Activation, PPARα

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

637-07-0

KNHUKKLJHYUCFP-UHFFFAOYSA-N

Clofibrate

ethyl-p-chlorophenoxyisobutyrate Propanoic acid, 2-(4-chlorophenoxy)-2-methyl-, ethyl ester 2-(p-Chlorophenoxy)-2-methylpropionic acid ethyl ester Abitrate Amotril Anparton Arteriosan Artevil Ateculon Ateriosan Atheropront Atromid S Atromidin Azionyl Bioscleran Cartagyl Claripex Claripex CPIB Clobren SF Clofibrat clofibrato Clofinit Ethyl (p-chlorophenoxy) isobutyrate Ethyl 2-(4-chlorophenoxy)-2-methylpropionate Ethyl 2-(4-chlorophenoxy)isobutyrate Ethyl 2-(p-chlorophenoxy)-2-methylpropionate Ethyl 2-(p-chlorophenoxy)isobutyrate Ethyl clofibrate Ethyl p-chlorophenoxyisobutyrate Ethyl α-(4-chlorophenoxy)isobutyrate Ethyl α-(4-chlorophenoxy)-α-methylpropionate Ethyl α-(p-chlorophenoxy)isobutyrate Ethyl α-(p-chlorophenoxy)-α-methylpropionate Hyclorate Lipavil Lipavlon Lipomid Liprinal Miscleron Misclerone Neo-Atromid Normolipol NSC 79389 p-Chlorophenoxyisobutyric acid ethyl ester Propionic acid, 2-(p-chlorophenoxy)-2-methyl-, ethyl ester Recolip Regelan Serotinex Sklerepmexe Sklerolip Skleromexe Sklero-Tablinene Ticlobran Xyduril

DTXSID3020336

3771-19-5

XJGBDJOMWKAZJS-UHFFFAOYNA-N

XJGBDJOMWKAZJS-UHFFFAOYSA-N

Nafenopin

DTXSID8020911

52214-84-3

KPSRODZRAIWAKH-UHFFFAOYNA-N

KPSRODZRAIWAKH-UHFFFAOYSA-N

Ciprofibrate

DTXSID8020331

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

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

49562-28-9

YMTINGFKWWXKFG-UHFFFAOYSA-N

Fenofibrate

Propanoic acid, 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-, 1-methylethyl ester 2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic acid 1-methylethyl ester Ankebin Clorofibrate Elasterin Fenobrate Fenofibrat fenofibrato Fenogal Fenotard Isopropyl 2-[p-(p-chlorobenzoyl)phenoxy]-2-methylpropionate Lipanthyl Lipantil Lipicard Lipidil Lipidil Supra Lipirex Lipoclar Lipofene Liposit MeltDose Nolipax NSC 281319 Procetofen Procetofene Procetoken Protolipan Secalip

DTXSID2029874

79902-63-9

RYMZZMVNJRMUDD-HGQWONQESA-N

Simvastatin

Butanoic acid, 2,2-dimethyl-, (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester (+)-Simvastatin Apo-Simvastatin Bestatin 20 Butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*,4S*),8aβ]]- Cholestat Co-Simvastatin Kolestevan L 644128-000U Lipinorm Liponorm Lipovas Lodales Modutrol Nor-Vastina Novo-Simvastatin Pms-simvastatin Simastin 20 Simovil Simvastatin lactone Simvotin Sinvacor Sinvascor Sivastin Starstat 20 Synvinolin Valemia Velostatin

DTXSID0023581

134523-00-5

XUKUURHRXDUEBC-KAYWLYCHSA-N

Atorvastatin

Cardyl Atorvastatin acid 1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, (βR,δR)-

DTXSID8029868

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

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

PR:000013056

PR peroxisome proliferator-activated receptor alpha

CHEBI:16113

CHEBI cholesterol

CHEBI:17002

CHEBI cholesteryl ester

CHEBI:34133

CHEBI 11-Keto-testosterone

FMA:67338

FMA Mature sperm cell

PCO:0000001

PCO population of organisms

GO:0035357

GO peroxisome proliferator activated receptor signaling pathway

GO:0006695

GO cholesterol biosynthetic process

GO:0030301

GO cholesterol transport

GO:0006702

GO androgen biosynthetic process

HP:0008669

HP Abnormal spermatogenesis

PCO:0000008

PCO population growth rate

WIKI increased

WIKI decreased

WIKI abnormal

Di(2-ethylhexyl) phthalate

2016-11-29T18:42:26

Mono(2-ethylhexyl) phthalate

2016-11-29T18:42:26

Stressor:205 pirinixic acid (WY-14,643)

2020-12-19T09:06:20

Clofibrate

2016-11-29T18:42:27

Nafenopin

2016-11-29T18:42:27

ciprofibrate

2016-11-29T18:42:27

Gemfibrozil Fibrate drug

2016-11-29T18:42:27

2020-03-31T10:24:40

PERFLUOROOCTANOIC ACID

2016-11-29T18:42:27

Bezafibrate

2016-11-29T18:42:27

Fenofibrate

2016-11-29T18:42:27

Simvastatin

2020-05-06T09:41:35

Atorvastatin

2020-03-31T10:30:56

beta-Sitosterol

2020-03-23T14:04:49

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

10116

NCBI rat

10090

NCBI mouse

WCS_9606

common toxicological species human

WikiUser_28

Vertebrates

70862

NCBI teleost fish

30483

NCBI Order carcharhiniformes

WikiUser_17

mammals

WikiUser_22

all species

9606

NCBI Homo sapiens

10095

NCBI mice

Activation, PPARα

Molecular

Gene expression occurs in a coordinated fashion (Judson et al., 2012). The many observations of altered gene expression following binding of ligand to PPARα led to systematic investigations of the genomic signature that corresponds to PPARα activation (Tamura et al., 2006; Kupershmidt et al., 2010; Rosen et al., 2017; Rooney et al., 2018; Corton et al., 2020; Hill et al., 2020; Lewis et al., 2020). Specific gene with increased expression following PPARα activation include Cyp4a1, Cpt1B, and Lpl. More generally, the pathways activated include: <ul> <li>Genes involved in Metabolism of lipids and lipoproteins</li> <li>Fatty acid metabolism</li> <li>Genes involved in Fatty acid, triacylglycerol, and ketone body metabolism</li> <li>PPAR signaling pathway</li> <li>Peroxisome</li> <li>Genes involved in Cell Cycle</li> </ul> Biological state The Peroxisome Proliferator Activated receptor α (PPARα) belongs to the <a href="/wiki/index.php/Peroxisome_Proliferator_Activated_receptors_(PPARs;_NR1C)" title="Peroxisome Proliferator Activated receptors (PPARs; NR1C)">Peroxisome Proliferator Activated receptors (PPARs; NR1C)</a> steroid/thyroid/retinoid receptor superfamily of transcription factors. Biological compartments PPARα is expressed in high levels in tissues that perform significant catabolism of fatty acids (FAs), such as brown adipose tissue, liver, heart, kidney, and intestine (Michalik et al. 2006). The receptor is present also in skeletal muscle, intestine, pancreas, lung, placenta and testes (Mukherjee et al. 1997), (Schultz et al. 1999). General role in biology PPARs are activated by fatty acids and their derivatives; they are sensors of dietary lipids and are involved in lipid and carbohydrate metabolism, immune response and peroxisome proliferation (Wahli and Desvergne 1999), (Evans, Barish, & Wang, 2004). PAPRα is a also a target of hypothalamic hormone signalling and was found to play a role in embryonic development (Yessoufou and Wahli 2010). Fibrates, activators of PPARα, are commonly used to treat hypertriglyceridemia and other dyslipidemic states as they have been shown to decrease circulating lipid levels (Lefebvre et al. 2006).

Binding of ligands to PPARα is measured using binding assays in vitro and in silico, whereas the information about functional activation is derived from transactivation assays (e.g. transactivation assay with reporter gene) that demonstrate functional activation of a nuclear receptor by a specific compound. Binding of agonists within the ligand-binding site of PPARs causes a conformational change of nuclear receptor that promotes binding to transcriptional co-activators. Conversely, binding of antagonists results in a conformation that favours the binding of co-repressors (Yu and Reddy 2007), (Viswakarma et al. 2010). Transactivation assays are performed using transient or stably transfected cells with the PPARα expression plasmid and a reporter plasmid, respectively. There are also other methods that have been used to measure PPARα activity, such as the Electrophoretic Mobility Shift Assay (EMSA) or commercially available PPARα transcription factor assay kits, see Table 1. The transactivation (stable transfection) assay provides the most applicable OECD Level 2 assay (i.e. In vitro assays providing mechanistic data) aimed at identifying the initiating event leading to an adverse outcome (LeBlanc, Norris, and Kloas 2011). A recent study characterized the PPARα ligand binding domain for the purpose of next-generation metabolic disease drugs (Kamata et al. 2020). The most direct measure of this MIE is microarray profiling from large gene expression databases TG-GATEs and DrugMatrix coupled with t statistical analysis of whole genome expression profiles (Svoboda et al., 2019; Igarashi et al., 2015) From these data, A gene expression signature of 131 PPARα-dependent genes was built using microarray profiles from the livers of wild-type and PPARα-null mice. A quantitative measure of this expression signature is a measure of similarity/correlation between the PPARα signature and positive and negative test sets is provided by the Running Fisher test (Corton et al., 2020; Hill et al., 2020; Kupershmidt et al., 2010; Lewis et al., 2020; Rooney et al., 2018). A gene expression signature of 131 PPARα-dependent genes was built using microarray profiles from the livers of wild-type and PPARα-null mice. A quantitative measure of this expression signature would be a measure of similarity/correlation between the PPARα signature and positive and negative test sets is provided by the Running Fisher test (Kupershmidt et al., 2010; Rooney et al., 2018; Corton et al., 2020). For all substances, MIE activation does not rise monotonically over dose or time. These fluctuations are likely due to variations in cofactor availability or access to the site of transcription (Gaillard et al., 2006; Koppen et al., 2009; Kupershmidt et al., 2010; Ong et al., 2010; Chow et al., 2011; De Vos et al., 2011; Simon et al., 2015). . <table align="left" border="1" cellpadding="1" cellspacing="1" style="height:3px; width:100px"> <caption>Measurements of PPARα Activation</caption> <thead> <tr> <th scope="row">Method/Test</th> <th scope="col">Test Principle</th> <th scope="col">Test Environment</th> <th scope="col">Test Outcome</th> <th scope="col">Assay Type/Domain</th> </tr> </thead> <tbody> <tr> <th scope="row"> molecular modelling; docking simulation </th> <td>Computational simulation of  ligand binding </td> <td>In silico</td> <td>Prediction off binding interaction </td> <td>Quantitative virtual screeings</td> </tr> <tr> <th scope="row">Scintillation proximity binding assay</th> <td>Direct binding of ligand</td> <td>In vitro</td> <td>Identifies compouds that bind to PPARα</td> <td>Qualitative in vitro screening</td> </tr> <tr> <th scope="row">PPARα reporter gene assay</th> <td>Quantify changes in in PPARα activation via a sensitive surrogate </td> <td>In vitro, Ex vivo</td> <td>Measures changes in activity of genes linked to a PPARα receptor element</td> <td>Quantitative in vitro screening</td> </tr> <tr> <th scope="row">Electrophoretic Band Shift</th> <td>determines if a protein or protein mixture will bind to a specific DNA or RNA sequence</td> <td>In vitro</td> <td>Measures cofactor binding by changes in gel mobility</td> <td>Quantitative in vitro screening</td> </tr> <tr> <th scope="row">Microarray profiling</th> <td>Develop MIE-specific sets of gene expression biomarkers</td> <td>In vivo</td> <td>Classification of PPARα biomarker genes with statistical methods</td> <td>Quantitative in vivo screening</td> </tr> </tbody> </table>

PPARα has been identified in frog (Xenopus laevis), mouse, human, rat, fish, hamster and chicken (reviewed in (Wahli and Desvergne 1999)).

UBERON:0002107

UBERON liver

CL:0000255

CL eukaryotic cell

High High High

Bhattacharya, Nandini, Jannette M Dufour, My-Nuong Vo, Janice Okita, Richard Okita, and Kwan Hee Kim. 2005. “Differential Effects of Phthalates on the Testis and the Liver.” Biology of Reproduction 72 (3) (March): 745–54. doi:10.1095/biolreprod.104.031583. Bility, Moses T, Jerry T Thompson, Richard H McKee, Raymond M David, John H Butala, John P Vanden Heuvel, and Jeffrey M Peters. 2004. “Activation of Mouse and Human Peroxisome Proliferator-Activated Receptors (PPARs) by Phthalate Monoesters.” Toxicological Sciences : An Official Journal of the Society of Toxicology 82 (1) (November): 170–82. doi:10.1093/toxsci/kfh253. Chow, C. C., Ong, K. M., Dougherty, E. J., & Simons, S. S. (2011). Inferring mechanisms from dose-response curves. Methods Enzymol, 487, 465-483. https://doi.org/10.1016/B978-0-12-381270-4.00016-0 Corton, J. C., Hill, T., Sutherland, J. J., Stevens, J. L., & Rooney, J. (2020). A Set of Six Gene Expression Biomarkers Identify Rat Liver Tumorigens in Short-Term Assays. Toxicol Sci. https://doi.org/10.1093/toxsci/kfaa101 De Vos, D., Bruggeman, F. J., Westerhoff, H. V., & Bakker, B. M. (2011). How molecular competition influences fluxes in gene expression networks. PLoS One, 6(12), e28494. https://doi.org/10.1371/journal.pone.0028494 Dufour, Jannette M, My-Nuong Vo, Nandini Bhattacharya, Janice Okita, Richard Okita, and Kwan Hee Kim. 2003. “Peroxisome Proliferators Disrupt Retinoic Acid Receptor Alpha Signaling in the Testis.” Biology of Reproduction 68 (4) (April): 1215–24. doi:10.1095/biolreprod.102.010488. Feige, Jérôme N, Laurent Gelman, Daniel Rossi, Vincent Zoete, Raphaël Métivier, Cicerone Tudor, Silvia I Anghel, et al. 2007. “The Endocrine Disruptor Monoethyl-Hexyl-Phthalate Is a Selective Peroxisome Proliferator-Activated Receptor Gamma Modulator That Promotes Adipogenesis.” The Journal of Biological Chemistry 282 (26) (June 29): 19152–66. doi:10.1074/jbc.M702724200. Gaillard, S., Grasfeder, L. L., Haeffele, C. L., Lobenhofer, E. K., Chu, T.-M., Wolfinger, R., Kazmin, D., Koves, T. R., Muoio, D. M., Chang, C.-y., & McDonnell, D. P. (2006). Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs. Mol Cell, 24(5), 797-803. https://doi.org/10.1016/j.molcel.2006.10.012 Hill, T., Rooney, J., Abedini, J., El-Masri, H., Wood, C. E., & Corton, J. C. (2020). Gene Expression Thresholds Derived From Short-Term Exposures Identify Rat Liver Tumorigens. Toxicol Sci. https://doi.org/10.1093/toxsci/kfaa102 Hurst, Christopher H, and David J Waxman. 2003. “Activation of PPARalpha and PPARgamma by Environmental Phthalate Monoesters.” Toxicological Sciences : An Official Journal of the Society of Toxicology 74 (2) (August): 297–308. doi:10.1093/toxsci/kfg145. Igarashi, Y., Nakatsu, N., Yamashita, T., Ono, A., Ohno, Y., Urushidani, T., & Yamada, H. (2015). Open TG-GATEs: a large-scale toxicogenomics database. Nucleic Acids Res, 43(Database issue), D921-7. https://doi.org/10.1093/nar/gku955 Kamata S, Oyama T, Saito K, Honda A, Yamamoto Y, Suda K, Ishikawa R, Itoh T, Watanabe Y, Shibata T, Uchida K, Suematsu M, Ishii I. PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates. iScience. 2020;23(11):101727. 10.1016/j.isci.2020.101727 Kaya, Taner, Scott C Mohr, David J Waxman, and Sandor Vajda. 2006. “Computational Screening of Phthalate Monoesters for Binding to PPARgamma.” Chemical Research in Toxicology 19 (8) (August): 999–1009. doi:10.1021/tx050301s. Koppen, A., Houtman, R., Pijnenburg, D., Jeninga, E. H., Ruijtenbeek, R., & Kalkhoven, E. (2009). Nuclear receptor-coregulator interaction profiling identifies TRIP3 as a novel peroxisome proliferator-activated receptor gamma cofactor. Mol Cell Proteomics, 8(10), 2212-2226. https://doi.org/10.1074/mcp.M900209-MCP200 Kupershmidt, I., Su, Q. J., Grewal, A., Sundaresh, S., Halperin, I., Flynn, J., Shekar, M., Wang, H., Park, J., Cui, W., Wall, G. D., Wisotzkey, R., Alag, S., Akhtari, S., & Ronaghi, M. (2010). Ontology-based meta-analysis of global collections of high-throughput public data. PLoS One, 5(9). https://doi.org/10.1371/journal.pone.0013066 Lampen, Alfonso, Susan Zimnik, and Heinz Nau. 2003. “Teratogenic Phthalate Esters and Metabolites Activate the Nuclear Receptors PPARs and Induce Differentiation of F9 Cells.” Toxicology and Applied Pharmacology 188 (1) (April): 14–23. doi:10.1016/S0041-008X(03)00014-0. Lapinskas, Paula J., Sherri Brown, Lisa M. Leesnitzer, Steven Blanchard, Cyndi Swanson, Russell C. Cattley, and J. Christopher Corton. 2005. “Role of PPARα in Mediating the Effects of Phthalates and Metabolites in the Liver.” Toxicology 207 (1): 149–163. Le Maire, Albane, Marina Grimaldi, Dominique Roecklin, Sonia Dagnino, Valérie Vivat-Hannah, Patrick Balaguer, and William Bourguet. 2009. “Activation of RXR-PPAR Heterodimers by Organotin Environmental Endocrine Disruptors.” EMBO Reports 10 (4) (April): 367–73. doi:10.1038/embor.2009.8. LeBlanc, GA, DO Norris, and W Kloas. 2011. “Detailed Review Paper State of the Science on Novel In Vitro and In Vivo Screening and Testing Methods and Endpoints for Evaluating Endocrine Disruptors” (178). Lefebvre, Philippe, Giulia Chinetti, Jean-Charles Fruchart, and Bart Staels. 2006. “Sorting out the Roles of PPAR Alpha in Energy Metabolism and Vascular Homeostasis.” The Journal of Clinical Investigation 116 (3) (March): 571–80. doi:10.1172/JCI27989. Lewis, R. W., Hill, T., & Corton, J. C. (2020). A set of six Gene expression biomarkers and their thresholds identify rat liver tumorigens in short-term assays. Toxicology, 443, 152547. https://doi.org/10.1016/j.tox.2020.152547 Maloney, Erin K., and David J. Waxman. 1999. “Trans-Activation of PPARα and PPARγ by Structurally Diverse Environmental Chemicals.” Toxicology and Applied Pharmacology 161 (2): 209–218. Michalik, Liliane, Johan Auwerx, Joel P Berger, V Krishna Chatterjee, Christopher K Glass, Frank J Gonzalez, Paul A Grimaldi, et al. 2006. “International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors.” Pharmacological Reviews 58 (4) (December): 726–41. doi:10.1124/pr.58.4.5. Mukherjee, R, L Jow, G E Croston, and J R Paterniti. 1997. “Identification, Characterization, and Tissue Distribution of Human Peroxisome Proliferator-Activated Receptor (PPAR) Isoforms PPARgamma2 versus PPARgamma1 and Activation with Retinoid X Receptor Agonists and Antagonists.” The Journal of Biological Chemistry 272 (12) (March 21): 8071–6. Ong, K. M., Blackford, J. A., Kagan, B. L., Simons, S. S., & Chow, C. C. (2010). A theoretical framework for gene induction and experimental comparisons. Proc Natl Acad Sci U S A, 107(15), 7107-7112. https://doi.org/10.1073/pnas.0911095107 Rooney, J., Hill, T., Qin, C., Sistare, F. D., & Corton, J. C. (2018). Adverse outcome pathway-driven identification of rat liver tumorigens in short-term assays. Toxicol Appl Pharmacol, 356, 99-113. https://doi.org/10.1016/j.taap.2018.07.023 Schultz, R, W Yan, J Toppari, A Völkl, J A Gustafsson, and M Pelto-Huikko. 1999. “Expression of Peroxisome Proliferator-Activated Receptor Alpha Messenger Ribonucleic Acid and Protein in Human and Rat Testis.” Endocrinology 140 (7) (July): 2968–75. doi:10.1210/endo.140.7.6858. Simon, T. W., Budinsky, R. A., & Rowlands, J. C. (2015). A model for aryl hydrocarbon receptor-activated gene expression shows potency and efficacy changes and predicts squelching due to competition for transcription co-activators. PLoS One, 10(6), e0127952. https://doi.org/10.1371/journal.pone.0127952. Staels, B., J. Dallongeville, J. Auwerx, K. Schoonjans, E. Leitersdorf, and J.-C. Fruchart. 1998. “Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism.” Circulation 98 (19) (November 10): 2088–2093. doi:10.1161/01.CIR.98.19.2088. Svoboda, D. L., Saddler, T., & Auerbach, S. S. (2019). An Overview of National Toxicology Program’s Toxicogenomic Applications: DrugMatrix and ToxFX.  In Advances in Computational Toxicology (pp. 141-157). Springer. https://link.springer.com/chapter/10.1007/978-3-030-16443-0_8 ToxCastTM Data. “ToxCastTM Data.” US Environmental Protection Agency. <a class="external free" href="http://www.epa.gov/ncct/toxcast/data.html" rel="nofollow" target="_blank">http://www.epa.gov/ncct/toxcast/data.html</a> Vanden Heuvel, John P, Jerry T Thompson, Steven R Frame, and Peter J Gillies. 2006. “Differential Activation of Nuclear Receptors by Perfluorinated Fatty Acid Analogs and Natural Fatty Acids: A Comparison of Human, Mouse, and Rat Peroxisome Proliferator-Activated Receptor-Alpha, -Beta, and -Gamma, Liver X Receptor-Beta, and Retinoid X Rec.” Toxicological Sciences : An Official Journal of the Society of Toxicology 92 (2) (August): 476–89. doi:10.1093/toxsci/kfl014. Venkata, Nagaraj Gopisetty, Jodie a Robinson, Peter J Cabot, Barbara Davis, Greg R Monteith, and Sarah J Roberts-Thomson. 2006. “Mono(2-Ethylhexyl)phthalate and Mono-N-Butyl Phthalate Activation of Peroxisome Proliferator Activated-Receptors Alpha and Gamma in Breast.” Toxicology Letters 163 (3) (June 1): 224–34. doi:10.1016/j.toxlet.2005.11.001. Viswakarma, Navin, Yuzhi Jia, Liang Bai, Aurore Vluggens, Jayme Borensztajn, Jianming Xu, and Janardan K Reddy. 2010. “Coactivators in PPAR-Regulated Gene Expression.” PPAR Research 2010 (January). doi:10.1155/2010/250126. Wahli, Walter, and B Desvergne. 1999. “Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism.” Endocrine Reviews 20 (5) (October): 649–88. Wu, Bin, Jie Gao, and Ming-wei Wang. 2005. “Development of a Complex Scintillation Proximity Assay for High-Throughput Screening of PPARgamma Modulators.” Acta Pharmacologica Sinica 26 (3) (March): 339–44. doi:10.1111/j.1745-7254.2005.00040.x. Xu, Chuan, Ji-An Chen, Zhiqun Qiu, Qing Zhao, Jiaohua Luo, Lan Yang, Hui Zeng, et al. 2010. “Ovotoxicity and PPAR-Mediated Aromatase Downregulation in Female Sprague-Dawley Rats Following Combined Oral Exposure to Benzo[a]pyrene and Di-(2-Ethylhexyl) Phthalate.” Toxicology Letters 199 (3) (December 15): 323–32. doi:10.1016/j.toxlet.2010.09.015. Yessoufou, a, and W Wahli. 2010. “Multifaceted Roles of Peroxisome Proliferator-Activated Receptors (PPARs) at the Cellular and Whole Organism Levels.” Swiss Medical Weekly 140 (September) (January): w13071. doi:10.4414/smw.2010.13071. Yu, Songtao, and Janardan K Reddy. 2007. “Transcription Coactivators for Peroxisome Proliferator-Activated Receptors.” Biochimica et Biophysica Acta 1771 (8) (August): 936–51. doi:10.1016/j.bbalip.2007.01.008. AOPWiki 2016-11-29T18:41:23

2020-12-28T12:48:16

Decreased, cholesterol

Tissue

Most cholesterol synthesis in vertebrates occurs within the endoplasmic reticulum of hepatic cells. First, acetyl-CoA is converted to HMG-CoA via HMG-CoA synthase. Next, HMG-CoA is converted to mevalonate via HMG-CoA reductase. Several other steps follow, but conversion of HMG-CoA to mevalonate is the rate-limiting step of cholesterol synthesis (Cerqueira et al. 2016; Risley 2002). Consequently, Statin drugs inhibit HMG-CoA reductase to reduce cholesterol (Pahan 2006). Cholesterol synthesis may also occur to a limited extent in steroidogenic cells where it’s used to produce steroid hormones (Azhar et al., 2007) Once cholesterol is produced in the liver, it’s transported in the plasma. Hydrophobic lipids like cholesterol, cholesteryl ester (a cholesterol molecule bound to a fatty acid), and triglycerides are transported via lipoprotein complexes. There are different groups of lipoproteins which use different proteins and ratios of lipids including high-density lipoprotein (HDL), low-density (LDL), and very low-density (VLDL). <a href="https://www.genome.jp/pathway/ko04979+K05641">Cholesterol metabolism KEGG Pathway</a>  ko04979

Commerical assay kits are available for measuring cholesterol using either colorimetric or fluorometric detection. Total cholesterol assay kits often include cholesteryl esters in the measurement (<a href="https://www.cellbiolabs.com/total-cholesterol-assay-kit">Cell Bio Labs</a>, <a href="https://www.thermofisher.com/order/catalog/product/A12216#/A12216">ThermoFisher</a>). Additional kits are availalbe for measuring the cholesterol in the different lipoprotein complexes (<a href="https://www.cellbiolabs.com/hdl-and-ldlvldl-cholesterol-assay-kit">Cell Bio Labs</a>).  Oil Red O staining can be used for organisms such as zebrafish larvae that are clear, however it stains triglycerides and lipids not just cholesterol (Zhou et al., 2015).  Plasma cholesterol is a common clinical measurement in humans and the Abell-Kendall technique is the standard chemical determination method (Cox et al. 1990), although there are a wide variety of viable methods.

Taxonomic Applicability: Cholesterol is synthesized in plants but acts as a precursor for different products than in animals (Sonawane et al. 2016). Within the animal kingdom most deuterostomes (including vertebrata, cyclostomata, cephalochordate, and echinodermata, but not chordata) possess the genes necessary for cholesterol biosynthesis. However, most protostomes (including arthropoda and nematomorpha) have lost these genes (Zhang et al., 2019). Thus far vertebrates are the primary consideration for this KE. Lifestage Applicability: Cholesterol can be measured in organisms at all life stages. However, the size of young organisms may limit the ability to collect plasma for cholesterol analysis. Whole-body measurements or pooled samples may be more feasible. Sex Applicability: Cholesterol measurements are applicable for all sexes

UBERON:0001969

UBERON blood plasma

High Male High Female

High

Adult

Moderate

All life stages

High

Al-Habsi, A.A., A. Massarsky, T.W. Moon (2016) “Exposure to gemfibrozil and atorvastatin affects cholesterol metabolism and steroid production in zebrafish (Danio rerio)”, Comparative Biochemistry and Physiology, Part B, Vol. 199, Elsevier, pp. 87-96. http://dx.doi.org/10.1016/j.cbpb.2015.11.009 Azhar, S., E. Reaven (2007) “Regulation of Leydig cell cholesterol metabolism”, in A.H. Payne, M.P. Hardy (eds.) The Leydig Cell in Health and Disease, Humana Press. https://doi.org/10.1007/978-1-59745-453-7 Cox RA, García-Palmieri MR. Cholesterol, Triglycerides, and Associated Lipoproteins. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 31. Available from: https://www.ncbi.nlm.nih.gov/books/NBK351/ Dai, W. et al. (2015) "High fat plus high cholesterol diet lead to hepatic steatosis in zebrafish larvae: a novel model for screening anti-hepatic steatosis drugs", Nutrition and Metabolism, Vol. 12(42), Springer Nature. DOI 10.1186/s12986-015-0036-z  Du, Z.Y. et al. (2008) “Hypolipidaemic effect of fenofibrate and fasting in the herbivorous grass carp (Ctenopharyngodon idella) fed a high-fat diet”, British Journal of Nutrition, Vol. 100, Cambridge University Press, pp. 1200-1212. doi:10.1017/S0007114508986840 Guo, X. et al. (2015) “Effects of lipid-lowering pharmaceutical clofibrate on lipid and lipoprotein metabolism of grass carp (Ctenopharyngodon idellal Val.) fed with the high non-protein energy diets”, Fish Physiology and Biochemistry, Vol. 41, Springer, pp. 331-343. doi: 10.1007/s10695-014-9986-8 Cerqueira, N. M., Oliveira, E. F., Gesto, D. S., Santos-Martins, D., Moreira, C., Moorthy, H. N., ... & Fernandes, P. A. (2016). Cholesterol biosynthesis: a mechanistic overview. Biochemistry, 55(39), 5483-5506. Prindiville, J.S. et al. (2011) “The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout”, Toxicology and Applied Pharmacology, Vol. 251, Elsevier, pp. 201-238. doi:10.1016/j.taap.2010.12.013 Pahan, K. (2006). Lipid-lowering drugs. Cellular and molecular life sciences CMLS, 63(10), 1165-1178. Risley, J. M. (2002). Cholesterol biosynthesis: Lanosterol to cholesterol. Journal of chemical education, 79(3), 377. Sonawane, P.D. et al. (2016) “Plant cholesterol biosynthetic pathway overlaps with phytosterol metabolism”, Nature Plants, Vol. 3, Nature Publishing Group, https://doi.org/10.1038/nplants.2016.205 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 Zhang, T. et al. (2019) “Evolution of the cholesterol biosynthesis pathway in animals”, Molecular Biology and Evolution, Vol. 36(11), Oxford University Press, pp. 2548-2556. doi:10.1093/molbev/msz167 Zhou, J. et al. (2015) "Rapid analysis of hypolipidemic drugs in a live zebrafish assay", Journal of Pharmacological and Toxicological Methods, Vol. 72, Elsevier, pp. 47-52. http://dx.doi.org/10.1016/j.vascn.2014.12.002 AOPWiki 2016-11-29T18:41:27

2022-05-24T11:10:52

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

Decreased, Viable Offspring

Individual

AOPWiki 2023-06-02T10:00:09

2023-06-02T10:00:09

<upstream-id>371b3ac5-ed98-4ddd-be82-dc5227400e08</upstream-id> <downstream-id>f2521f2b-1538-47ee-a251-6e03b3e4dbcf</downstream-id> PPARα is a nuclear receptor. With an agonist it promotes transcription of many genes, several of which are involved in cholesterol transport and metabolism (reviewed in Rakhshandehroo et al., 2010). Hydrophobic lipid molecules (such as cholesterol, cholesteryl ester, and triglycerides) are transported in the aqueous plasma of organisms by forming lipoprotein complexes with apolipoproteins. There are different groups of lipoproteins which use different apolipoproteins and ratios of lipids: low-density (LDL), very low-density (VLDL), and high density (HDL). Fibrates are a class of drug that agonize PPARα to lower LDL and VLDL while slightly increasing HDL in humans (Singh & Correa, 2020).

See below.

There are 4 proposed mechanisms through which PPARα agonists [fibrates] lower cholesterol in humans (Staels et al., 1998; Chruściel et al., 2015): <ol> <li>Increasing lipoprotein lipase (LPL) and decreasing its inhibitor, APOC3. LPL catabolizes triglycerides in VLDL which lowers the amount VLDL.</li> <li>Formation of LDL with a higher affinity for the LDL receptor resulting in increased cellular uptake and breakdown of LDL.</li> <li>Reduced cholesterol ester transfer protein (CEPT) expression. CEPT transfers cholesteryl ester and triglycerides between HDL and VLDL</li> <li>Increased APOA1 and APOA2, the protein components of HDL, in the liver causing increased production of HDL.</li> </ol>

<table border="1" cellpadding="0" cellspacing="0" style="width:800px"> <tbody> <tr> <td style="width:120px"> Speies </td> <td style="width:156px"> PPARα Agonist </td> <td style="width:108px"> Total CHL </td> <td style="width:84px"> HDL </td> <td style="width:90px"> LDL </td> <td style="width:56px"> VLDL </td> <td style="width:94px"> Citation </td> </tr> <tr> <td style="width:120px"> Adult Nile tilapia (O. niloticus) </td> <td style="width:156px"> 200 mg fenofibrate/kg BW for 4 weeks </td> <td style="width:108px"> decreased </td> <td style="width:84px"> increased </td> <td style="width:90px"> n.s. </td> <td style="width:56px"> -- </td> <td style="width:94px"> Ning et al. 2017 </td> </tr> <tr> <td style="width:120px"> Juvenile female rainbow trout (O. mykiss) </td> <td style="width:156px"> 100 mg gemfibrozil/kg BW every 3 days for 15 days </td> <td style="width:108px"> -22% </td> <td style="width:84px"> -27% </td> <td style="width:90px"> -34% </td> <td style="width:56px"> -58% </td> <td style="width:94px"> Prindiville et al. 2011 </td> </tr> <tr> <td style="width:120px"> Medaka (O. latipes) embryos </td> <td style="width:156px"> 0.04 – 3.7 mg gemfibrozil /L for 155 days </td> <td style="width:108px"> n.s. </td> <td style="width:84px"> -- </td> <td style="width:90px"> -- </td> <td style="width:56px"> -- </td> <td rowspan="2" style="width:94px"> Lee et al. 2019 </td> </tr> <tr> <td style="width:120px"> Medaka (O. latipes) adults </td> <td style="width:156px"> 0.04 – 3.7 mg gemfibrozil /L for 21 days </td> <td style="width:108px"> n.s. (females) decreased (males) </td> <td style="width:84px"> -- </td> <td style="width:90px"> -- </td> <td style="width:56px"> -- </td> </tr> <tr> <td style="width:120px"> Adult zebrafish (D. rerio) </td> <td style="width:156px"> 16 mg gemfibrozil/kg BW per day for 30 days </td> <td style="width:108px"> -15% (females) -19% (males) </td> <td style="width:84px"> -- </td> <td style="width:90px"> -- </td> <td style="width:56px"> -- </td> <td style="width:94px"> Al-Habsi et al. 2016 </td> </tr> <tr> <td style="width:120px"> Adult Male Zebrafish (D. rerio) </td> <td style="width:156px"> 35, 667, & 1428 mg bezafibrate/kg BW for 48 hours, 7 days, & 21 days </td> <td style="width:108px"> -30% by 21 days, all doses </td> <td style="width:84px"> -- </td> <td style="width:90px"> -- </td> <td style="width:56px"> -- </td> <td style="width:94px"> Velasco-Santamaría et al. 2011 </td> </tr> <tr> <td style="width:120px"> Juvenile grass carp (C. idella) fed HFD </td> <td style="width:156px"> 100 mg fenofibrate/kg BW per day for 2 weeks </td> <td style="width:108px"> -22% </td> <td style="width:84px"> n.s. </td> <td style="width:90px"> -45% </td> <td style="width:56px"> -- </td> <td style="width:94px"> Du et al. 2008 </td> </tr> <tr> <td style="width:120px"> Adult grass carp (C. idella) fed HFD or HCD </td> <td style="width:156px"> 50 mg clofibrate/kg BW per day for 4 weeks </td> <td style="width:108px"> -28% (both) </td> <td style="width:84px"> -9% (HCD) -16% (HFD) </td> <td style="width:90px"> -23% (HCD) -34% (HFD) </td> <td style="width:56px"> -- </td> <td style="width:94px"> Guo et al. 2015 </td> </tr> <tr> <td style="width:120px"> Adult fathead minnow (P. promelas) </td> <td style="width:156px"> 1 mg/L clofibric acid for 21 days </td> <td style="width:108px"> Decreased (females) n.s. (males) </td> <td style="width:84px"> n.s. </td> <td style="width:90px"> n.s. </td> <td style="width:56px"> -- </td> <td style="width:94px"> Runnalls et al. 2007 </td> </tr> <tr> <td style="width:120px"> Juvenile Turbot (S. maximus) </td> <td style="width:156px"> 5 or 50 mg WY-14,643/kg BW for 7 or 21 days </td> <td style="width:108px"> decreased </td> <td style="width:84px"> decreased </td> <td style="width:90px"> -- </td> <td style="width:56px"> -- </td> <td style="width:94px"> Urbatzka et al. 2015 </td> </tr> </tbody> </table> Table 1: Concordance Table for Teleost Fish. Body Weight (BW), Not Significant (n.s.), Cholesterol (CHL), High Fat Diet (HFD), High Carbohydrate Diet (HCD)

Although humans taking fibrate medications show lowed LDL and VLDL but slightly increased HDL, this pattern is not seen in fish (Prindiville et al., 2011). The exact reason(s) why is not well understood.

Modulating factors haven't been evaluated yet.

See below

After a 7 day exposure to bezafibrate (BZF), male zebrafish exposed to 1.7 mg BZF/g food showed no significant decrease in plasma cholesterol (p>0.05). However, those exposed to 33 and 70 mg BZF/g food showed a 25 and 48% reduction, respectively, in plasma cholesterol (p=0.04 and p<0.001, respectively) (Velasco-Santamaría et al., 2011).

Lowered cholesterol in adult male zebrafish due to bezafibrate exposure can be seen after 7 days, but not after just 48 hours (Velasco-Santamaría et al., 2011).

Feedback/feedforward loops haven't been evaluated yet.

High Male Moderate Female

High

Adults

High High High Moderate

TAXONOMIC APPLICABILITY The understanding of the effects of PPARα agonists on cholesterol primarily comes from studies on mice and humans to develop pharmaceuticals. However, lowered cholesterol in response to a PPARα agonist occurs in other mammals including rats, dogs, and guinea pigs at low, non-toxic doses (Meyer et al., 1999). There are several studies showing that in fish PPARα agonism decreases cholesterol via the same mechanisms as in humans:  <ol> <li>LPL is conserved in zebrafish (NCBI). It is increased in several fish species exposed to PPARα agonists (Prindiville et al., 2011; Teles et al., 2016; Guo et al., 2015)</li> <li>LDL is decreased in several fish species exposed to PPARα agonists (see Table 1)</li> <li>CETP is conserved in zebrafish (NCBI)</li> <li>APOA1 is conserved in zebrafish (NCBI). However, results are mixed on the effects of PPARα agonists on APOA1 (Corcoran et al., 2015; Teles et al., 2016) and HDL (see table 1) . In mice APOA1 is not regulated by PPARα (Staels & Auwerx, 1998), so this may be the case in fish.</li> </ol> SEX APPLICABILITY Male and female mice show different effects in several endpoints, including total cholesterol, in response to fibrate administration. This is likely due to estrogen partially and indirectly inhibiting PPARα (Yoon, 2010; Jeong & Yoon, 2012). In fish, males and females often show differing effects on cholesterol (Lee et al., 2019; Runnalls et al., 2007).

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43005c9950> AOPWiki 2020-04-06T10:42:26

2020-05-01T11:10:03

<upstream-id>f2521f2b-1538-47ee-a251-6e03b3e4dbcf</upstream-id> <downstream-id>9c0b09fa-2c28-4c83-8e35-c7fcb47c634e</downstream-id> The cholesterol molecule is the precursor for all steroid hormone synthesis. Cholesterol is obtained from de novo synthesis within cells or uptake of extracellular cholesterol (Eacker et al., 2008), however the dependence on either source varies by species (Klinefelter et al., 2014). Cholesterol is then transported into the inner mitochondrial membrane via the steroidogenic acute regulatory protein (StAR). Cholesterol is then converted to pregnenolone via the enzyme cytochrome P450 side-chain cleavage (cyp11a1). This is the rate-limiting step of steroidogenesis (Arukwe, 2008). Pregnenolone is then used to produce all other steroid hormones. 11-KT is synthesized from testosterone primarily using the enzymes CYP11β1 and HSD11β2 (Yazawa et al., 2008).

<table border="1" cellpadding="0" cellspacing="0"> <tbody> <tr> <td style="width:62px"> Time </td> <td style="width:124px"> Dose </td> <td style="width:150px"> Decreased Cholesterol? </td> <td style="width:132px"> Decreased 11-KT? </td> <td style="width:90px"> Citation </td> <td style="width:66px"> Species </td> </tr> <tr> <td style="width:62px"> 48 hours </td> <td style="width:124px"> 1.7, 33, & 70 mg/g Bezafibrate </td> <td style="width:150px"> No </td> <td style="width:132px"> No </td> <td rowspan="4" style="width:90px"> Velasco-Santamaría et al. 2011 </td> <td rowspan="4" style="width:66px"> Danio Rerio </td> </tr> <tr> <td style="width:62px"> 7 days </td> <td style="width:124px"> 33 & 70 mg/g Bezafibrate </td> <td style="width:150px"> Yes </td> <td style="width:132px"> No </td> </tr> <tr> <td style="width:62px"> 21 days </td> <td style="width:124px"> 1.7 & 33 mg/g Bezafibrate </td> <td style="width:150px"> Yes </td> <td style="width:132px"> No </td> </tr> <tr> <td style="width:62px"> 21 days </td> <td style="width:124px"> 70 mg/g Bezafibrate </td> <td style="width:150px"> Yes </td> <td style="width:132px"> Yes </td> </tr> <tr> <td style="width:62px"> 67 days </td> <td style="width:124px"> 10 ug/L Gemfibrozil </td> <td colspan="2" style="width:282px"> Decreased ex vivo 11-KT production unless supplemented with 25OH-cholesterol </td> <td style="width:90px"> Fraz et al. 2018 </td> <td style="width:66px"> Danio Rerio </td> </tr> <tr> <td style="width:62px"> 21 days </td> <td style="width:124px"> 0.04 mg/L Gemfibrozil </td> <td style="width:150px"> Yes </td> <td style="width:132px"> No </td> <td rowspan="2" style="width:90px"> Lee et al. 2019 </td> <td rowspan="2" style="width:66px"> Oryzias latipes </td> </tr> <tr> <td style="width:62px"> 21 days </td> <td style="width:124px"> 0.4 & 3.7 mg/L Gemfibrozil </td> <td style="width:150px"> Yes </td> <td style="width:132px"> Yes </td> </tr> </tbody> </table>

The process of steroid hormone biosynthesis is well understood, and cholesterol is the precursor for all steroid hormones.

<h3>Dose Concordance</h3> In male zebrafish bezafibrate lowers cholesterol in lower doses than 11KT (Velasco-Santamaría et al. 2011). In male medaka gemfibrozil lowers cholesterol in a lower dose than 11KT (Lee et al. 2019) <h3>Temporal Concordance</h3> Male zebrafish fed bezafibrate show lowered cholesterol days before lowered 11KT (Velasco-Santamaría et al. 2011). <h3>Incidence Concordance</h3> Fraz et al. (2018) show reduced ex vivo production of 11KT in male Zebrafish, due to gemfibrozil exposure, is corrected by addition of 25-hydroxycholesterol. This means the decreased steroid synthesis is due to decreased cholesterol availability. Addition of human chorionic gonadotropin, which binds to the LHCG receptor to promote 11KT synthesis, does not correct the decrease in 11KT.

Although Al-Habsi et al. (2016) show female zebrafish exposed to gemfibrozil and/or atorvastatin have decreased cholesterol and testosterone, decreased testosterone was not seen in males. Although several papers show 11KT is generally correlated with testosterone concentrations (Spanò et al., 2004; Maclatchy & Vanderkraak 1995; Lorenzi et al., 2008), it’s uncertain if 11KT was actually affected. 11KT levels can have high variability between fish. Although Lee et al. (2019) shows a decrease in testosterone and 11KT in a 21-day study, steroid measurements from the 155-day study showed no significant effects. This is possibly due to limited samples size (n=3-5).

Velasco-Santamaría et al. (2011) sampled male zebrafish fed several doses of bezafibrate (1.7, 33, & 70 mg BZF/g food) at several timepoints (48 hours, 7 days, and 21 days). Decreased plasma cholesterol is observed after 7 days to 33 mg/g. However, 11-KT isn’t significantly decreased until 21 days to 70 mg/g. There is a positive linear correlation between cholesterol and 11KT (r=0.291, p=0.0004). These decreases are observed without significant changes to cyp11a1 or StAR. Male medaka exposed to gemfibrozil for 21 days show decreased cholesterol with doses of 0.03, 0.3, and 3.0 mg/L. However, decreases in 11KT is only significant at doses of 0.3 and 3.0 mg/L (Lee et al. 2019).

Decreases in cholesterol in Zebrafish due to bezafibrate exposure can be seen after 7 days, however, decreases in plasma 11-KT aren’t significant until 14 days later (Velasco-Santamaría et al. 2011). A six-week exposure to gemfibrozil, a cholesterol-lowering pharmaceutical, is sufficient to lower 11-KT levels in the plasma, testes, and whole-body samples of male Zebrafish (Fraz et al. 2018). A 21-day exposure to gemfibrozil is sufficient to lower plasma cholesterol and 11-KT levels in male Japanese Medaka (Lee et al. 2019).

Decreases in plasma cholesterol are correlated with a slight increase in StAR in zebrafish (Velasco-Santamaría et al. 2011). This is a possible compensatory mechanism to increase the amount of cholesterol in the mitochondria.

High Male Low Female High Low

Taxanomic Applicability: The understanding of steroid hormone biosynthesis is developed from human and rodent studies but is generally conserved among vertebrates. Cyp11a1, which performs the first step of converting cholesterol to steroid hormones, is only found in vertebrates (Slominski et al., 2015). However, the relationship may not be relevant or studied in organisms in which 11KT isn't a primary androgen. 11KT is particularly relevant teleost fish as it is the dominant androgen and involved in testicular development and courtship behavior (Brantley et al., 1993; Barannikova et al., 2004; Gemmell et al., 2019). Evidence supporting this KER comes from a few fish species, including zebrafish and medaka, but is biologically plausible for all teleost fish. Sex Applicability: Male and female fish use the same biological processes to produce steroids and express the necessary enzymes. In most fish species 11KT is significantly lower in females versus males, however a a few species of the order Perciformes show no sexual dimorphism (Lokman et al. 2002). In species with sexual dimorphism, males could show more significant effects resulting from lowered 11-KT than females. Decreased production of 11-KT in females may not be detectable due to low baseline production, however there are few studies available showing the relationship between cholesterol and 11KT in female fish.  Life-Stage Applicability:

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430069ccb0> AOPWiki 2020-03-23T11:10:17

2020-05-06T09:31:22

<upstream-id>9c0b09fa-2c28-4c83-8e35-c7fcb47c634e</upstream-id> <downstream-id>fe95dd27-3eae-481f-9633-c426409d2836</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:0x00007b4308a00110> AOPWiki 2020-04-16T12:14:55

2021-04-19T13:32:05

<upstream-id>fe95dd27-3eae-481f-9633-c426409d2836</upstream-id> <downstream-id>b16fb8f9-82e2-4691-ab46-c941b81094cd</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc6143f0> AOPWiki 2023-06-02T10:04:25

2023-06-02T10:04:25

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc7155b0> AOPWiki 2023-06-02T10:04:51

2023-06-02T10:04:51

PPARalpha Agonism Leading to Decreased Viable Offspring via Decreased 11-Ketotestosterone

PPARa Agonism Impairs Fish Reproduction

Arthur Author

Ashley Kittelson, ORISE participant at US Environmental Protection Agency John Hoang, ORISE participant at US Environmental Protection Agency Robin Kutsi, ORISE participant at US Environmental Protection Agency

BY-SA

2.0

Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor. Along with retinoid x receptor (RXR) and a ligand, it promotes transcription of many genes including those involve in fatty acid β-oxidation and cholesterol metabolism. Fibrates are synthetic ligands of PPARα prescribed to lower cholesterol in humans. In fish this decrease in cholesterol causes a decrease in reproductive hormones, notably 11-ketotestosterone. This impairs the fish’s ability to reproduce. Fibrates’ effects on fish are relevant as they’re present in the environment.

Fibrates are ligands of PPARα (Staels et al. 1998). Phthalates MHEP (CAS 4376-20-9) directly binds in vitro to PPARα (Lapinskas et al. 2005) and activates this receptor in transactivation assays PPARα (Lapinskas et al. 2005), (Maloney and Waxman 1999), (Hurst and Waxman 2003), (Bility et al. 2004), (Lampen, Zimnik, and Nau 2003), (Venkata et al. 2006) ]. DEHP (CAS 117-81-7) has not been found to bind and activate PPARα (Lapinskas et al. 2005), (Maloney and Waxman 1999). However, the recent studies shown activation of PPARα (ToxCastTM Data). Notably, PPARα are responsive to DEHP in vitro as they are translocated to the nucleus (in primary Sertoli cells) (Dufour et al. 2003), (Bhattacharya et al. 2005). Expression of PPARα [mRNA and protein] has been reported to be also modulated by phthtalates: (to be up-regulated in vivo upon DEHP treatment (Xu et al. 2010) and down-regulated by Diisobutyl phthalate (DiBP) (Boberg et al. 2008)). Perfluorooctanoic Acid (PFOA) is known to activate PPARα (Vanden Heuvel et al. 2006). Organotin Tributyltin (TBT) activates all three heterodimers of PPAR with RXR, primarily through its interaction with RXR (le Maire et al. 2009)

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

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

High adjacent

Not Specified

Not Specified adjacent

Not Specified

High Male

High

Adult

High

<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>

AOPWiki 2020-04-09T10:47:50

2023-09-25T16:27:02