11β-hydroxylase inhibition

54-36-4

FJLBFSROUSIWMA-UHFFFAOYSA-N

Metyrapone

1-Propanone, 2-methyl-1,2-di-3-pyridinyl- 1,2-Bis(3-pyridyl)-2-methyl-1-propanone 1-Propanone, 2-methyl-1,2-di-3-pyridyl- 2-Methyl-1,2-bis(3-pyridyl)-1-propanone 2-Methyl-1,2-di(β-pyridyl)-1-propanone 2-Methyl-1,2-di-3-pyridyl-1-propanone Mepyrapone Methapyrapone Methbipyranone Methopirapone Methopyrapone Methopyrinine Methopyrone metirapona Metopiron Metopirone Metopyrone Metroprione Metyrapon NSC 25265

DTXSID1023314

164203-73-0

JWBOIMRXGHLCPP-CYBMUJFWSA-N

Lysodren, Mitotan, Mitotane

DTXSID30425146

33125-97-2

NPUKDXXFDDZOKR-UHFFFAOYNA-N

NPUKDXXFDDZOKR-UHFFFAOYSA-N

Etomidate

1H-Imidazole-5-carboxylic acid, 1-[(1R)-1-phenylethyl]-, ethyl ester (+)-Etomidate 1H-Imidazole-5-carboxylic acid, 1-(1-phenylethyl)-, ethyl ester, (R)- Amidate D-Etomidate Etomidat etomidato Hypnomidate Imidazole-5-carboxylic acid, 1-(α-methylbenzyl)-, ethyl ester, (R)-(+)- Propiscin Radenarcon

DTXSID5023033

65277-42-1

XMAYWYJOQHXEEK-OZXSUGGESA-N

Ketoconazole

, 2R,4S- Piperazine, 1-acetyl-4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-, rel- (.+-.)-Ketoconazole Brizoral cis-1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine Ethanone, 1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]-, rel- Fungarest Fungoral Ketoconazol Ketoderm Ketoisdin Ketozoral Nizoral Onofin K Orifungal M Panfungol Piperazine, 1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-, cis- Piperazine,1-acetyl-4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-, rel-

DTXSID7029879

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

CHEBI:34133

CHEBI 11-Keto-testosterone

PCO:0000001

PCO population of organisms

GO:0006702

GO androgen biosynthetic process

PCO:0000008

PCO population growth rate

D005298

MESH fertility

WIKI decreased

Metyrapone

2020-07-12T10:26:36

Lysodren, Mitotan, Mitotane

2020-07-12T10:27:10

Etomidate

2020-07-12T10:27:52

Ketoconazole

2017-05-02T11:08:42

Osilodrostat(LCI699)

2020-07-12T10:30:59

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

70862

NCBI teleost fish

30483

NCBI Order carcharhiniformes

WikiUser_17

mammals

WikiUser_22

all species

10116

NCBI rat

10090

NCBI mouse

WCS_9606

common toxicological species human

WikiUser_6

ApacheUser fish

11β-hydroxylase inhibition

Molecular

AOPWiki 2020-07-13T04:28:59

2020-07-13T04:28:59

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

Decreased spermatogenesis

Organ

AOPWiki 2020-07-13T04:32:49

2021-02-09T08:36:06

Cortisol and 11β-(OH) testosterone decreased

Cellular

AOPWiki 2021-02-09T08:25:50

2021-02-09T08:25:50

Decreased plasma Cortisol level

Tissue

AOPWiki 2021-02-09T08:27:22

2021-02-09T08:27:22

decreased oocyte maturation

Organ

AOPWiki 2021-02-09T08:32:18

2021-02-09T08:32:18

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

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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

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430223b430> AOPWiki 2020-07-21T09:54:35

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4302520e98> AOPWiki 2020-07-13T04:42:08

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43024b3cd0> AOPWiki 2021-03-26T15:24:01

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Inhibition of 11β-hydroxylase leading to decresed population trajectory

11β-hydroxylase inhibition, infertility in fish

Allie Always

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

<div>This AOP links inhibition of 11β-hydroxylase to reproductive toxicity in fish. The present AOP suggests the inhibition of 11β-hydroxylase mediated adverse outcome (AO) in fishes. In teleost, cyp11c1 encodes 11β-hydroxylase, one of the critical enzymes mediating testosterone conversion to 11β-(OH) testosterone, critical for biosynthesis of 11-KT and 11-deoxycortisol to cortisol in the differentiating gonads of both sexes at the juvenile stage. Qifeng Zhang et al, 2020 showed that the 11β-hydroxylase knockout male fish showed delayed and prolonged juvenile ovary-to-testis transition and displayed defective spermatogenesis at the adult stage, significantly reduced 11-KT and cortisol levels. Male zebrafish are infertile, have smaller testis, possess very little spermatozoa volume, and exhibit defective secondary sexual characteristics (Tang H et al.2018). </div>   <div> <table align="left"> <tbody> <tr> <td style="vertical-align:top"> 11β-hydroxylase is prominently expressed in the Leydig cells of the testis in teleost. Ribas L, et al, 2017 reported that elevated cortisol, primary glucocorticoid, during the stress response might play a role in teleost's masculinization. Cortisol has also been cross talked to be involved in reproduction and sex differentiation at a proper level for the success of spawning, oocyte maturation, and the survival of progeny in teleosts. In females, the 11β-hydroxylase knockout females showed less spawned eggs and the eggs were defective in germinal vesicle breakdown. Stress conditions or inhibition of 11β-hydroxylase activities finally decreased 11KT and cortisol in the Leydig and Sertoli cells. Taken together, the inhibitors of 11β-hydroxylase (i.e metyrapone, lysodren, eomidate and ketoconazole etc.) could result in decreased 11-KT and cortisol, subsequently, leading to impairment of spermatogenesis and oocyte maturation and ovulation.        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)   </td> </tr> </tbody> </table> </div>

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

Moderate

High adjacent

Moderate

Moderate adjacent

Moderate

Moderate adjacent

High

High adjacent

High

High adjacent

High

High Mixed

High

Adult, reproductively mature

Moderate

<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"> 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"> Production of experimental data for in vitro/in vivo </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>

This AOP is designed to estimate changes in the trajectory of fishes by potential inhibitors. Decreased trajectory applicable to both sex in the fish which is a potential endpoint for endocrine disruptions by inhibition of 11β-hydroxylase. The proposed endpoint will provide a useful high throughput risk assessment screening tool for possible chemicals. Consequently, this AOP can be applied to the prediction of VMG-eco and relevant to EDTA caused by the inhibition of 11β-hydroxylase.

High

Moderate

<ol> <li>Zebrafish cyp11c1 Knockout Reveals the Roles of 11-ketotestosterone and Cortisol in Sexual Development and Reproduction. Endocrinology 2020 Jun 1;161(6):bqaa048.</li> <li>Appropriate rearing density in domesticated zebrafish to avoid masculinization: links with the stress response, J Exp Biol. 2017;220(Pt 6):1056-1064</li> <li>Loss of Cyp11c1 Causes Delayed Spermatogenesis Due to the Absence of 11-ketotestosterone. J Endocrinol 2020 Mar;244(3):487-499.</li> <li>The Onset of Spermatogenesis in Fish. Ciba Found Symp 1994;182:255-67; discussion 267-70.</li> <li>Impaired Spermatogenesis in the Japanese Eel, Anguilla Japonica: Possibility of the Existence of Factors That Regulate Entry of Germ Cells Into Meiosis.  Dev Growth Differ 1997 Dec;39(6):685-91</li> <li>Zebrafish 20β-Hydroxysteroid Dehydrogenase Type 2 Is Important for Glucocorticoid Catabolism in Stress Response PLOS 2013 8 (1) e54851</li> <li>A newly cyp11c1-GFP transgenic zebrafish model to study corticosteroidogenesis and its perturbation by endocrine active substances at early developmental stages. Conference paper</li> <li>Large-scale transcriptome sequencing reveals novel expression patterns for key sex-related genes in a sex-changing fish. Biol Sex Differ. 2015; 6: 26.</li> <li>A Critical Role of Follicle-Stimulating Hormone (Fsh) in Mediating the Effect of Clotrimazole on Testicular Steroidogenesis in Adult Zebrafish. Toxicology 2012 Aug 16;298(1-3):30</li> <li>Maternal stress and fish reproduction: The role of cortisol revisited Fish and Fisheries November 2018, Nov, 19(6) Pages 1016-1030</li> <li>Effects of steroid hormones on in vitro oocyte maturation in white sturgeon (Acipenser transmontanus)Fish Physiology and Biochemistry, 2000 volume 23, pages317–325</li> <li>Some aspects of oocyte maturation in catfish Journal of Steroid Biochemistry Volume 11, Issue 1, Part 3, July 1979, Pages 701-707       </li> <li> The in vitro metabolism of cortisol by ovarian follicles of rainbow trout (Oncorhynchus mykiss): comparison with ovulated oocytes and pre-hatch embryos  Reproduction, Pages 713–722 Volume 144: Issue 6 </li> </ol> AOPWiki 2020-07-12T10:16:17

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