic Toxicology, Vol. 105, Elsevier, pp. 107-118. doi:10.1016/j.aquatox.2011.05.018 Wang, X.G. and L. Orban (2007) “Anti-Müllerian hormone and 11β-hydroxylase show reciprocal expression to that of aromatase in the transforming gonad of zebrafish males”, Developmental Dynamics, Vol 236(5), Wiley-Liss, pp. 1329-1338. https://doi.org/10.1002/dvdy.21129 Xia, H. et al. (2018) “Mettl3 mutation disrupts gamete maturation and reduced fertility in zebrafish”, Genetics, Vol. 208(2), Genetics Society of America, pp. 729-743. DOI: 10.1534/genetics.117.300574  Yazawa, T. (2008) “Cyp11b1 is induced in the murine gonad by luteinizing hormone/human chorionic gonadotropin and involved in the production of 11-ketotestosterone, a major fish androgen: Conservation and evolution of the androgen metabolic pathway”, Endocrinology, Vol. 149(4), Oxford Academy, pp. 1786-1792. https://doi.org/10.1210/en.2007-1015 Zheng, Q. et al. (2020) “Loss of cyp11c1 causes delayed spermatogenesis due to the absence of 11-ketotestosterone", Journal of Endocrinology, Vol. 244(3), Bioscientifica, pp. 487-499. https://doi.org/10.1530/JOE-19-0438  AOPWiki 2020-03-23T11:09:03

2022-05-24T13:51:43

Impaired, Spermatogenesis

Organ

Spermatogenesis is a multiphase process of cellular transformation that produces mature male gametes known as sperm for sexual reproduction (Xu et al., 2015). The process of spermatogenesis can be broken down into 3 phases: the mitotic proliferation of spermatogonia, meiosis, and post-meiotic differentiation(spermiogenesis) (Boulanger et al., 2015). Spermatogenesis can be impaired within these phases or due to external factors such as chemical exposures or the gonadal tissue environment. For example, zebrafish and fathead minnow exposed to flutamide, an antiandrogen, have shown signs of impaired spermatogenesis such as spermatocyte degradation(Jensen et al., 2004, Yin et al., 2017).

Impairment of spermatogenesis can be measured and detected in a multitude of ways. One example of this is qualitative histological assessments (Jensen et al., 2004). Through histology, sperm morphology can be examined and quantified through the number and stage of the sperm. Sperm morphology, overall quantity, and quantity within each stage can be ways to detect impaired spermatogenesis(Uhrin et al., 2000, Xie et al., 2020). Additionally, sperm quality can also be another assessment of impaired spermatogenesis such as sperm motility, velocity, ATP content, and lipid peroxidation(Gage et al., 2004, Xia et al., 2018, Chen et al., 2015). Impaired spermatogenesis can also be seen by measuring sperm density(Chen et al., 2015).

Taxonomic Applicability: The relevance for invertebrates has not been evaluated.  Life Stage Applicability: Only applicable for sexually mature adults Sex Applicability: Only applicable to males

UBERON:0000473

UBERON testis

High Male

High

Adult, reproductively mature

High

Boulanger, G., Cibois, M., Viet, J., Fostier, A., Deschamps, S., Pastezeur, S., Massart, C., Gschloessl, B., Gautier-Courteille, C., & Paillard, L. (2015). Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice. Molecular and cellular biology, 35(18), 3244–3253. <a href="https://doi.org/10.1128/MCB.00074-15">https://doi.org/10.1128/MCB.00074-15</a> Chen, J., Xiao, Y., Gai, Z., Li, R., Zhu, Z., Bai, C., Tanguay, R. L., Xu, X., Huang, C., & Dong, Q. (2015). Reproductive toxicity of low level bisphenol A exposures in a two-generation zebrafish assay: Evidence of male-specific effects. Aquatic toxicology (Amsterdam, Netherlands), 169, 204–214. https://doi.org/10.1016/j.aquatox.2015.10.020 Golshan, M. & S.M.H. Alvai (2019) “Androgen signaling in male fishes: Examples of anti-androgenic chemicals that cause reproductive disorders”, Theriogenology, Vol. 139, Elsevier, pp. 58-71. https://doi.org/10.1016/j.theriogenology.2019.07.020  Jensen, K.M. et al. (2004) “Characterization of responses to the antiandrogen flutamide in a short-term reproduction assay with the fathead minnow”, Aquatic Toxicology, Vol. 70(2), Elsevier, pp. 99-110. https://doi.org/10.1016/j.aquatox.2004.06.012  Uhrin, P., Dewerchin, M., Hilpert, M., Chrenek, P., Schöfer, C., Zechmeister-Machhart, M., Krönke, G., Vales, A., Carmeliet, P., Binder, B. R., & Geiger, M. (2000). Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility. The Journal of clinical investigation, 106(12), 1531–1539. <a href="https://doi.org/10.1172/JCI10768">https://doi.org/10.1172/JCI10768</a> Xia, H., Zhong, C., Wu, X., Chen, J., Tao, B., Xia, X., Shi, M., Zhu, Z., Trudeau, V. L., & Hu, W. (2018). Mettl3 Mutation Disrupts Gamete Maturation and Reduces Fertility in Zebrafish. Genetics, 208(2), 729–743. https://doi.org/10.1534/genetics.117.300574 Xie, H., Kang, Y., Wang, S., Zheng, P., Chen, Z., Roy, S., & Zhao, C. (2020). E2f5 is a versatile transcriptional activator required for spermatogenesis and multiciliated cell differentiation in zebrafish. PLoS genetics, 16(3), e1008655. https://doi.org/10.1371/journal.pgen.1008655 Xu, K., Wen, M., Duan, W., Ren, L., Hu, F., Xiao, J., Wang, J., Tao, M., Zhang, C., Wang, J., Zhou, Y., Zhang, Y., Liu, Y., & Liu, S. (2015). Comparative analysis of testis transcriptomes from triploid and fertile diploid cyprinid fish. Biology of reproduction, 92(4), 95. <a href="https://doi.org/10.1095/biolreprod.114.125609">https://doi.org/10.1095/biolreprod.114.125609</a> Yin, P. et al. (2017) “Diethylstilbestrol, flutamide and their combination impaired the spermatogenesis of male adult zebrafish through disrupting HPG axis, meiosis and apoptosis”, Aquatic Toxicology, Vol. 185, Elsevier, pp. 129-137. https://doi.org/10.1016/j.aquatox.2017.02.013 AOPWiki 2020-04-16T12:02:39

2022-05-16T02:14:34

Decrease, Population growth rate

Population

A population can be defined as a group of interbreeding organisms, all of the same species, occupying a specific space during a specific time (Vandermeer and Goldberg 2003, Gotelli 2008).  As the population is the biological level of organization that is often the focus of ecological risk assessments, population growth rate (and hence population size over time) is important to consider within the context of applied conservation practices. If N is the size of the population and t is time, then the population growth rate (dN/dt) is proportional to the instantaneous rate of increase, r, which measures the per capita rate of population increase over a short time interval. Therefore, r, is a difference between the instantaneous birth rate (number of births per individual per unit of time; b) and the instantaneous death rate (number of deaths per individual per unit of time; d) [Equation 1]. Because  r is an instantaneous rate, its units can be changed via division.  For example, as there are 24 hours in a day, an r of 24 individuals/(individual x day) is equal to an r of 1 individual/(individual/hour) (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020).  Equation 1:  r = b - d This key event refers to scenarios where r < 0 (instantaneous death rate exceeds instantaneous birth rate). Examining r in the context of population growth rate: ● A population will decrease to extinction when the instantaneous death rate exceeds the instantaneous birth rate (r < 0).              ● The smaller the value of r below 1, the faster the population will decrease to zero.   ● A population will increase when resources are available and the instantaneous birth rate exceeds the instantaneous death rate (r > 0)            ● The larger the value that r exceeds 1, the faster the population can increase over time       ● A population will neither increase or decrease when the population growth rate equals 0 (either due to N = 0, or if the per capita birth and death rates are exactly balanced).  For example, the per capita birth and death rates could become exactly balanced due to density dependence and/or to the effect of a stressor that reduces survival and/or reproduction (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020).      Effects incurred on a population from a chemical or non-chemical stressor could have an impact directly upon birth rate (reproduction) and/or death rate (survival), thereby causing a decline in population growth rate.   ● Example of direct effect on r:  Exposure to 17b-trenbolone reduced reproduction (i.e., reduced b) in the fathead minnow over 21 days at water concentrations ranging from 0.0015 to about 41 mg/L (Ankley et al. 2001; Miller and Ankley 2004).              Alternatively, a stressor could indirectly impact survival and/or reproduction.   ● Example of indirect effect on r:  Exposure of non-sexually differentiated early life stage fathead minnow to the fungicide prochloraz has been shown to produce male-biased sex ratios based on gonad differentiation, and resulted in projected change in population growth rate (decrease in reproduction due to a decrease in females and thus recruitment) using a population model. (Holbech et al., 2012; Miller et al. 2022) Density dependence can be an important consideration: ● The effect of density dependence depends upon the quantity of resources present within a landscape.  A change in available resources could increase or decrease the effect of density dependence and therefore cause a change in population growth rate via indirectly impacting survival and/or reproduction.   ● This concept could be thought of in terms of community level interactions whereby one species is not impacted but a competitor species is impacted by a chemical stressor resulting in a greater availability of resources for the unimpacted species.  In this scenario, the impacted species would experience a decline in population growth rate. The unimpacted species would experience an increase in population growth rate (due to a smaller density dependent effect upon population growth rate for that species).        Closed versus open systems: ● The above discussion relates to closed systems (there is no movement of individuals between population sites) and thus a declining population growth rate cannot be augmented by immigration.   ● When individuals depart (emigrate out of a population) the loss will diminish population growth rate.   Population growth rate applies to all organisms, both sexes, and all life stages.

Population growth rate (instantaneous growth rate) can be measured by sampling a population over an interval of time (i.e. from time t = 0 to time t = 1).  The interval of time should be selected to correspond to the life history of the species of interest (i.e. will be different for rapidly growing versus slow growing populations). The population growth rate, r, can be determined by taking the difference (subtracting) between the initial population size, Nt=0 (population size at time t=0), and the population size at the end of the interval, Nt=1 (population size at time t = 1), and then subsequently dividing by the initial population size.  Equation 2:  r = (Nt=1 - Nt=0) / Nt=0 The diversity of forms, sizes, and life histories among species has led to the development of a vast number of field techniques for estimation of population size and thus population growth over time (Bookhout 1994, McComb et al. 2021).   ● For stationary species an observational strategy may involve dividing a habitat into units. After setting up the units, samples are performed throughout the habitat at a select number of units (determined using a statistical sampling design) over a time interval (at time t = 0 and again at time t = 1), and the total number of organisms within each unit are counted. The numbers recorded are assumed to be representative for the habitat overall, and can be used to estimate the population growth rate within the entire habitat over the time interval.   ● For species that are mobile throughout a large range, a strategy such as using a mark-recapture method may be employed (i.e. tags, bands, transmitters) to determine a count over a time interval (at time = 0 and again at time =1).    Population growth rate can also be estimated using mathematical model constructs (for example, ranging from simple differential equations to complex age or stage structured matrix projection models and individual based modeling approaches), and may assume a linear or nonlinear population increase over time (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). The AOP framework can be used to support the translation of pathway-specific mechanistic data into responses relevant to population models and output from the population models, such as changing (declining) population growth rate, can be used to assess and manage risks of chemicals (Kramer et al. 2011). As such, this translational capability can increase the capacity and efficiency of safety assessments both for single chemicals and chemical mixtures (Kramer et al. 2011).   Some examples of modeling constructs used to investigate population growth rate: ● A modeling construct could be based upon laboratory toxicity tests to determine effect(s) that are then linked to the population model and used to estimate decline in population growth rate.  Miller et al. (2007) used concentration–response data from short term reproductive assays with fathead minnow (Pimephales promelas) exposed to endocrine disrupting chemicals in combination with a population model to examine projected alterations in population growth rate.   ● A model construct could be based upon a combination of effects-based monitoring at field sites (informed by an AOP) and a population model.  Miller et al. (2015) applied a population model informed by an AOP to project declines in population growth rate for white suckers (Catostomus commersoni) using observed changes in sex steroid synthesis in fish exposed to a complex pulp and paper mill effluent in Jackfish Bay, Ontario, Canada. Furthermore, a model construct could be comprised of a series of quantitative models using KERs that culminates in the estimation of change (decline) in population growth rate.   ● A quantitative adverse outcome pathway (qAOP) has been defined as a mathematical construct that models the dose–response or response–response relationships of all KERs described in an AOP (Conolly et al. 2017, Perkins et al. 2019). Conolly et al. (2017) developed a qAOP using data generated with the aromatase inhibitor fadrozole as a stressor and then used it to predict potential population‐level impacts (including decline in population growth rate). The qAOP modeled aromatase inhibition (the molecular initiating event) leading to reproductive dysfunction in fathead minnow (Pimephales promelas) using 3 computational models: a hypothalamus–pituitary–gonadal axis model (based on ordinary differential equations) of aromatase inhibition leading to decreased vitellogenin production (Cheng et al. 2016), a stochastic model of oocyte growth dynamics relating vitellogenin levels to clutch size and spawning intervals (Watanabe et al. 2016), and a population model (Miller et al. 2007). ● Dynamic energy budget (DEB) models offer a methodology that reverse engineers stressor effects on growth, reproduction, and/or survival into modular characterizations related to the acquisition and processing of energy resources (Nisbet et al. 2000, Nisbet et al. 2011).  Murphy et al. (2018) developed a conceptual model to link DEB and AOP models by interpreting AOP key events as measures of damage-inducing processes affecting DEB variables and rates. ● Endogenous Lifecycle Models (ELMs), capture the endogenous lifecycle processes of growth, development, survival, and reproduction and integrate these to estimate and predict expected fitness (Etterson and Ankley, 2021).  AOPs can be used to inform ELMs of effects of chemical stressors on the vital rates that determine fitness, and to decide what hierarchical models of endogenous systems should be included within an ELM (Etterson and Ankley, 2021).

Consideration of population size and changes in population size over time is potentially relevant to all living organisms.

Not Specified Unspecific

Not Specified

All life stages

High

<ul> <li>Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, Henry TR, Denny JS, Leino RL, Wilson VS, Cardon MD, Hartig PC, Gray LE. 2003. Effects of the androgenic growth promoter 17b-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environ. Toxicol. Chem. 22: 1350–1360.</li> <li>Bookhout TA. 1994. Research and management techniques for wildlife and habitats. The Wildlife Society, Bethesda, Maryland. 740 pp.</li> <li>Caswell H. 2001. Matrix Population Models. Sinauer Associates, Inc., Sunderland, MA, USA</li> <li>Cheng WY, Zhang Q, Schroeder A, Villeneuve DL, Ankley GT, Conolly R.  2016.  Computational modeling of plasma vitellogenin alterations in response to aromatase inhibition in fathead minnows. Toxicol Sci 154: 78–89.</li> <li>Conolly RB, Ankley GT, Cheng W-Y, Mayo ML, Miller DH, Perkins EJ, Villeneuve DL, Watanabe KH. 2017. Quantitative adverse outcome pathways and their application to predictive toxicology. Environ. Sci. Technol. 51:  4661-4672.</li> <li>Etterson MA, Ankley GT.  2021.  Endogenous Lifecycle Models for Chemical Risk Assessment. Environ. Sci. Technol. 55:  15596-15608. </li> <li>Gotelli NJ, 2008. A Primer of Ecology. Sinauer Associates, Inc., Sunderland, MA, USA.</li> <li>Holbech H, Kinnberg KL, Brande-Lavridsen N, Bjerregaard P, Petersen GI, Norrgren L, Orn S, Braunbeck T, Baumann L, Bomke C, Dorgerloh M, Bruns E, Ruehl-Fehlert C, Green JW, Springer TA, Gourmelon A. 2012 Comparison of zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) as test species in the Fish Sexual Development Test (FSDT). Comp. Biochem. Physiol. C Toxicol. Pharmacol. 155:  407–415.</li> <li>Kramer VJ, Etterson MA, Hecker M, Murphy CA, Roesijadi G, Spade DJ, Stromberg JA, Wang M, Ankley GT.  2011.  Adverse outcome pathways and risk assessment: Bridging to population level effects.  Environ. Toxicol. Chem. 30, 64-76.</li> <li>McComb B, Zuckerberg B, Vesely D, Jordan C.  2021.  Monitoring Animal Populations and their Habitats: A Practitioner's Guide.  Pressbooks, Oregon State University, Corvallis, OR Version 1.13, 296 pp. </li> <li>Miller DH, Villeneuve DL, Santana Rodriguez KJ, Ankley GT. 2022.  A multidimensional matrix model for predicting the effect of male biased sex ratios on fish populations. Environmental Toxicology and Chemistry 41(4): 1066-1077.</li> <li>Miller DH, Tietge JE, McMaster ME, Munkittrick KR, Xia X, Griesmer DA, Ankley GT. 2015. Linking mechanistic toxicology to population models in forecasting recovery from chemical stress: A case study from Jackfish Bay, Ontario, Canada. Environmental Toxicology and Chemistry 34(7):  1623-1633.</li> <li>Miller DH, Jensen KM, Villeneuve DE, Kahl MD, Makynen EA, Durhan EJ, Ankley GT. 2007. Linkage of biochemical responses to population-level effects: A case study with vitellogenin in the fathead minnow (Pimephales promelas). Environ Toxicol Chem 26:  521–527.</li> <li>Miller DH, Ankley GT. 2004. Modeling impacts on populations: Fathead minnow (Pimephales promelas) exposure to the endocrine disruptor 17b-trenbolone as a case study. Ecotox Environ Saf 59: 1–9.</li> <li>Murphy CA, Nisbet RM, Antczak P, Garcia-Reyero N, Gergs A, Lika K, Mathews T, Muller EB, Nacci D, Peace A, Remien CH, Schultz IR, Stevenson LM, Watanabe KH.  2018.  Incorporating suborganismal processes into dynamic energy budget models for ecological risk assessment.  Integrated Environmental Assessment and Management 14(5):  615–624.</li> <li>Murray DL, Sandercock BK (editors).  2020.  Population ecology in practice.  Wiley-Blackwell, Oxford UK, 448 pp.</li> <li>Nisbet RM, Jusup M, Klanjscek T, Pecquerie L.  2011.  Integrating dynamic energy budget (DEB) theory with traditional bioenergetic models.  The Journal of Experimental Biology 215: 892-902.</li> <li>Nisbet RM, Muller EB, Lika K, Kooijman SALM. 2000. From molecules to ecosystems through dynamic energy budgets. J Anim Ecol 69:  913–926.</li> <li>Perkins EJ,  Ashauer R, Burgoon L, Conolly R, Landesmann B,, Mackay C, Murphy CA, Pollesch N, Wheeler JR, Zupanic A, Scholzk S.  2019.  Building and applying quantitative adverse outcome pathway models for chemical hazard and risk assessment.  Environmental Toxicology and Chemistry 38(9): 1850–1865. </li> <li>Vandermeer JH, Goldberg DE. 2003.  Population ecology: first principles.  Princeton University Press, Princeton NJ, 304 pp.</li> <li>Villeneuve DL, Crump D, Garcia-Reyero N, Hecker M, Hutchinson TH, LaLone CA, Landesmann B, Lattieri T, Munn S, Nepelska M, Ottinger MA, Vergauwen L, Whelan M. Adverse outcome pathway (AOP) development 1: Strategies and principles. Toxicol Sci. 2014: 142:312–320</li> <li>Watanabe KH, Mayo M, Jensen KM, Villeneuve DL, Ankley GT, Perkins EJ.  2016.  Predicting fecundity of fathead minnows (Pimephales promelas) exposed to endocrine‐disrupting chemicals using a MATLAB(R)‐based model of oocyte growth dynamics. PLoS One 11:  e0146594.</li> </ul> AOPWiki 2016-11-29T18:41:24

2023-01-03T09:09:06

impaired, Fertility

Individual

Biological state capability to produce offspring Biological compartments System General role in biology Fertility is the capacity to conceive or induce conception. Impairment of fertility represents disorders of male or female reproductive functions or capacity.

As a measure, fertility rate, is the number of offspring born per mating pair, individual or population.

High

Adult, reproductively mature

High High High

AOPWiki 2016-11-29T18:41:24

2016-12-02T09:21:49

<upstream-id>02ff878a-9694-4ce9-8980-a37d5e8187f9</upstream-id> <downstream-id>8571c3a2-38e2-41bd-a0f7-a24ba089d940</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e9a4abd0> AOPWiki 2020-07-13T09:31:15

2020-07-13T09:31:15

<upstream-id>8571c3a2-38e2-41bd-a0f7-a24ba089d940</upstream-id> <downstream-id>c0ca37c1-e0e3-435c-a854-e85742bc4aa3</downstream-id> Androgens are critical for maintaining the normal male reproductive system (Tang, H., et al. 2018). Of these androgens, 11-KT has been identified as the most important in teleost fish (Borg, B. 1994). 11-KT is produced by the cyp11c1 encoded enzyme, 11ß-hydroxylase (Zheng, et al. 2020). 11-KT has been shown to bind to the androgen receptor with similar affinity as testosterone in zebrafish (Jorgensen, et al. 2007). It is well documented that 11-KT is involved in spermatogenesis, spermiation, male secondary sexual characteristics, and breeding behaviors (Geraudie, P. et al. 2010; Amer, M.A. et al. 2001). 11-KT is needed for the inducement of spermatogenesis and sperm production in teleost fish, with 10 ng/ml 11-KT being sufficient to induce full spermatogenesis in the Japanese eel (Miura, C. and T. Miura 2011). The mechanism through which 11-KT induces spermatogenesis is believed to be via activation of Sertoli cells and activin B (Miura et al. 2011; Miura et al. 2001; Sales, C.F., et al. 2020; Cavaco J.E.B., et al. 1998). 11-KT is not responsible for the acquisition of sperm motility in salmonids (Miura, et al. 1992).

Table 2. Effect of either 11-ketotestosterone (11-KT) treatment or increased testicular production/plasma concentrations of 11-KT on spermatogenesis.  <table cellspacing="0" class="Table" style="border-collapse:collapse; width:863px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:131px"> Species  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:132px"> Experimental design  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:132px"> 11-KT treatment or response  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:1px solid black; vertical-align:top; width:176px"> Spermatogenesis effect  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:81px"> 11-KT (+) 1 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:108px"> Spermatogenesis (+) 1 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:103px"> Citation  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:131px"> Senegalese sole (Solea senegalensis)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Treated with saline (control) or with 50 μg/kg GnRHa, with or without another implant containing 2 or 7 mg/kg 11-ketoandrostenedione for 28 days </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Fish treated with GnRHa + OA saw increased 11-KT levels compared to control and GnRHa alone  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Fish treated with GnRHa + OA saw lower number of spermatogonia and spermatocytes and a higher number of spermatids than those of GnRHa or control  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Agulleiro, M.J., et al. 2007  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:131px"> Japanese huchen (Hucho perryi)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Incubated immature testis fragments  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 10 ng/ml for 15 days  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> BrdU (proliferation marker) index reached 34.5% ± 1.7%; percentage of late type B spermatogonia reached about 7.5% compared to 0% in control </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Amer, M.A. et al. 2001     </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:131px"> African catfish (Clarias gariepinus)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Juvenile male catfish implanted with pellets containing 30 μg/g body weight of 11-KT </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 30 μg/g body weight of 11-KT; <a name="_Hlk63793707">plasma 11-KT levels reached 8.3 ± 0.6 ng/ml after 2 weeks </a> </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> GSI increased compared to control; testicular stage 1 (contain spermatogonia only) and 2 (contain spermatogonia and spermatocytes) increased from about 90% stage 1 and 10% stage 2 in end control to about 25% stage 1 and 75% stage 2    </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Cavaco, J.E.B. et al. 2001     </td> </tr> <tr> <td rowspan="3" style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:131px"> African catfish (Clarias gariepinus)      </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Male catfish at beginning of spermatogenesis implanted with pellets containing 30 μg/g body weight of 11-KT  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Plasma 11-KT levels reached 6.1 ± 0.8 ng/ml after 2 weeks  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Testicular stages changed from about 65% stage 1 and 35% stage 2 in the end control to about 65% stage 2 and 35% stage 3 (contain spermatogonia, spermatocytes and spermatids) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td rowspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Cavaco J.E.B., et al. 1998      </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Male catfish at beginning of spermatogenesis implanted with pellets containing 30 μg/g body weight of 11β-hydroxyandrostenedione  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Plasma 11-KT levels reached 7.3 ± 0.7 ng/ml after 2 weeks  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Testicular stages changed from about 65% stage 1 and 35% stage 2 in the end control to about 55% stage 2 and 40% stage 3  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Male catfish at beginning of spermatogenesis implanted with pellets containing 30 μg/g body weight of androstenetrione </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Plasma 11-KT levels reached 2.4 ± 0.3 ng/ml after 2 weeks  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Testicular stages changed from about 65% stage 1 and 35% stage 2 in the end control to about 50% stage 2 and 50% stage 3   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:131px"> Atlantic salmon (Salmo salar)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Immature fish injected with 25 μg adrenosterone/g of body weight  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> After 7 and 14 days, 11-KT plasma levels significantly increased compared to control (7 days post-treatment were higher)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> 5-fold higher number of type A differentiated spermatogonia than control fish after 14 days (7-day samples lost - no data)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Melo, M.C. et al. 2015  </td> </tr> <tr> <td rowspan="5" style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:131px"> Japanese eel (Anguilla japonica)          </td> <td rowspan="5" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Immature testes were removed and cultured in medium with varying levels of 11-KT          </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 0.01 ng/ml 11-KT for 15 days  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> No effect  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> No  </td> <td rowspan="5" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Miura, T., et al. 1991          </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 0.1 ng/ml 11-KT for 15 days  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> No effect  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> No  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 1 ng/ml 11-KT for 15 days  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> No effect  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> No  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 10 ng/ml 11-KT for 15 days  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Mitosis occurred in 50-60% of cysts (as effective as 100 ng/ml 11-KT treatment)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 100 ng/ml 11-KT for 15 days  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Mitosis occurred in 50-60% of cysts (as effective as 10 ng/ml 11-KT treatment)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td rowspan="4" style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:131px"> Japanese eel (Anguilla japonica)        </td> <td rowspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Immature testis fragments cultured in media with 11-KT for up to 36 days        </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 10 ng/ml of 11-KT for 9 days  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Began mitotic division; produced late-type B spermatogonia  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td rowspan="4" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Miura, T., et al. 1991        </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 10 ng/ml of 11-KT for 18 days  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Produced zygotene spermatocytes from meiotic prophase  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 10 ng/ml of 11-KT for 21 days  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Spermatids and spermatozoa observed  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 10 ng/ml of 11-KT for 36 days  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> All stages of germ cells present  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:131px"> Chub mackerel (Scomber japonicus)  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Peptide mix containing synthetic peptides corresponding to chub mackerel Kiss1-15 at a final concentration of 250 ng/g fish were injected 3 times at 2-week interval (immature adult) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Treated fish showed significantly higher 11-KT levels  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Significantly higher levels of spermatids and spermatozoa </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Selvaraj, S., et al. 2013  </td> </tr> <tr> <td rowspan="5" style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:131px"> Japanese eel (Anguilla japonica) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Testicular fragment treated with 0.01 ng/ml cortisol  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> No significant change in 11-KT production compared to control  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Nonsignificant increase in BrdU Index compared to control  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> No  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> No  </td> <td rowspan="5" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Ozaki, Y., et al. 2006 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Testicular fragment treated with 0.1 ng/ml cortisol  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> No significant change in 11-KT production compared to control  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Significant increase in BrdU Index compared to control  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:81px"> No  </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:132px"> Testicular fragment t treated with 1 ng/ml cortisol  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Nonsignificant, slight increase in 11-KT production compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Significant increase in BrdU Index compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:81px"> No  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:132px"> Testicular fragment treated with 10 ng/ml cortisol  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Nonsignificant increase in 11-KT production compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Significant increase in BrdU Index compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:81px"> No  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:132px"> Testicular fragment treated with 100 ng/ml cortisol  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> Significant increase in 11-KT production compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Significant increase in BrdU Index compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:81px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:131px"> Zebrafish (Danio rerio)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:132px"> cyp11c1 knockout rescue via 11-ketoandrostenedione (11-KA) treatment  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:132px"> 100 nM 11-KA for 4 hours per day for 10 days  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:176px"> Promoted the juvenile ovary-to-testis transition; genes associated with Leydig cell development/function restored; increased sperm volume  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:81px"> Yes </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:108px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:103px"> Zhang, Q., et al. 2020  </td> </tr> </tbody> </table> 1 (+) represents an effect on the key event has been established.

<table align="left" border="1" cellpadding="1" cellspacing="1" style="width:575px"> <caption> It is well known that 11-KT is a critical androgen for proper male reproduction in teleost fish. The males' primary reproductive role is to fertilize the oocytes. Seasonal changes in 11-KT are correlated with cyclic spermatogenesis events in teleosts (Basak, R., et al. 2016). In many teleost fish, 11-KT levels peak at spawning (see Table 1 below). 11-KT is proposed to induce spermatogenesis via the activation of Sertoli cells, which in turn regulates factors including activin B (Miura et al. 2011; Miura et al. 2001). Activin B stimulates spermatogonial proliferation (Sales, C.F., et al. 2020; Cavaco J.E.B., et al. 1998). Zhang et al. (2020) showed that zebrafish with cyp11c1 knockout have reduced 11-KT levels, smaller genitalia, inability naturally mate, defective Leydig and Sertoli cells, and insufficient spermatogenesis. This is corrected by treatment of 100 nM 11-KA (which is converted to 11-KT in vivo) for 4 hours per day for 10 days. This shows that spermatogenesis was arrested due to insufficient 11-KT levels.   Table 1. Plasma concentrations of 11-KT peak during spawning and decline shortly after in a variety of species. <table cellspacing="0" class="Table" style="border-collapse:collapse"> <tbody> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:1px solid #909090; vertical-align:top"> Species  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:1px solid #909090; vertical-align:top"> Scientific name  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:1px solid #909090; vertical-align:top; width:152px"> Reproductive strategy 1 </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:1px solid #909090; vertical-align:top; width:205px"> Citation  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Japanese huchen  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Hucho perryi  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Single </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Amer et al., 2001  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Bester  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Huso huso L. female x Acipenser ruthenus L. male  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Single </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Amiri et al., 1996  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Spotted snakehead   </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Channa punctatus  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Basak et al., 2016  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Chanchita </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Cichlasoma dimerus  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Birba et al., 2015  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Largemouth bass  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Micropterus salmoides salmoides  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Brown et al., 2019  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Chinook salmon  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Oncorhynchus tshawytscha  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Single </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Campbell et al., 2003  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Gilthead seabream  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Sparus aurata L.  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Chaves-Pozo et al., 2008  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Mummichog  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Fundulus heteroclitus  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Cochran, 1987  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Eastern Mosquitofish   </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Gambusia holbrooki  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Edwards et al., 2013  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Rainbow trout  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Salmo gairdneri  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Single  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Fostier et al., 1984  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Senegalese sole  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Solea senegalensis  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> García-López et al., 2006  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Roach  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Rutilus rutilus  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Geraudine et al., 2010  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Sterlet   </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Acipenser ruthenus  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Single </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Golpour et al., 2017  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Sablefish  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Anoplopoma fimbria  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Guzmán et al., 2018  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Brook trout  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Salvelinus fontinalis  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Single </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> de Montgolfier et al., 2009  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Brill  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Scophthalmus rhombus L.  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Hachero-Cruzado et al., 2012  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Three-spined stickleback  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Gasterosteus aculeatus  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Hellqvist et al., 2006  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Red-spotted grouper  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Epinephelus akaara  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Li et al., 2007  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Japanese dace  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Tribolodon hakonesis  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Ma et al., 2005  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Walleye  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Stizostedion vitreum  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Single </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Malison et al., 1994  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Florida gar  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Lepisosteus platyrhincus  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Orlando et al., 2003  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Chum Salmon  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Oncorhynchus keta  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Single </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Onuma et al., 2009  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Hornyhead Turbot  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Pleuronichthys verticalis  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Reyes et al., 2012  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Golden mahseer  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Tor putitora  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Shahi et al., 2015  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Plainfin midshipman  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Porichthys notatus  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Single  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Sisneros et al., 2004  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Amago salmon  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Oncorhynchus rhodurus  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Single </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Ueda et al., 1983; Sakai et al., 1989  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top"> Atlantic halibut  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top"> Hippoglossus hippoglossus L.   </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:152px"> Multiple </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:205px"> Weltzien et al., 200 </td> </tr> </tbody> </table>   1 Defined as single spawning species (spawn once/year) or multiple spawning species (spawn multiple clutches of eggs per reproductive period).   </caption> <tbody> </tbody> </table>

In African catfish, 11-ketotestosterone, but not testosterone, stimulated spermatogenesis (Cavaco et al., 2001) Juvenile atlantic salmon injected with adrenosterone, which is converted to 11KT, show increased 11KT in their plasma and increased differentiation of spermatogonia (Melo et al., 2015) Nile tilapia lacking cyp11c1 show dramatically reduced 11KT levels and delayed spermatogenesis. Spermatogenesis is rescued by 11KT supplementation. Without 11KT supplementation, spermatogenesis occurred later with fewer viable sperm (Zheng et al., 2020) Injection of female honeycomb grouper, a protogynous hermaphroditic fish, with 11KT induces a female-to-male sex change and stimulates spermatogenesis (Bhandari et al., 2006) In nile tilapia the absence of functional eukaryotic elongation factor 1 alpha (eEF1A) causes infertility and arrest of spermatogenesis. Heterozygous mutation causes significantly reduced 11KT and abnormal spermiogenesis (Chen et al., 2017) Dose concordance Increases in 11-KT levels correspond with increases in spermatogenesis in multiple studies (see Table 2 above). Melo et al. (2015) showed that treatment of adrenosterone - or OA - (which is converted to 11-KT in vivo) increases 11-KT levels, and this sustained increase induces spermatogonial differentiation. Decreases in 11-KT levels correspond with decreases in spermatogenesis in multiple studies (see Table 3 above). Liu, Z.H., et al. (2018) showed that exposure to 10 ng/L DES for 28 days significantly decreases 11-KT levels and disrupts spermatogenesis. Additionally, exposure to 100 ng/L DES for 28 days has further negative effects on 11-KT levels and spermatogenesis. Temporal concordance 11-KT peaks at spawning in a number of teleost fish (see Table 1 above). Melo et a. (2015) showed treatment with adrenosterone (OA) caused an increase in 11-KT levels, which sustained through 7 days after treatment and (to a lesser extent) 14 days after treatment. Type A differentiated spermatogonial numbers also increased 14 days after treatment. There was no spermatogenesis data for 7 days after treatment, due to the samples being lost. A study by de Waal et al. (2009) showed treatment with 10 nM E2 for 6 and 21 days resulted in decreased 11-KT levels and decreased spermatogonial proliferation. The 21 day treatment saw more spermatogonial arrest than the 6 day treatment.   Table 3. Effect of either decreased plasma concentration or testicular production of 11-ketotestosterone (11-KT) on spermatogenesis.  <table cellspacing="0" class="Table" style="border-collapse:collapse"> <tbody> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:1px solid #909090; vertical-align:top; width:143px"> Species  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:1px solid #909090; vertical-align:top; width:138px"> Experimental design </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:1px solid #909090; vertical-align:top; width:138px"> 11-KT treatment or response </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:1px solid #909090; vertical-align:top; width:162px"> Spermatogenesis effect  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:1px solid #909090; vertical-align:top; width:84px"> 11-KT (<a name="_Hlk69460910">─)</a> 1 </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:1px solid #909090; vertical-align:top; width:108px"> Spermatogenesis (─) 1 </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:1px solid #909090; vertical-align:top; width:89px"> Citation  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Guinean tilapia (Tilapia guineensis)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Fish from multiple sites contaminated with pesticides were studied </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Levels significantly lower in contaminated sites  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Amounts of spermatids and spermatozoa were decreased in contaminated sites  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td rowspan="2" style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> Agbohessi, P.T., et al. 2015    </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> African catfish (Clarias gariepinus)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px">   </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Levels significantly lower in contaminated sites; larger change than in Guinean tilapia  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Amounts of spermatozoa were decreased in contaminated sites  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Nile tilapia (Oreochromis niloticus)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Heterozygous mutation of eEF1A1b (eEF1A1b+/−) via CRISPR/Cas9  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significantly decreased serum 11-KT at 90 and 180 days after hatch (dah)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Absence of spermatocytes at 90 dah, and decreased number of spermatocytes, spermatids and spermatozoa at 180 dah </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> Chen, J. et al. 2017  </td> </tr> <tr> <td rowspan="2" style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Zebrafish (Danio rerio)    </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Adult fish exposed to 10 nM 17β-estradiol (E2) via water for 6 days   </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significantly decreased ex vivo testicular production; 6 day exposure to 10 nM E2  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Type B spermatogonia, primary spermatocytes, and secondary spermatocytes decreased to 54-60% of control levels  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td rowspan="2" style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> de Waal et al. 2009    </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Adult fish exposed to 10 nM E2 via water for 21 days  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significantly decreased ex vivo testicular production; 6 day exposure to 10 nM E2 </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Type B spermatogonia, primary and secondary spermatocytes, and spermatids significantly decreased further (e.g, spermatids to 19% of control)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td rowspan="3" style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Goldfish (Carassius auratus)      </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Mature fish exposed for 30 days to 100 μg/L anti-androgen vinclozolin (VZ) water </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Increase in 11-KT level (compared to control)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Nonsignificant decrease (compared to control) in sperm volume, motility, and velocity  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> No  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> No  </td> <td rowspan="3" style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> Hatef, A. et al. 2012      </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Mature fish exposed for 30 days to 400 μg/L anti-androgen vinclozolin (VZ) water </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> No significant change in 11-KT level (compared to control)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Nonsignificant decrease (compared to control) in sperm volume, motility and velocity; spermatozoa without flagella or with damaged flagella were observed  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> No  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Mature fish exposed for 30 days to 800 μg/L anti-androgen vinclozolin (VZ) water </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Decrease in 11-KT level (compared to control); similar level to E2 negative control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Significant decrease (compared to control) in sperm volume, motility, and velocity; spermatozoa without flagella or with damaged flagella were observed  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td rowspan="2" style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Yellow catfish (Pelteobagrus fulvidraco)    </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Juvenile fish exposed to 10 ng/L DES for 28 days via water </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Plasma levels lightly (but significantly) decreased compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Loss of spermatids; presence of several lacunas  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td rowspan="2" style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> Liu, Z.H., et al. 2018    </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Juvenile fish exposed to 100 ng/L DES for 28 days via water </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Plasma levels lightly (but significantly) decreased compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Loss of spermatids; more lacunae than 10 ng/L exposure  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td rowspan="4" style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Nile tilapia (Oreochromis niloticus)        </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Sexually mature males exposed via water to 200 ng/L diuron for 25 days </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> No significant change compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> No change to seminiferous tubules, and no change to spermatid or spermatozoa numbers  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> No  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> No  </td> <td rowspan="4" style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> Pereira, T.S., et al. 2015        </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Sexually mature males exposed to 200 ng/L DCA (diuron metabolite) for 25 days </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significant decrease of 11% compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Seminiferous tubules reduced about 60% and spermatid and spermatozoa amounts decreased by about 10% compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Sexually mature males exposed to 200 ng/L DCPU (diuron metabolite) for 25 days </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significant decrease of 11% compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Seminiferous tubules reduced about 60% and spermatid and spermatozoa amounts decreased by about 10% compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Sexually mature males exposed to 200 ng/L DCPMU (diuron metabolite) for 25 days </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significant decrease of 11% compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Seminiferous tubules reduced about 60% and spermatid and spermatozoa amounts decreased by about 10% compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td rowspan="4" style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Nile tilapia (Oreochromis niloticus)        </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Adult males; starvation for 7 days  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significant reduction in plasma 11-KTcompared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Significant decrease in number of spermatocytes and spermatozoa  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td rowspan="4" style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> Sales, C.F., et al. 2020        </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Adult males; starvation for 14 days  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significant reduction in plasma 11-KT compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Significant decrease in number of spermatocytes and spermatozoa  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Adult males; starvation for 21 days  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significant reduction in plasma 11-KT compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Significant decrease in number of spermatocytes and spermatozoa; significant decrease type A undifferentiated and differentiated spermatogonia </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Adult males; starvation for 28 days  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significant reduction in plasma 11-KT compared to other starvation durations  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Significant decrease in number of spermatocytes and spermatozoa; significant decrease type A undifferentiated and differentiated spermatogonia </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Zebrafish (Danio rerio)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Androgen receptor (ar) knockout  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significantly decreased in adult whole-body homogenate  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Significant decrease in number of germ cells, most of which were stopped at early stages of development; some spermatozoon found  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> Tang, H., et al. 2018  </td> </tr> <tr> <td rowspan="3" style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Zebrafish (Danio rerio)      </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Bezafibrate (BZF) administered orally to adult males at 1.7 mg BZF/g food for 21 days </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Non-significant decrease compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Did not report results  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> No  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> n/a  </td> <td rowspan="3" style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> Velasco-Santamaría, Y.M., et al. 2011      </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Bezafibrate (BZF) administered orally to adult males at 33 mg BZF/g food for 21 days  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Non-significant decrease compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Did not report results  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> No  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> n/a  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Bezafibrate (BZF) administered orally to adult males at 70 mg BZF/g food for 21 days </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significant decrease compared to control  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Testicular degeneration; increased syncytia and spermatocytes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td rowspan="3" style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Zebrafish (Danio rerio)      </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Adult males exposed for 30 days to 100 ng/L DES (estrogen) via water </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Plasma levels decreased 3-fold  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Adverse effect on testicular development and spermatogenesis; sperm concentration decreased 3-fold  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td rowspan="3" style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> Yin, P. et al. 2017      </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Adult males exposed for 30 days to 300 μg/L FLU (anti-androgen)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Plasma levels decreased 2-fold  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Adverse effect on testicular development and spermatogenesis; sperm concentration decreased 3-fold  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Adult males exposed for 30 days to combo of 100 ng/L DES and 300 μg/L FLU </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Plasma levels decreased 6-fold  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Adverse effect on testicular development and spermatogenesis; sperm concentration decreased 4-fold  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Zebrafish (Danio rerio)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Mettl3 mutation  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Serum concentration significantly decreased  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Little or no mature sperm; 24.4% spermatogonia, 56.1% spermatocytes, and 10.4% spermatozoa (compared to 7.5%, 26.7%, and 50.1% in wild type)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> Xia, H. et al. 2018  </td> </tr> <tr> <td style="border-bottom:1px solid #909090; border-left:1px solid #909090; border-right:1px solid #909090; border-top:none; vertical-align:top; width:143px"> Zebrafish (Danio rerio)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> cyp11c1 knockout via CRISPR/Cas9 (homozygous mutation)  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:138px"> Significantly decreased levels  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:2px double black; border-top:none; vertical-align:top; width:162px"> Insufficient spermatogenesis, but not completely blocked; sperm volume significantly decreased  </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:84px"> Yes </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:108px"> Yes </td> <td style="border-bottom:1px solid #909090; border-left:none; border-right:1px solid #909090; border-top:none; vertical-align:top; width:89px"> Zhang, Q., et al. 2020  </td> </tr> </tbody> </table>  1 (─) represents an effect on the key event has been established.

In a study by Hatef, A. et al. (2012), treatment with the anti-androgen vinclozolin at 100 μg/L saw an increase in 11-KT levels with no significant change to spermatogenesis. This is consistent with other studies provided. Additionally, treatment at 400 μg/L saw no significant change in 11-KT levels with a decrease in spermatogenesis (although this decrease may not be statistically significant). The reason for these increases in 11-KT remains unknown; however, it is hypothesized that it is due to competitive androgen receptor binding. Ozaki et al. (2006) showed that treatment with 100 ng/ml of cortisol significantly increased 11-KT levels. However, the less concentrated doses only saw non-significant increases in 11-KT with significant increases in spermatogenesis observed in all but the lowest dose. Despite this, Ozaki et al. make the generalization that cortisol treatment increased 11-KT and, in turn, spermatogenesis. The study by Runnalls et al. (2007) saw treatment with Clofibric acid caused no significant changes to 11-KT levels, but that the levels did appear lower. Additionally, these treatments saw no significant effect on sperm number, but did see a significant increase in the number of non-viable sperm. In a study by Zhang, Q., et al. (2020), cyp11c1 knockout did not completely block spermatogenesis. Zhang et al. explain this could be due to other androgens (11β-hydroxyandrostenedione and testosterone) compensating for the reduction in 11-KT, as they can both bind to the androgen receptor to influence downstream signaling.

Decreases in 11-KT levels were also seen with decreases in spermatogenesis in several studies (see table above). 10 ng/ml of 11-KT has been shown to be needed to induce full spermatogenesis in Japanese eel (Amer, M.A. et al. 2001; Miura, C. et al. 2011).

High Male

High

Adult, reproductively mature

High

Taxonomic: 11-KT is the main androgen in teleost fish (Borg, B. 1994). Sex Applicability: 11-KT is present in both male and female fish; however, spermatogenesis is a male-specific process. Life Stage Applicability: Spermatogenesis is observable in male fish that have reached the reproductive stage.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42ea233518> AOPWiki 2020-04-16T12:14:55

2021-04-19T13:32:05

<upstream-id>c0ca37c1-e0e3-435c-a854-e85742bc4aa3</upstream-id> <downstream-id>98d0033d-5ca5-484d-a270-64c41f4a1287</downstream-id> Spermatogenesis is a multiphase process of cellular transformation that produces mature male gametes known as sperm for sexual reproduction (Kang et al., 2015). The process of spermatogenesis can be broken down into 3 phases: the mitotic proliferation of spermatogonia, meiosis, and post meiotic differentiation(spermiogenesis) (Boulanger et al., 2015). Male fertility is dependent on the quantity as well as the proper cellular morphology of the sperm formed in the testes (Chen et al., 2020). The fusion of sperm and oocytes is the key step for the beginning of life known as fertilization (Alavi et al., 2019). Impaired spermatogenesis may impact fertility and, consequently, also reduce reproduction.

The majority of papers used in evidence supporting the key event relationship were found through AbstractSifter, a Microsoft Excel-based application that extracts papers from PubMed. AbstractSifter ranks abstracts based on their relevance through key search and filter terms. Initial papers were found through the search engine, Google Scholar, utilizing the search terms “Impaired spermatogenesis male infertility” and “Impaired spermatogenesis male infertility in fish”. These papers were used to help curate search and filter terms used in Abstract Sifter. This search yielded 41600 search results but only papers found on the first page of results were further examined. In AbstractSifter, 3 different searches were done to curate a subset of 40 papers. Search terms for the 3 searches included “spermatogenesis AND fish” and “spermatogenesis AND zebrafish” which yielded an initial set of 1587 and 192 results respectively. Filter terms for the 3 searches included “male, infertility, and reduced”, “male, infertility, and impaired”, and “male and infertil”. The first 2 filter set of words were used for the spermatogenesis and fish search which yielded 9 and 11 papers respectively. The last set of filter terms was used for the spermatogenesis and zebrafish search which yielded a respective 25 papers. Additional sources used towards the weight of evidence were provided through expert knowledge and found through sources in papers initially curated in the AbstractSifter search.

Evidence supporting the KER is shown below. Table 1: Concordance Table (A-Ha) <table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; width:922px"> <tbody> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:101px"> Species </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:156px"> Experimental design </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:162px"> Evidence of Impaired Spermatogenesis (IS) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:144px"> Evidence of Impaired Fertility (IR) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:78px"> IS observed? </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:78px"> IR observed? </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:84px"> Citation </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:119px"> Notes </td> </tr> <tr> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Persian sturgeon (Acipenser persicus) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 0 minutes frozen/thawed </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>No sperm quality difference from fresh sperm</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>No significant difference in fertilization or hatching rate</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Aramli and Nazari, 2014     </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> Cryopreserved for a certain period of time (storage wise) </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 30 minutes frozen/thawed </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>No significant sperm quality difference from fresh sperm</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>No significant difference in fertilization or hatching rate</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 60 minutes frozen/thawed </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Decreased sperm duration and motility</li> <li>Decreased percentage of mitotic cells</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Decreased fertilization rate and hatching rate</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 1 nM BPA exposure for 2 continuous generations </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Decreased sperm density (2.25 x 10^9/g of F1 & 2.34 x 10^9/g of F2 vs 2.8 x 10^9/g) </li> <li>Decreased sperm quality as measured by motility, velocity, ATP content and lipid peroxidation in F1 and F2 males</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Delayed hatching at 48hpf and increased malformation and mortality were found in the offspring from BPA exposed F2 </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Chen et al., 2015 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Tilapia (Oreochromis niloticus) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> CRISPR/Cas9 mediated mutation of eEF1A1b; F1 sampled at 90, 120, 150 and 180 days after hatch </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Significant downregulation of key genes involving spermatogenesis</li> <li>Reduced motility</li> <li>Spermatogenesis arrested and caused reduced # of spermatogonia and spermatocytes</li> <li>Altered morphology </li> <li>Delayed spermatogenesis</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Reduced in vitro fertilization rate (5%) vs 80% in WT</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Chen et al., 2017 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> eEF1A1b - elongation factor  </td> </tr> <tr> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) milt </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 2 uM of ruthenium red (RR) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Experienced inhibition of sperm motility and increased progressive sperm % loss (82.1% and 79.4% vs 93.5% and 90.8% for control)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Fertility not evaluated</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> N/A </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Chen et al., 2020     </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> <ul> <li>RR - noncompetitive TRPV antagonist which has been proved to block zebrafish Trpv1 was applied</li> <li>RR was applied to the milt of the sperm</li> <li>in vitro fertilization test</li> </ul> </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 10 uM of RR </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Experienced inhibition of sperm motility and increased progressive sperm % loss even greater than 2 uM (64% and 58%)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Only experienced a decrease in fertility rate when sperm concentration was decreased to 1.5 x 10^4/ml (37.2% vs 66.4% in control) </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 50 uM of RR </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Experienced inhibition of sperm motility and increased progressive sperm % loss even greater than 10 uM (9.6% and 3.6%)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Experienced a decrease in fertility rate when sperm concentration was decreased to 1.5 x 10^4/ml and 1.5 x 10^6 /ml (28.7% in 10^4 and 57% in 10^6 with control being 78%) </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Adult males exposed to 50 nM of rapamycin for 14 days (long-term in vivo drug exposure)  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Significantly higher % of immotile sperm</li> <li>No change in frequency of spermatogonia and spermatocytes</li> <li>Increased apoptosis signals</li> <li>Increased frequency of spermatozoa</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Males failed to induce spawning</li> <li>Reduction in milt volume with some males failing to produce milt</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Chen et al., 2020 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> <ul> <li>Authors state spermatogenesis was normal, but maturation of sperm impaired</li> <li>Increased apoptosis suggests loss of Sertoli cells impacting sperm maturations in testes treated with rapamycin </li> </ul> </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Adult males exposed to two concentrations of bis-(2-ethylexhyl) phthalate (DEHP; 0.2 or 20 μg/L) for three weeks </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Areas of spermatogonial and spermatid cysts were larger in fish exposed to 20 μg/L of DEHP as compared with controls</li> <li>Testicular area of spermatocyte cysts was lower in males exposed to 0.2 μg/L of DEHP</li> <li>Testicular area occupied by spermatocytes was reduced in fish exposed to DEHP compared to controls, with a concomitant increase in the area occupied by spermatogonia</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Both doses of DEHP caused a marked decrease in fertilization success</li> <li>Number of embryos decreased significantly in DEHP-exposed groups compared to controls</li> <li>Total number of embryos reduced (by approximately 90%) in males treated with DEHP (0.2 and 20 μg/L)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Corradetti et al., 2013 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Targeted genetic disruption of Tdrd12 through TALEN techniques  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Reduced expression of vasa, dnd, piwil1 and amh in mutants</li> <li>Deformed and apoptotic spermatogonia at 35 dpf found in mutants </li> <li>Lack of spermatozoa at adult stage </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Infertile under standard breeding despite being able to induce female egg laying (0% fertilization)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Dai et al., 2017 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> Tudor domain-related proteins (Tdrds) have been demonstrated to be involved in spermatogenesis and Piwi-interacting RNA (piRNA) pathway  </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Target-selected mutagenesis of exons 2-4 and 8-10 of mlh1 gene; mutant was outcrossed with WT and then F1 was incrossed for F2 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Post meiosis I stages of spermatogenesis were absent</li> <li>Chromosomes were dispersed throughout nucleus in mutant primary spermatocytes</li> <li>Increased apoptosis</li> <li>Increased primary spermatocytes</li> <li>Reduced # of spermatids and spermatozoa in mutant female x WT male offspring</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Infertile under standard breeding where female egg spawn was induced but none of the eggs were fertilized</li> <li>Reduced fertility seen from mutant females and WT male offsprings </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Feitsma et al., 2007 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> <ul> <li>Mlh1 is a member of DNA mismatch repair machinery and essential for stabilization of crossovers during first meiotic division </li> </ul> </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Oryzias latipes and O. curvinotus hybrids </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Fertility testing of a cross between Oryzias latipes and O. curvinotus </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Sperm nuclei diameters were 1.6 times larger</li> <li>Binucleated spermatids </li> <li>Sometimes had more than one flagellum</li> <li>Abnormalities in # of microtubules </li> <li>More than one pair of centrioles sometimes </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Infertile under standard breeding despite being able to induce female egg laying (0% fertilization) </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Hamaguchi and Sakaizumi, 1992 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Goldfish (Carassius auratus) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Mature fish exposed to nominal vinclozolin (VZ) concentrations of 100, 400, and 800 μg/L for 1 month </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Sperm volume was reduced in fish exposed to VZ in a concentration-dependent manner, and a significant decrease was observed at 800 μg/L compared to control</li> <li>Sperm abnormalities include spermatozoa without flagella or with damaged flagella observed in fish exposed to 400 and 800 μg/L VZ </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Sperm motility decreased in fish exposed to 800 μg/L VZ evaluated at 15, 30 and 45 s post activation and in fish exposed to 400 and 800 μg/L VZ at 60 s post activation</li> <li>Sperm velocity evaluated at 15 and 30 s post activation decreased in fish exposed to 800 μg/L VZ</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Hatef et al., 2012 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> Main objective was to study sperm quality (volume, motility and velocity) as endpoints for male fertility </td> </tr> </tbody> </table>

Spermatogenesis is one of the most conserved biological processes from Drosophila to humans (Wu et al., 2016). The process itself is well understood and gametes produced from spermatogenesis are required for sexual reproduction. Table 2: Concordance Table (Hi - P) <table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; width:922px"> <tbody> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:101px"> Species </td> <td style="border-bottom:none; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:156px"> Experimental design </td> <td style="border-bottom:none; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:162px"> Evidence of Impaired Spermatogenesis (IS) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:144px"> Evidence of Impaired Fertility (IR) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:78px"> IS observed? </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:78px"> IR observed? </td> <td style="border-bottom:none; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:84px"> Citation </td> <td style="border-bottom:none; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:119px"> Notes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:none; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:156px"> <ul> <li>Fish were exposed from 2 to 60 days post-hatch (dph) to nonylphenol (NP; 10, 30, or 100 μg/l nominal) or ethinylestradiol (EE; 1, 10, or 100 ng/l nominal)</li> </ul> </td> <td style="border-bottom:none; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:162px"> <ul> <li>Majority of fish exposed to 10 ng/l EE lacked differentiated gonadal tissue (undeveloped gonads) at 60 dph</li> <li>One fish at NP-30 μg/l and two fish at NP-100 μg/l were observed to have ovatestes at 60 dph</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Zebrafish exposed to 10 ng/l of EE exhibited a significant reduction in the percent of viable eggs</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:none; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:84px"> Hill and Janz, 2003 </td> <td style="border-bottom:none; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:119px"> Due to high mortality in the 100 ng/l EE group, insufficient fish were available for analyses </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio); Transgenic (TG) Asp </td> <td rowspan="7" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:156px"> <ul> <li>Metronidazole exposure during the embryo phase for 14-21 days (5 mM concentration exposure for 14 days usually as a concentration of 5mM resulted in complete loss of fluorescence w/o deleterious effects)</li> <li>5 mM Met treatment after every other day of Met treatment for a week.</li> <li>Transgenic lines exposed to metronidazole (either ASp, Odf, Sam or a combination of the 3) </li> </ul>         </td> <td rowspan="7" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:162px"> <ul> <li>No large abnormalities were present pre-Met treatment</li> <li>Post-Met treatment, at 4 months, arrest of spermatogenesis at metaphase I was present for transgenic lines AO, AS, and OS. </li> <li>AS and AO transgenic lines had few spermatozoa and mainly spermatogonia present</li> <li>OS had less severe effects compared to AS and AO </li> <li>At 6 months, AOS spermatogenesis had completely disappeared</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Post-Met exposure, infertility was significantly higher (0% → 68% post exposure)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td rowspan="7" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:84px"> Hsu et al., 2010             </td> <td rowspan="7" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:119px"> <ul> <li>Asp - A-kinase anchoring protein-associated protein (sperm motility)</li> <li>Odf - cytoskeletal structure of the animal sperm tail </li> <li>Sam - sperm acrosomal membrane-associated protein (may play a role in fertilization)</li> <li>Infertility is assessed by offspring reproduction after a 4-month period</li> <li>WT did not experience infertility post Met exposure </li> <li>Shows before and after exposure, effects on sperm and reproduction</li> </ul>   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) TG Odf </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Post-Met exposure, infertility was significantly higher (0% → 59.1% post exposure)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) TG Sam </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Post-Met exposure, infertility was significantly higher (0% → 54.1% post exposure)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) TG Asp-Odf </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Post-Met exposure, infertility increased significantly (0% → 85.7% post exposure)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) TG Asp-Sam </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Post Met exposure, infertility increased significantly (0% → 95% post exposure)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) TG Odf-Sam </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Post-Met exposure, infertility increased significantly (0% → 76.4% post exposure)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) TG Asp-Odf-Sam </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Post-Met exposure, infertility increased significantly (0% → 100% post exposure)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Roach (Rutilus rutilus) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Mature adult roach collected from both reference and river (effluent contaminated) sites during two consecutive spawning seasons; artificially induced to spawn in laboratory </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Volume of milt released from spermiating male fish significantly lower in the intersex fish than in the reference males</li> <li>Most fish that did not spermiate had testes that were clearly immature</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Fertilization rate significantly reduced when sperm from intersex males used to fertilize eggs collected from females</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Jobling et al., 2002 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Japanese medaka (Oryzias latipes) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Adult medaka exposed for 21 days to 29.3, 55.7, 116, 227, and 463 ng/l 17β-estradiol (E2) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>GSI of male medaka exposed to 463 ng/l E2 significantly less than control fish</li> <li>In males exposed to 463 ng/l, a few oocytes were observed in the testis, and the testicular tissue was almost completely replaced by connective tissue</li> <li>Accompanied by presence of macroscopic atrophy and degenerated spermatozoa and spermatocytes suggest a lack of spermatogenesis</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Fertility of medaka exposed to 463 ng/l E2 were significantly less compared with those of the control fish</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Kang et al., 2002 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Founder fish with originally mlh1 mutation was crossed out twice to WT fish of the TL line from which the founder was generated.  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Decreased weight of post-meiotic cells compared to WT.</li> <li>Increased # and proportion of spermatogenic stages prior to spermatids compared to WT. </li> <li>Increase in apoptotic cells</li> <li>Spermatozoa significantly reduced (0.1 mg vs 1.8 mg in WT); some spermatozoa were visible in testes of all mutant fish</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Reduced fertilization rates under standard breeding conditions (0.4%)</li> <li>From 118 crosses, 28 contained fertilized eggs. Total # of fertilized eggs is 86 out of 22266 eggs. </li> <li>Eggs that are fertilized are malformed embryos and aneuploid</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Leal et al., 2008 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> <ul> <li>Mlh1 is a member of DNA mismatch repair machinery and essential for stabilization of crossovers during first meiotic division </li> </ul> </td> </tr> <tr> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 3-month-old fish exposed to 10 ug/L of DEHP for 3 months </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>No significant changes in percentages of spermatogonia, spermatocytes or spermatids</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Slightly reduced but non-significant </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Ma et al., 2018     </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> Semi-static system for all 3 exposures; half water renewed daily; whole water renewed weekly  </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 3-month-old fish exposed to 30 ug/L of DEHP for 3 months </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>No significant changes in percentages of spermatogonia, spermatocytes or spermatids</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Reduced but non-significant</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 3-month-old fish exposed to 100 ug/L of DEHP for 3 months </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Percent of spermatocytes increased significantly by 27.4% </li> <li>Significant decrease of 32.2% in spermatids</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Decreased fertilization rate by 22%</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Multi-generational study to 0.5 and 5 ng/L ethynylestradiol (EE2) or 5 ng/L 17β-estradiol (E2) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>None of the males exposed to 5 ng/L EE2 had normal testes; 43% had gonads not fully differentiated</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>5 ng/L EE2 resulted in complete population failure of F1 with no fertilization</li> <li>Proportion of nonviable eggs significantly higher for all treatments compared to control</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px">   </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px">   </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Nash et al., 2004 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Targeted genetic disruption of fdx1b using a TALEN approach </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Reduced sperm count compared to control (p=0.0097%)</li> <li>sox9a downregulation</li> <li>igf3 and insl3 downregulation</li> <li>nanos2 and piwil1 upregulation</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Infertile under standard breeding despite being able to cause spawning of eggs (0% fertilization) </li> <li>Fertile during in vitro but no data shown</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Oakes et al., 2019 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> <ul> <li>fdx1b is an electron- providing cofactor for steroidogenic cytochrome P450. </li> </ul> </td> </tr> <tr> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Sea Urchin (Paracentrotus lividus) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 10 uM of metergoline in the presence of eggs and sperm in a 2:1 ratio </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Without 0.1 mM of serotonin, experienced a significant decrease in sperm motility % (100% in control vs 60%)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Fertilization of eggs decreased to around 50% </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Parisi et al., 1984     </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> Serotonin antagonist - metergoline   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 20 uM of metergoline in the presence of eggs and sperm in a 2:1 ratio </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Without 0.1 mM of serotonin, experienced a significant decrease in sperm motility % greater than 10 uM (50%)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Fertilization of eggs decreased to around 20%</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 30 uM of metergoline in the presence of eggs and sperm in a 2:1 ratio </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Without and with 0.1 mM of serotonin, experienced a significant decrease in sperm motility % greater than 20 uM (20%)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Fertilization of eggs decreased to around 10%</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> </tbody> </table>

<ul> <li>Dose concordance <ul> <li>When exposed to 50 mg DEHP kg-1 via intraperitoneal injection for 10 days, zebrafish (Danio rerio) experienced a reduction in the proportion of spermatozoa present compared to the control group. However, the zebrafish did not experience a significant decrease in fertilization success. Whereas when exposed to 5000 mg of DEHP kg-1 the same method, it experienced both a reduction in spermatozoa and fertilization success (Uren-Webster et al., 2010).</li> <li>Spermatozoa from mice (Mus musculus) exposed to 0.0001, 0.01, and 1 µM for 6 hours did not experience any significant changes in sperm motility parameters, fertilization rate, and developmental success. However, when exposed to 100 µM for 6 hours, spermatozoa experienced significant decreases in sperm motility parameters, fertilization rate, and developmental success (Rahman et al., 2014).</li> </ul> </li> <li>Temporal concordance <ul> <li>At 40-, 45-, and 65-days post fertilization(dpf), Fshr and lhcgr double mutant zebrafish (Danio rerio) encountered arrest of spermatogonial stage with apoptotic oocyte-like germ cells and at 90 dpf, the double knockouts were completely infertile (Zhang et al., 2015).</li> <li>At 65 dpf, zebrafish (Danio rerio) exposed to 10 uM of BPA experienced significantly reduced size of testis and delayed spermatogenesis. At 120 dpf, the same zebrafish were completely infertile and unable to induce egg laying by females (Song et al., 2020).</li> </ul> </li> </ul> Table 3: Concordance Table (R - S) <table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; width:922px"> <tbody> <tr> <td style="border-bottom:none; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:101px"> Species </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:156px"> Experimental design </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:162px"> Evidence of Impaired Spermatogenesis (IS) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:144px"> Evidence of Impaired Fertility (IR) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:78px"> IS observed? </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:78px"> IR observed? </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:84px"> Citation </td> <td style="border-bottom:none; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:119px"> Notes </td> </tr> <tr> <td rowspan="4" style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:101px"> Mice (ICR) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Spermatozoa was collected from sexually-mature male mice and exposed to 0.0001 uM of BPA for 6 h in air  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>No significant differences seen in sperm motility parameters compared to control however a slight decrease was seen in curvilinear velocity and average path velocity</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Experienced a non-significant decrease in cleavage and blastocyst formation</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Rahman et al., 2014  </td> <td rowspan="4" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:119px"> Experiment exposed spermatozoa to BPA for a short period of time rather than the animal </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Spermatozoa was collected from sexually-mature male mice and exposed to 0.01 uM of BPA for 6 h in air  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>No significant differences seen in sperm motility parameters compared to control but did experience a small decrease in curvilinear velocity and average path velocity</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Experienced a non-significant decrease in cleavage and blastocyst formation</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Spermatozoa was collected from sexually-mature male mice and exposed to 1 uM of BPA for 6 h in air  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>No significant differences seen in sperm motility parameters however did experience decrease in all parameters but # of motile spermatozoa</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Experienced a non-significant decrease in cleavage and blastocyst formation</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Spermatozoa was collected from sexually-mature male mice and exposed to 100 uM of BPA for 6 h in air  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Significantly decreased percentage of motile spermatozoa, curvilinear velocity, average path velocity, and straight-line velocity</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Experienced a significant decrease in rates of cleavage(fertilization) and blastocyst formation </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Studied a zebrafish line with insertional mutation that disrupts brca2 exon-11 and look at the f2 generation.  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Meiotic arrest of spermatocytes</li> <li>Observed spermatogonia and spermatocytes but no spermatids and sperm at 32 dpf vs WT who had all stages of spermatogenesis. </li> <li>Detection of active-caspase-3 (marker of apoptosis) </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Infertile under standard breeding where female egg spawning was induced (0% vs 80% in WT) </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Rodriguez-Mari et al., 2011 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> BRCA2 - human tumor suppressor gene  </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> <ul> <li>ENU mutagenesis screen to find mutations that lead to defects in gonadogenesis</li> <li>3 mutants focused on (its, isa, imo) </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Post meiotic germ cells absent at 3 months old (found aberrant germ cells instead)</li> <li>Only spermatogonia and primary spermatocytes were present</li> <li>Its mutant fail to progress past the leptotene stage</li> <li>isa and imo, spermatocytes fail to progress past the zygotene stage </li> <li>Arrest at prophase I as seen through increased Sycp3 expression</li> <li>Arrest occurs during zygotene stage as no pachytene stage spermatocytes were present </li> <li>Absent y-H2AX signals in isa and imo mutants </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Decreased fertilization rates in cells from mutant testes (<2% vs 41.9 in heterozygotes and 65.8 in WT)</li> <li>its 0.2% fertilization rate vs 56%</li> <li>isa 1.3% FR vs 65.8 in WT</li> <li>imo 0.2% FR vs 41.9% in WT </li> <li>Infertility under standard breeding conditions (could induce spawning but unfertilized eggs) </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Saito et al., 2011 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> ENU= N‐ethyl‐N‐nitrosourea </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> HSF5 mutants obtained by CRISPR/Cas9 technology targeting exon2 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Loss of spermatozoa along with increase in primary spermatocytes compared to WT </li> <li>Decrease in sperm count and sperm motility</li> <li>Altered morphology (microtubule arrangement, flagellar axoneme, sperm heads) </li> <li>Accumulation of cells during leptotene and zygotene-pachytene stages</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>No viable offspring when mutants were crossed with any types of females</li> <li>Lethality of embryos via in vitro fertilization with WT females (before 1 dpf) </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Saju et al., 2018 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> Heat shock protein 5  </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Medaka (Oryzias latipes)   </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Mature fish exposed to ethinylestradiol (EE2) concentrations of 32.6, 63.9, 116, 261, and 488 ng/L for 21 d under ﬂow-through conditions   </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Testicular tissue composed of abnormally developed connective tissue, with only a few sper-matozoa and spermatocytes compared to control</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Reduction in fertility was associated with cessation of spawning at 448 ng/L</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Seki et al., 2002 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Mice </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Generation of Rfx-2-deficient mice using embryonic stem cell that insert itself into the 1st intron of Rfx2 gene.  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Absence of sperm in testes</li> <li>Observed clusters of abnormal symplasts of round spermatids in mutants while normal spermatids in WT</li> <li>Spermatogonial cells and spermatocytes were normal in mutants</li> <li>Tnp1 and Tnp2 downregulated </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Infertility under standard breeding conditions (normal mating and plugging behavior)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Shawlot et al., 2015 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> RFX transcription factors are key regulators of ciliogenesis in vertebrates  </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Zebrafish line established with Brca2 nonsense mutation in exon 11  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Spermatogenesis was arrested in testes from homozygotes with only spermatogonia and primary spermatocytes present (normal in WT and heterozygotes) </li> <li>Increased # of spermatocysts containing spermatocytes with meiotic nuclear morphology (when compared to WT and hetero).</li> <li>Increased spermatocyte apoptosis in homozygotes. </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Infertile under standard breeding despite being able to induce egg laying (0% fertilization) </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Shive et al., 2010 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> BRCA2 is a component of DNA repair machinery and mediates homologous recombination in somatic cells and meiotic recombination in germ cells  </td> </tr> <tr> <td rowspan="2" style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Exposed to 1 uM of BPA from 20 to 150 dpf  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>At 65 dpf, significantly reduced size of testis and delayed spermatogenesis</li> <li>Majority of cells were cystic spermatogonia with only a few cysts entering spermatocytes and few spermatozoa</li> <li>At 100 and 150 dpf, comparable level of spermatozoa to positive control</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Fertility significantly reduced compared to control (~50% vs 85%)</li> <li>Fertilization rate of eggs fertilized by the sperm from BPA-treated males similar to control</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td rowspan="2" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Song et al., 2020 </td> <td rowspan="2" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> Spawning test done from 100-140 dpf; fertility defined as spawning rate (ratio of spawned fish number/total; Figure 4D); fertilization rate defined as the ratio of fertilized eggs to spawned eggs (Figure 4E) </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Exposed to 10 uM of BPA from 20 to 150 dpf </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>At 65 dpf, no mature spermatozoa observed vs control which showed normal spermatogenesis</li> <li>At 100 and 150 dpf, small amount of spermatozoa were observed but significantly lower vs 1 uM and positive control</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Completely infertile and unable to spawn </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 3 months of adult exposure to a daily amount of 30 mg/L COD </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Reduced percentage of sperm motile time and motile mean path velocity in exposed group</li> <li>Sperm progressive and progressive motile mean path velocity also reduced</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Percentage of hatching rate of zebrafish in exposed group was decreased in 72 h compared to control (delayed embryo hatching time)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Su et al., 2021 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> COD (chemical oxygen demand); commonly used parameter to reflect contamination by ODPs (oxygen-demanding pollutants) </td> </tr> </tbody> </table>

<ul> <li>When exposed to 10 and 100 ng/L of EE2 for 62 days leading to spawning, Rainbow trout (Oncorhynchus mykiss) experienced a decrease in GSI and increases in sperm concentration and spermatocrit. However, there were no significant changes to spermatogenesis. Despite this, there was a decrease in viability of embryos. (Schultz et al., 2003) </li> <li>Male Sprague-Dawley rats (Rattus norvegicus) fed a high fat diet(allowing them to develop Non-alcoholic fatty liver disease) experienced decreased testosterone levels along with reduced sperm number and motility. However, this did not affect fertility of the rats (Li et al., 2013).</li> </ul> Table 4: Concordance Table (T-Z)   <table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; width:922px" summary=""> <tbody> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:101px"> Species </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:156px"> Experimental design </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:162px"> Evidence of Impaired Spermatogenesis (IS) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:144px"> Evidence of Impaired Fertility (IR) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:78px"> IS observed? </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:78px"> IR observed? </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:84px"> Citation </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:1px solid #a3a3a3; vertical-align:top; width:119px"> Notes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> <ul> <li> TALEN mRNAs injected into one-cell stage zebrafish embryos to generate parent gen that was outcrossed with WT for F1</li> <li>F1 was then self-crossed for mutants</li> <li>Targeted the androgen receptor (AR)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Upregulation of amh and gsdf</li> <li>Downregulation igf3</li> <li>Reduced # of sperm</li> <li>Reduction in # of germ cells observed in AR mutant fish</li> <li>Increased proportion of pre-spermatids sperm cells</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Reduced in vitro fertilization (20%)</li> <li>Failed to induce spawning</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Tang et al., 2018  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> Androgen receptor </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Mice   </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> <ul> <li>Disruption of Protein C inhibitor (PCI) through combining mutant embryonic stem cells with swiss morula embryos to create mutants</li> <li>F1 heterozygous mice were then bred to create an F2 that was subsequently used in the study</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Morphologically abnormal sperm</li> <li>Reduced motility (12.5%) compared to control (51.5%)</li> <li>Apoptotic spermatocytes likely due to destruction of Sertoli cells</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Reduced in vivo fertilization rate (n=416 blastocysts) (0.5%) vs control (n= 420 blastocysts) (94%)</li> <li>In vivo fertilization rate: only 0.5% (n=416) oocytes were fertilized and developed into the blastocyst stage compared to PCI+/+ or PCI+/– males (92% (n = 415) and 94% (n = 420), respectively)</li> <li>Infertile under standard breeding despite showing signs of normal sexual activity</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Uhrin et al., 2000 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> <ul> <li>PCI - inhibitor of anticoagulant serine protease activated protein C and a variety of proteases</li> <li>PCI is largely present in seminal plasma and is responsible for inhibiting acrosin </li> </ul> </td> </tr> <tr> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Adults exposed to 0.5 mg DEHP kg-1 (body weight) for 10 days via intraperitoneal injection </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>No large observable difference</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>No significant decrease in fertilization success</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Uren-Webster et al., 2010 </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> DEHP is phthalate which is a plasticizer in many mass-produced products </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Adults exposed to 50 mg DEHP kg-1 for 10 days via intraperitoneal injection </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Reduction in the proportion of spermatozoa and an increase in the proportion of spermatocytes</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>No significant decrease in fertilization success</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Adults exposed to 5000 mg DEHP kg-1 for 10 days via intraperitoneal injection </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Reduction in the proportion of spermatozoa and an increase in the proportion of spermatocytes</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Reduction of fertilization success of oocytes spawned by females especially during the second 5-day period</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Marine medaka (Oryzias melastigma) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Multi-generational study evaluating hypoxia; initial exposure sexually mature fish (F0) for 1 month; F1H and F2H reared in hypoxic conditions; F1T and FT2 reared in normoxia </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Significant decrease in curvilinear velocity, straight line velocity and average path velocity of sperm (FO, F1H and F2H)</li> <li>Decrease in percentage of spermatids, number of spermatids, and increases in interstitial space of the testis (F1H, F2T, F3H)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Percentage of fertilization success significantly reduced in F1</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Wang et al., 2016 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Mice (C57BL/6) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Knockout of BRD7 was done through Cre/loxP and flp/FRT recombination and embryonic cells to create a positive clone that was then used to create BRD7-deficient mice </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Irregular head shape</li> <li>Deformed acrosome</li> <li>Post-meiotic development of elongating spermatids disruption</li> <li>Increased proportion of abnormal spermatids (49.95 ± 7.13% of round spermatids, 67.84 ± 3.51% of elongating spermatids, 80.65 ± 5.8 % of condensing spermatids and 100% of condensed spermatids) </li> <li>Downregulation of various spermatogenic markers</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Infertile under standard breeding despite showing signs of normal sexual activity</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Wang et al., 2016 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> <ul> <li>BRD7 is a bromodomain gene that inhibits cell growth and cell cycle progression and is a co-factor for p53</li> <li>BRD7 has high expression in mice testes </li> </ul> </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Flies (Drosophila) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> CRISPR/Cas9-mediated genome editing to SNP locus  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>64% of cysts contained germ cells and only 25% of those progressed to spermatocyte stage in mutants </li> <li>Lacked mature sperm</li> <li>Lack of mei-p26 protein which facilitates transition from amplifying to differentiating spermatogonia </li> <li>Accumulation of mitotic spermatogonia that fail to differentiate into spermatocytes</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Reduced fertility rate (70%)</li> <li>Some were completely sterile</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Wu et al., 2016 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px">   </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> <ul> <li>TALEN target of the 1st exon of mettl3 that is injected into WT zebrafish embryos which are raised and outcrossed with WT to obtain F1</li> <li>F1 outcrossed again for F2 then F2 self-crossed. </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Sperm motility reduced (average path velocity, curvilinear velocity, and straight-line velocity)</li> <li>Decreased male GSI (0.62%) compared to WT (1.02%)</li> <li>Reduced # of mature sperm</li> <li>Increased proportions of spermatogonia (24.4% vs 7.5% in WT) and spermatocytes (56.1% vs 26.7% in WT) </li> <li>Decreased proportion of spermatozoa (10.4% vs 50.1% in WT)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Decreased standard breeding rates (48.8.% vs 91.4% in WT)</li> <li>8.1% of mutant male x WT female spawned successfully vs 94.4% in WT</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Xia et al., 2018  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> MEttl3 - multicomponent methyltransferase complex  </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> CRISPR/Cas9 gene targeting of E2f5  </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Reduced # of spermatozoa compared to WT</li> <li>Increased % of spermatocytes at leptotene and zygotene stages compared to WT </li> <li>Suggests arrest at zygotene stage due to strong y-H2AX staining during mid-leptotene stage</li> <li>Arrested during prophase I</li> <li>Increased apoptosis</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Decreased fertilization rates (3% vs 94% in WT) under standard breeding conditions</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Xie et al., 2020 </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> E2f5 is a transcriptional repressor during cell-cycle progression </td> </tr> <tr> <td rowspan="4" style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Marine medaka (Oryzias melastigma) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 0.1 mg/L of DEHP for 6 months from larval stage </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Increased GSI vs control (1.18 vs 0.81)</li> <li>Contained mostly spermatocytes (Sp) and spermatids (Sd) with few spermatozoa especially in this treatment</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Decreased fertilization success vs control (84.12% vs 94.21%)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td rowspan="4" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Ye et al., 2014        </td> <td rowspan="4" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> DEHP - phthalate MEHP - active metabolite of DEHP       </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 0.5 mg/L of DEHP for 6 months from larval stage </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Increased GSI vs control (1.05 vs 0.81)</li> <li>Contained mostly Sp and Sd with few spermatozoa</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Decreased fertilization success vs control (81.61% vs 94.21%)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 0.1 mg/L of MEHP for 6 months from larval stage </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Increased GSI vs control (1.09 vs 0.81)</li> <li>Contained mostly Sp and Sd with few spermatozoa</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Decreased fertilization success vs control (87.46% vs 94.21%)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> 0.5 mg/L of MEHP for 6 months from larval stage </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Increased GSI vs control (1.03 vs 0.81)</li> <li>Contained mostly Sp and Sd with few spermatozoa</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>Decreased fertilization success vs control (82.16% vs 94.21%)</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> <tr> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:1px solid #a3a3a3; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:101px"> Zebrafish (Danio rerio) </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> fshr mutant zebrafish line created using TALEN-induced gene knockout </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>At 40 dpf, control (heterozygotes) could induce spermatogenesis whereas mutants remained undeveloped</li> <li>At 45 and 65 dpf, testes in mutant males showed significant retardation in growth with delayed spermatogenesis and arrest at spermatogonial stage vs control who had mature spermatozoa</li> <li>At 90 dpf, testes of most mutant males were normal and could induce normal fertilization</li> <li>Testes of mutant males that failed to spawn showed retarded spermatogenesis, fewer spermatocytes and more abundant spermatogonia</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>At 90 dpf, 7 out of 10 fshr mutant males could induce spawning with normal fertilization</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:84px"> Zhang et al., 2015     </td> <td rowspan="3" style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:119px"> <ul> <li>fshr mutant zebrafish develop as all-male population and the mutants who could not induce spawning are believed to be females who had follicles arrested</li> <li>105-d fshr mutant zebrafish well developed testis with degenerating oocytes</li> </ul>     </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> lhcgr mutant zebrafish line created using TALEN-induced gene knockout </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>No observable differences between control and mutants </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>No observable differences between control and mutants </li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> No </td> </tr> <tr> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:156px"> Fshr and lhcgr double mutant zebrafish line created using TALEN-induced gene knockout </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:162px"> <ul> <li>Arrest of spermatogonial stage with apoptotic oocyte-like germ cells early on</li> <li>Underdeveloped testis and retarded spermatogenesis at adult stage</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:144px"> <ul> <li>At 90 dpf, double knockout completely infertile</li> </ul> </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> <td style="border-bottom:1px solid #a3a3a3; border-left:none; border-right:1px solid #a3a3a3; border-top:none; vertical-align:top; width:78px"> Yes </td> </tr> </tbody> </table>

<ul> <li>Fertilization success in Chinook salmon (Oncorhynchus tshawytscha) was significantly biased towards the male whose sperm swam fastest in the female’s ovarian fluid (Rosengrave et al., 2016).</li> <li>Seminal plasma pH(R2=0.525) is positively correlated with fertilization rate in Rainbow Trout (Oncorhynchus mykiss) and African catfish (Clarias gariepinus) (Lahnsteiner et al., 1998, Mansour et al., 2005).</li> </ul>

Quantitative understanding is shown bellow.

<ul> <li>Lahnsteiner et al.(1998) determined that fertilization rate in Rainbow Trout (Oncorhynchus mykiss) can be described by sperm motility rate(y=0.72x * 25.99 where y is fertilization rate and x is sperm motility rate, R=0.594, P < 0.001), seminal plasma pH(R2=0.525, P < 0.001), and spermatozoal respiration activation(R2=0.554, P < 0.001). They found a positive correlation between % of motile spermatozoa and total swimming velocity with fertilization rate (P < 0.001) and % of immotile spermatozoa inversely. The 2 parameters accounted for 65% of total variance in fertilization rate. </li> <li>Relative sperm velocity(p=0.008) and longevity (p < 0.0001) showed significant association with sperm competition success in Atlantic salmon (Salmo salar). Males with faster spermatozoa achieved greater fertilization success. (Gage et al., 2004)</li> <li>Highly significant correlations were found between sperm motility (R=0.932, p < 0.001) and fertilization rate in Rainbow Trout (Oncorhynchus mykiss) (Ciereszko and Dabrowski, 1993).</li> </ul>

<ul> <li>The duration of spermatogenesis in humans (Homo sapiens) is reported to be 74 days (Griswold, M.D, 2016). Consequently, effects on spermatogenesis may not manifest as observable impacts on fertility until perhaps 74 days after impacts on spermatogenesis began. This may vary depending on the stage(s) of spermatogenesis that are impacted by the stressor.</li> <li>The duration of the meiotic and spermiogenic phases in zebrafish (Danio rerio) is reported to be 6 days which means there could be a delay of at least 6 days before signs of impaired fertility may be detected (Leal et al., 2009).</li> </ul>

Feedforward/feedback loops haven’t been evaluated yet. However, given that fertilization pertains to the interaction between sperm and oocyte, it seems unlikely that fertilization rates (external to the male) would feedback on and impact spermatogenesis.

High Male

High

Adult, reproductively mature

High High

<ul> <li>Taxonomic Applicability: Spermatogenesis is one of the most conserved biological processes from Drosophila to humans (Wu et al., 2016). As a result, animals who utilize sexual reproduction as their way to produce offspring are heavily reliant on spermatogenesis being effective and normal (Kang et al., 2015). There are studies on reproduction and spermatogenesis across a multitude of taxas. </li> <li>Sex Applicability: Spermatogenesis is a male-specific process (Tang et al., 2018, Wu et al., 2015, Kang et al., 2015, Wang et al., 2015). Thus, the present relationship is only relevant for males.</li> <li>Life Stage Applicability: Spermatogenesis and reproduction are only relevant for sexually-mature adults.</li> </ul>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43135518e8> AOPWiki 2021-01-29T11:37:25

2022-08-15T02:44:24

<upstream-id>98d0033d-5ca5-484d-a270-64c41f4a1287</upstream-id> <downstream-id>34f70cce-17bf-42e4-b698-91de83d3e15a</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43136a9560> AOPWiki 2021-03-26T15:24:01

2021-03-26T15:24:01

Inhibition of 11β-Hydroxysteroid Dehydrogenase leading to decreased population trajectory

11βHSD inhibition, decreased population trajectory

Agnes Aggy

Young Jun Kim,  Environmental Safety Group, Korea Institute of Science and Technology (KIST) Europe Forschungsgesellschaft mbH, 66123 Saarbruecken, Germany Park Chang-Beom, Korea Institute of Toxicology JRC-APT (Joint Research Center for Alternative and Predictive Toxicology)

BY-SA

Under Development

1.93

2.0

This AOP links inhibition of 11βHSD to reproductive toxicity in fish. This AOP describes impaired spermatogenesis that may result from the inhibition of 11βHSD. Chemical inhibition of 11βHSD, the molecular-initiating event (MIE), results in decreased 11-KT and cortisone synthesis. The reduction of 11-KT induces the cumulative cortisol by enzymatic conversion insufficiency of cortisone, which leads to decreased spermatogonial proliferation. Impaired fertility is a significant endpoint for evaluation of reproductive toxicity caused by endocrine disruption. It can be used as an endpoint for endocrine disruptor screening. Therefore, this AOP would be useful to identify chemicals with known potential to affect male fish fertility.   In fish spermatogenesis,11-KT is the main androgen in teleosts, where it has functions in spermatogenesis and their main action of 11-beta dehydrogenase(11βHSD Type 2)  is generally regarded as the induction of sperm maturation. it has also its role is to protect these tissues from an excess of cortisol. Stress conditions or inhibition of 11bHSD dehydrogenase activities result in a cortisol excess in the Leydig cells. A surplus of glucocorticoids causes delayed genomic repression of 11KT production through GR or a rapid nongenomic decrease in 11 KT production. The rapid depression has been hypothesized to occur via the putative plasma membrane corticosteroid receptor11βHSD2 is unidirectional with NAD+ as a cofactor. It is expressed not only in mineralocorticoid sensitive tissues such as testis.11βHSD has enzyme activities, metabolizing cortisol to cortisone, and 11 beta -hydroxytestosterone to 11-ketotestosterone (11-KT) which is the main androgen functions spermatogenesis. Especially, spermatogenesis can induce by 11-ketotestosterone(11-KT), a significant androgen in teleost. However, excess circulating cortisol, which is produced by 11β-hydroxylase and decline of 11KT by 11βHSD inhibition, leads to inhibition of the DNA replication in spermatogonial mitosis, gonadal function, and spermatogonial proliferation in male fish. Acknowledgements: This research was supported by the National Research Council of Science & Technology(NST) grant by the Korea government (MSIP) (No. CAP-17-01-KIST Europe)

Maintenance of sustainable fish and wildlife populations (i.e., adequate to ensure long-term delivery of valued ecosystem services) is a widely accepted regulatory goal upon which risk assessments and risk management decisions are based.

adjacent

Moderate

High adjacent

Moderate

High adjacent

High

High adjacent

High

High Male

Moderate

Adult, reproductively mature

High

11KT has functions in spermatogenesis and their main action of 11βHSD Type 2 is generally regarded as the induction of sperm maturation thus,This AOP will start with reviews about inhibitors of 11βHSD2 as MIE. Stressors for inhibiton were found in table and 11βHSD1 inhibitors were also denoted in previous studies (Jana Vitku et al 2016) . We will further find KERs with Androgen antagonisms and their impact on male fish. <table cellspacing="0" class="Table" style="border-collapse:collapse; border:none; margin-left:30px; width:841px"> <tbody> <tr> <td colspan="2" style="background-color:#aeaaaa; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:17px; width:695px"> To do </td> <td style="background-color:#aeaaaa; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:17px; width:147px"> Expected duration </td> </tr> <tr> <td rowspan="2" style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:16px; width:253px"> Building the AOP frame </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:16px; width:442px"> Development of KEs </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:16px; vertical-align:top; width:147px"> 6 month </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:17px; width:442px"> Production of experimental data using inhibitors </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:17px; vertical-align:top; width:147px"> 18 month </td> </tr> <tr> <td rowspan="5" style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:16px; width:253px"> Overall assessment of the AOP </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:16px; width:442px"> Biological domain of applicability </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:16px; vertical-align:top; width:147px"> 3 month </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:17px; width:442px"> Essentiality of all KEs </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:17px; vertical-align:top; width:147px"> 3 month </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:16px; width:442px"> Evidence supporting all KERs </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:16px; vertical-align:top; width:147px"> 5 month </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:17px; width:442px"> Quantitative WoE considerations </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:17px; vertical-align:top; width:147px"> 5 month </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:17px; width:442px"> Quantitative understanding for each KER </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:17px; vertical-align:top; width:147px"> 6 month </td> </tr> </tbody> </table> Domain(s) of Applicability Chemical: This AOP applies to inhibitors of 11KT (Androgen antagonists). Compounds which can bind the 11βHSD as follows <table border="0" cellpadding="0" cellspacing="0" style="width:593px"> <tbody> <tr> <td>Inhibitors of 11bHSD2</td> <td>Testing system</td> <td>IC50(μM)</td> </tr> <tr> <td>(1E,4E)-1,5-Bis(3-methylthiophen-2-yl)penta-1,4-dien-3-one</td> <td>Human microsomes</td> <td>19.58</td> </tr> <tr> <td>Abietic acid</td> <td>HEK 293 cells</td> <td>12</td> </tr> <tr> <td>Zearalenone</td> <td>HEK 293 cells</td> <td>107</td> </tr> <tr> <td>Fusidic acid</td> <td> HEK 293 cells</td> <td>134</td> </tr> <tr> <td>Euphane-3b,20-dihydroxy-24-ene</td> <td>HEK 293 cells </td> <td>8.18</td> </tr> <tr> <td>Kansuinone</td> <td>HEK 293 cells </td> <td>2.63</td> </tr> <tr> <td>Euphol</td> <td>HEK 293 cells </td> <td>0.4</td> </tr> <tr> <td>Kansenone</td> <td>HEK 293 cells </td> <td>0.11</td> </tr> <tr> <td>(24R)-Eupha-8,25-diene-3b,24-diol</td> <td>HEK 293 cells </td> <td>1.69</td> </tr> <tr> <td>(20R,23E)-Eupha-8,23-diene-3b,25-diol</td> <td>HEK 293 cells </td> <td>0.67</td> </tr> <tr> <td>Carbenoxolone</td> <td>CHO cells</td> <td>0.02</td> </tr> <tr> <td>Endosulfan</td> <td>HEK 293 cells</td> <td>61</td> </tr> <tr> <td>BPA</td> <td>HEK 293 cells</td> <td>50</td> </tr> <tr> <td>Disulfiram</td> <td>HEK 293 cells</td> <td>0.13</td> </tr> <tr> <td>Thiram</td> <td>HEK 293 cells</td> <td>0.13</td> </tr> <tr> <td rowspan="2">Diethyldithiocarbamate (DEDTC)</td> <td>HEK 293 cells</td> <td>1.7</td> </tr> <tr> <td>HEK 293 cells</td> <td>6.3</td> </tr> <tr> <td>Pyrrolidine dithiocarbamate (PDTC)</td> <td>HEK 293 cells</td> <td>6.3</td> </tr> <tr> <td>Maneb</td> <td>HEK 293 cells</td> <td>0.75</td> </tr> <tr> <td>Zineb</td> <td>HEK 293 cells</td> <td>1.42</td> </tr> <tr> <td rowspan="3">Diphenyltin</td> <td>HEK 293 cells</td> <td>2.89</td> </tr> <tr> <td>Human microsomes</td> <td>3.3</td> </tr> <tr> <td>HEK 293 cells </td> <td>3.19</td> </tr> <tr> <td rowspan="3">Triphenyltin</td> <td>HEK 293 cells </td> <td>0.99</td> </tr> <tr> <td>Human microsomes</td> <td>16.5</td> </tr> <tr> <td>HEK 293 cells</td> <td>1.9</td> </tr> <tr> <td rowspan="2">Tributyltin</td> <td>HEK 293 cells</td> <td>1.52</td> </tr> <tr> <td>HEK 293 cells</td> <td>1.95</td> </tr> <tr> <td rowspan="2">Dibutyltin</td> <td>HEK 293 cells</td> <td>5.03</td> </tr> <tr> <td>Human microsomes</td> <td>8.9</td> </tr> <tr> <td rowspan="2">4-t-Octylphenol</td> <td>HEK 293 cells</td> <td>30</td> </tr> <tr> <td>Human microsomes</td> <td>20.3</td> </tr> <tr> <td>4-Nonylphenol</td> <td>HEK 293 cells</td> <td>79</td> </tr> <tr> <td>4-n-Octylphenol</td> <td>Human microsomes</td> <td>23.5</td> </tr> <tr> <td>4-n-Nonylphenol</td> <td>Human microsomes</td> <td>26.2</td> </tr> <tr> <td rowspan="2">Dicyclohexyl phtalate</td> <td>Human microsomes</td> <td>46.5</td> </tr> <tr> <td>Rat microsomes</td> <td>32.64</td> </tr> <tr> <td>Dipropyl phthalate</td> <td>Rat microsomes</td> <td>85.59</td> </tr> <tr> <td>Di-n-butyl phthlate</td> <td>Rat microsomes</td> <td>13.69</td> </tr> <tr> <td>Mono(2-ethylhexyl)phthalate</td> <td>Rat microsomes</td> <td>121.8</td> </tr> <tr> <td>Mono(2-ethylhexyl)phthalate</td> <td>Human microsomes</td> <td>110.8</td> </tr> <tr> <td rowspan="2">Perfluorooctyl sulphonate</td> <td>Human microsomes</td> <td>0.05</td> </tr> <tr> <td>Rat microsomes</td> <td>0.29</td> </tr> <tr> <td rowspan="2">Perfluorooctanoic acid</td> <td>Human microsomes</td> <td>24.41</td> </tr> <tr> <td>Rat microsomes</td> <td>3.8</td> </tr> <tr> <td rowspan="2">Perfluorohexanesulfonate</td> <td>Human microsomes</td> <td>18.97</td> </tr> <tr> <td>Rat microsomes</td> <td>62.87</td> </tr> <tr> <td rowspan="2">2-Bis(p-hydroxyphenyl)-1,1,1-trichloroethane</td> <td>Human microsomes</td> <td>55.57</td> </tr> <tr> <td>Rat microsomes</td> <td>12.96</td> </tr> <tr> <td colspan="2">Source: Journal of Steroid Biochemistry & Molecular Biology 2016 Jan;155(Pt B):207-16</td> </tr> </tbody> </table> Sex: The AOP applies to males only. Life stages: The relevant life stages for this AOP are reproductively mature spermatogenesis.  Taxonomic: At present, the assumed taxonomic applicability domain of this AOP is iteroparous teleost fish species.

<ul> <li>Many studies showed that the essentiality of the proposed sequence of key events in teleost.</li> <li>The essentiality of the proposed negative regulation of 11βHSD is supported by experimental work that evaluated the ability of inhibition to reduce 11KT production in vitro and in vivo</li> </ul>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

A decrease in 11keto levels leads afterward to adverse changes in spermatogenesis. Therefore, it seems that 11βHSD  could be a target for EDs and this could be one of the possible mechanisms of endocrine disruption in the testis that leads to impaired spermatogenesis. Consequently, this AOP can be applied to the prediction of VMG-eco and relevant to EDTA caused by the inhibition of 11β-HSD.

High

Moderate

<ol> <li>Roles of 11β-Hydroxysteroid Dehydrogenase in Fish Spermatogenesis. Endocrinology 147(11):5139–5146</li> <li>Hormonal induction of all stages of spermatogenesis in vitro in the male Japanese eel (Anguilla japonica). Proc Natl Acad Sci USA 88:5774–5778</li> <li>17α,20 β Dihydroxy-4-pregnen-3-one: plasma levels during sexual maturation and in vitro production by the testes of amago salmon (Oncorhynchus rhodurus) and rainbow trout (Salmo gairdneri). Gen Comp Endocrinol 51:106–11</li> <li>Steroid profiles during spawning in male common carp. Gen Comp Endocrinol 80:223–231</li> <li>11 β-Hydroxysteroid dehydrogenase complementary deoxyribonucleic acid in rainbow trout: cloning, sites of expression, and seasonal changes in gonads. Endocrinology 144:2534–2545</li> <li>11 β –Hydroxysteroid dehydrogenase is a predominant reductase in intact Leydig cells. J Endocrinol 159:233–238</li> <li>Large-scale transcriptome sequencing reveals novel expression patterns for key sex-related genes in a sex-changing fish.  Biology of Sex Differences 6:26</li> <li>Sex Steroids and Their Involvement in the Cortisol-Induced Inhibition of Pubertal Development in Male Common Carp, BIOLOGY OF REPRODUCTION 67, 465–472</li> <li>Natural sex change in fish Current Topics in Developmental Biology, Volume 134</li> <li>Absence of 11-keto reduction of cortisone and 11-ketotestosterone in the model organism zebrafish Journal of Endocrinology 232,323–335</li> <li>Endocrine disruptors and other inhibitors of 11b-hydroxysteroid dehydrogenase 1 and 2: Tissue-specific consequences of enzyme inhibition.Journal of Steroid Biochemistry & Molecular Biology 155(Pt B):207-16.</li> </ol> AOPWiki 2020-07-03T12:44:29

2023-09-25T16:27:03