Antagonism, Androgen receptor

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

131983-72-7

PPDBOQMNKNNODG-UHFFFAOYNA-N

PPDBOQMNKNNODG-UHFFFAOYSA-N

Triticonazole

5-[(4-Chlorophenyl)methylene]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol

DTXSID0032655

85509-19-9

FQKUGOMFVDPBIZ-UHFFFAOYSA-N

Flusilazole

NuStar

DTXSID3024235

133855-98-8

ZMYFCFLJBGAQRS-UHFFFAOYNA-N

ZMYFCFLJBGAQRS-UHFFFAOYSA-N

Epoxiconazole

DTXSID1040372

67747-09-5

TVLSRXXIMLFWEO-UHFFFAOYSA-N

Prochloraz

1H-Imidazole-1-carboxamide, N-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl]- BTS 40542-7877 N-propil-N-[2-(2,4,6-triclorofenoxi)etil]-1H-imidazol-1-carboxamida N-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl]-1H-imidazole-1-carboxamide N-Propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl-1H-imidazole-1-carboxamide N-Propyl-N-[2-(2,4,6-trichlorphenoxy)ethyl]-1H-imidazol-1-carboxamid Plocloraz Prelude Sportak Sportake

DTXSID4024270

60207-90-1

STJLVHWMYQXCPB-UHFFFAOYNA-N

STJLVHWMYQXCPB-UHFFFAOYSA-N

Propiconazole

ppz 1H-1,2,4-Triazole, 1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]- (.+-.)-1-[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl-methyl]-1H-1,2,4-triazole (.+-.)-1-[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole 1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole 1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolane-2-yl]methyl]-1H-1,2,4-triazole 1-[[2-(2,4-Dichlorphenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazol 1-[[2-(2,4-diclorofenil)-4-propil-1,3-dioxolan-2-il]metil]-1H-1,2,4-triazol Bamper 25EC Banner Maxx Cane Sett Treatment Fertilome Liquid Systemic Fungicide Microban PZ Microban S 2140 Mycostat P Proconazole PROPICONAZOL Tilt Premium Wocosen Technical Wocosin Wocosin 50TK

DTXSID8024280

107534-96-3

PXMNMQRDXWABCY-UHFFFAOYNA-N

PXMNMQRDXWABCY-UHFFFAOYSA-N

Tebuconazole

1H-1,2,4-Triazole-1-ethanol, .alpha.-(2-(4-chlorophenyl)ethyl)-.alpha. +- 1H-1,2,4-Triazole-1-ethanol, α-[2-(4-chlorophenyl)ethyl]-α-(1,1-dimethylethyl)- (.+-.)-Tebuconazole 1-(4-Chlorophenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-ylmethyl)pentan-3-ol 1H-1,2,4-Triazole-1-ethanol, α-[2-(4-chlorophenyl)ethyl]-α-(1,1-dimethylethyl)-, (.+-.)- 1H-1,2,4-Triazole-1-ethanol,α-[2-(4-chlorophenyl) ethyl]-α-(1,1-dimethylethyl)-, (.+-.)- BAY-HWG 1608 ETHANOL, α-[2-(4-CHLOROPHENYL)ETHYL]-α- (1,1-DIMETHYLETHYL)-1H-1,2,4-TRIAZOLE Ethyltrianol Etiltrianol Fenetrazole Folicur Microban S 2142 Microban TZ Preventol A 8 TEBUCONAZOL Tebuconazole Resp. HWG 1608 Terbutrazole α-[2-(4-Chlorophenyl)-ethyl]-α-(1,1-dimethylethyl)-1H-1,2,4-triazole-1-ethanol α-[2-(4-chlorophenyl)ethyl]-α-(1,1-dimethylethyl)-1H-1,2,4-triazole-1-ethanol α-tert-Butyl-α-(p-chlorophenethyl)-1H-1,2,4-triazole-1-ethanol

DTXSID9032113

427-51-0

UWFYSQMTEOIJJG-FDTZYFLXSA-N

Cyproterone acetate

3'H-Cyclopropa[1,2]pregna-1,4,6-triene-3,20-dione, 17-(acetyloxy)-6-chloro-1,2-dihydro-, (1β,2β)- 1,2α-Methylene-6-chloro-17α-acetoxy-4,6-pregnadiene-3,20-dione 1,2α-Methylene-6-chloro-pregna-4,6-diene-3,20-dione 17α-acetate 1,2α-Methylene-6-chloro-Δ4,6-pregnadien-17α-ol-3,20-dione acetate 17-acetate de 6-chloro-1-β,2-β-dihydro-17-hydroxy-3'H-cyclopropa[1,2]pregna-1,4,6-triene-3,20-dione 17-acetato de 6-cloro-1-β,2-β-dihidro-17-hidroxi-3'H-ciclopropa[1,2]pregna-1,4,6-trieno-3,20-diona 17α-Acetoxy-6-chloro-1α,2α-methylenepregna-4,6-diene-3,20-dione 3'H-Cyclopropa[1,2]pregna-1,4,6-triene-3,20-dione 3'H-Cyclopropa[1,2]pregna-1,4,6-triene-3,20-dione, 6-chloro-1β,2β-dihydro-17-hydroxy-, acetate 6-Chlor-1-β,2-β-dihydro-17-hydroxy-3'H-cyclopropa[1,2]pregna-1,4,6-trien-3,20-dion-17-acetat 6-Chloro-1,2α-methylene-17α-hydroxy-Δ6-progesterone acetate 6-Chloro-1,2α-methylene-6-dehydro-17α-hydroxyprogesterone acetate 6-Chloro-17-hydroxy-1α,2α-methylenepregna-4,6-diene-3,20-dione acetate 6-chloro-1-β,2-β-dihydro-17-hydroxy-3'H-cyclopropa[1,2]pregna-1,4,6-triene-3,20-dione 17-acetate Androcur Cyprostat Cyproterone 17-O-acetate Cyproterone 17α-acetate Cyproviron NSC 81430 Pregna-4,6-diene-3,20-dione, 6-chloro-17-hydroxy-1α,2α-methylene-, acetate

DTXSID5020366

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

94-26-8

QFOHBWFCKVYLES-UHFFFAOYSA-N

4-Hydroxybenzoic acid butyl ester

Butyl 4-hydroxybenzoate Benzoic acid, 4-hydroxy-, butyl ester 4-(Butoxycarbonyl)phenol 4-hidroxibenzoato de butilo 4-Hydroxybenzoate de butyle 4-HYDROXYBENZOESAEURE-BUTYLESTER 4-Hydroxybenzoic acid butyl ester Aseptoform Butyl BENZOATE, 4-HYDROXY-, BUTYL Benzoic acid, p-hydroxy-, butyl ester Butoben Butyl Butex Butyl chemosept BUTYL PARABEN Butyl parabens Butyl parasept Butyl Tegosept Butyl-4-hydroxybenzoat Mekkings B n-Butyl 4-hydroxybenzoate n-Butyl p-hydroxybenzoate n-Butylparaben Nipabutyl NSC 13164 NSC 8475 p-Hydroxybenzoic acid butyl ester P-OXYBUTYLBENZOATE Preserval B Solbrol B Tegosept B Tegosept Butyl Butyl p-hydroxybenzoate n-Butyl-p-hydroxybenzoate

DTXSID3020209

72-55-9

UCNVFOCBFJOQAL-UHFFFAOYSA-N

p,p'-DDE

1,1-Dichloro-2,2-bis(4-chlorophenyl)ethene p,p'-Dichlorodiphenyl dichloroethylene Benzene, 1,1'-(dichloroethenylidene)bis[4-chloro- 1,1'-(Dichloroethenylidene)bis(4-chlorobenzene) 1,1-Bis(4-chlorophenyl)-2,2-dichloroethene 1,1-BIS-(4-CHLORPHENYL)-2,2-DICHLOR-AETHEN 1,1-Bis(p-chlorophenyl)-2,2-dichloroethylene 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene 1,1-Dichloro-2,2-di(p-chlorophenyl)ethylene 2,2-bis(4-Chlorophenyl)-1,1-dichloroethylene 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene 2,2-Bis(p-chlorphenyl)-1,1-dichlorethylen 2,2-bis(p-clorofenil)-1,1-dicloroetileno 2,2-Dichloro-1,1-bis(4-chlorophenyl)ethylene 4,4'-Dichlorodiphenyldichloroethylene Benzene, 1,1'-(2,2-dichloroethenylidene)bis[4-chloro- Benzene, 1,1'-(dichloroethenylidene)bis(4-chloro- Dichloro diphenyl dichloroethane DICHLORODIPHENYLDICHLOROETHYLENE Ethylene, 1,1-dichloro-2,2-bis(p-chlorophenyl)- Ethylene, 1,1-dichloro-2,2-bis(p-chlorophenyl)-, NSC 1153 p,p'-Dichlorodiphenyldichloroethylene

DTXSID9020374

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

50-02-2

UREBDLICKHMUKA-CXSFZGCWSA-N

Dexamethasone

Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-, (11beta,16alpha)- (11beta,16alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione 16alpha-Methyl-9alpha-fluoro-1,4-pregnadiene-11beta,17alpha,21-triol-3,20-dione 16alpha-Methyl-9alpha-fluoro-11beta,17alpha,21-trihydroxypregna-1,4-diene-3,20-dione 16alpha-Methyl-9alpha-fluoroprednisolone 16alpha-Methyl-9alpha-fluoro-delta1-hydrocortisone 1-Dehydro-16alpha-methyl-9alpha-fluorohydrocortisone 9-Fluoro-11beta,17,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione 9alpha-Fluoro-11beta,17alpha,21-trihydroxy-16alpha-methyl-1,4-pregnadiene-3,20-dione 9alpha-Fluoro-16alpha-methyl-1,4-pregnadiene-11beta,17alpha,21-triol-3,20-dione 9alpha-Fluoro-16alpha-methyl-11beta,17,21-trihydroxypregna-1,4-diene-3,20-dione 9alpha-Fluoro-16alpha-methylprednisolone Adexone Aeroseb-Dex Aphtasolon Aphthasolone Calonat Corsone Cortisumman Decacort Decaderm Decadron A Decalix Decasone Dekacort Delipos Deltafluorene Dergramin Deronil Desadrene Desameton Deseronil Dexacort Dexacortal Dexa-Cortidelt Dexacortin Dexadeltone Dexafarma Dexalona Dexaltin Dexa-Mamallet dexametasona Dexameth Dexamethason Dexamethasone alcohol Dexamonozon Dexapolcort Dexapos Dexaprol Dexa-Scheroson Dexa-sine Dexason Dexasone Dexinoral Dexonium Dextelan Dinormon Etacortilen Fluormone Fluorocort Gammacorten Gentalipos Hexadecadrol Hexadrol Isopto-Dex Lokalison F Loverine Luxazone Maxidex Millicorten NSC 34521 Oradexon Pet-Derm III Prednisolon F Prednisolone F Pregna-1,4-diene-3,20-dione, 9-fluoro-11beta,17,21-trihydroxy-16alpha-methyl- Superprednol Surodex Visumetazone Aeroseb-D Anaflogistico Auxiron Bisu DS Decacortin Decadron Decaspray Dectancyl Desametasone Desamethasone Dexa Mamallet Dexa-Cortisyl Dex-ide Dexinolon EINECS 200-003-9 Fluormethylprednisolone delta1-9alpha-Fluoro-16alpha-methylcortisol 4-alpha-Fluoro-16-alpha-methyl-11-beta,17,21-trihydroxypregna-1,4-diene-3,20-dione Mediamethasone 16alpha-Methyl-9alpha-fluoro-1-dehydrocortisol 16-alpha-Methyl-9-alpha-fluoro-1-dehydrocortisol 16-alpha-Methyl-9-alpha-fluoroprednisolone 16alpha-Methyl-9alpha-fluoro-delta(sup 1)-hydrocortisone 16-alpha-Methyl-9-alpha-fluoro-delta(sup 1)-hydrocortisone 16-alpha-Methyl-9-alpha-fluoro-11-beta,17-alpha,21-trihydroxypregna-1,4-diene-3,20-dione Mexidex Ocu-trol Pet Derm III Policort Prednisolone, 9alpha-fluoro-16alpha-methyl- SK-Dexamethasone Spoloven Sunia Sol D delta(sup 1)-9-alpha-Fluoro-16-alpha-methylcortisol Dexamethasone Intensol Dexone 0.75 Mymethasone Decaject Decaject-L.A. Decameth Methylfluorprednisolone Dexamethasonum UNII-7S5I7G3JQL Ozurdex

DTXSID3020384

122-14-5

ZNOLGFHPUIJIMJ-UHFFFAOYSA-N

Fenitrothion

Phosphorothioic acid, O,O-dimethylO-(3-methyl-4-nitrophenyl) ester Accothion Agriya 1050 Agrothion Arbogal Bayer 41831 Bayer S 5660 Dimethyl 4-nitro-m-tolyl phosphorothionate Fenition fenitrotion Fenutrithion Folithion Folithion EC 50 Insectigas F Metathion Metathion E 50 Metathione Metathionine E 50 Metation Metation E 50 Methadion Methylnitrophos Mglawik F Monsanto CP 47114 Nitrophos Nuvanol O, O-Dimethyl-O-(3-methyl-4-nitrophenyl) phosphorothioate O,O-DiMe O-(3-methyl-4-nitrophenyl) thiophosphate O,O-Dimethyl O-(3-methyl-4-nitrophenyl) phosphorothioate O,O-Dimethyl O-(3-methyl-4-nitrophenyl) thiophosphate O,O-Dimethyl O-(4-nitro-3-methylphenyl)thiophosphate O,O-Dimethyl O-4-nitro-m-tolyl phosphorothioate O,O-Dimethyl O-4-nitro-m-tolyl thiophosphate Oleometathion Oleosumifene Ovadofos Owadofos Owadophos Phenitrothion PHOSPHOROTHIOATE, O,O-DIMETHYL O-(3-METHYL- 4-NITROPHENYL) Phosphorothioic acid O,O-dimethyl O-(3-methyl-4-nitrophenyl) ester Phosphorothioic acid, O,O-dimethyl O-(3-methyl-4-nitrophenyl) ester Phosphorothioic acid, O,O-dimethyl O-(4-nitro-m-tolyl) ester Sumi oil Sumifene Sumigran Sumithion Sumithion 20F Sumithion 20MC Sumithion 50EC Super Sumithion Tionfos 50 LE Verthion

DTXSID4032613

65277-42-1

XMAYWYJOQHXEEK-OZXSUGGESA-N

Ketoconazole

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

DTXSID7029879

330-55-2

XKJMBINCVNINCA-UHFFFAOYSA-N

Linuron

Urea, N'-(3,4-dichlorophenyl)-N-methoxy-N-methyl- 1-(3,4-Dichlorophenyl)-3-methoxy-3-methylurea 1-Methoxy-1-methyl-3-(3,4-dichlorophenyl)urea 3-(3',4'-Dichlorophenyl)-1-methoxy-1-methylurea 3-(3,4-Dichlorophenyl)-1-methoxy-1-methylurea 3-(3,4-Dichlorophenyl)-1-methyl-1-methoxyurea Afalon inuron Alfalon Alfalone Aphalon Cephalon Du Pont 326 Du Pont Herbicide 326 Herbicide 326 Linurex Methoxydiuron N'-(3,4-Dichlorophenyl)-N-methoxy-N-methylurea N-(3,4-Dichlorophenyl)-N'-methoxy-N'-methylurea N-(3,4-Dichlorophenyl)-N'-methyl-N'-methoxyurea Sarclex Sinuron Urea, 3-(3,4-dichlorophenyl)-1-methoxy-1-methyl-

DTXSID2024163

32809-16-8

QXJKBPAVAHBARF-UHFFFAOYNA-N

QXJKBPAVAHBARF-UHFFFAOYSA-N

Procymidone

3-(3,5-Dichlorophenyl)-1,5-dimethyl-3-azabicyclo(3.1.0)hexane-2,4-dione 3-Azabicyclo[3.1.0]hexane-2,4-dione, 3-(3,5-dichlorophenyl)-1,5-dimethyl- 1,2-Cyclopropanedicarboximide, N-(3,5-dichlorophenyl)-1,2-dimethyl- 1,2-Dimethyl-N-(3,5-dichlorophenyl)cyclopropanedicarboximide 3-(3,5-dichlorophenyl)-1,5-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione 3-(3,5-Dichlorphenyl)-1,5-dimethyl-3-azabicyclo[3.1.0]hexan-2,4-dion 3-(3,5-diclorofenil)-1,5-dimetil-3-azabiciclo[3.1.0]hexano-2,4-diona Dicyclidine Kenolex N-(3,5-Dichlorophenyl)-1,2-dimethyl-1,2-cyclopropanedicarboximide N-(3,5-Dichlorophenyl)-1,2-dimethylcyclopropane-1,2-dicarboximide PROCYMIDON Procymidor Procymidox Salithiex Sumilex Sumilex 50WP Sumisclex

DTXSID9033923

84-61-7

VOWAEIGWURALJQ-UHFFFAOYSA-N

Dicyclohexyl phthalate

1,2-Benzenedicarboxylic acid, dicyclohexyl ester

DTXSID5025021

FMA:264621

FMA Musculature of male perineum

GO:0030521

GO androgen receptor signaling pathway

WIKI disrupted

Finasteride

2016-11-29T18:42:27

Flutamide

2016-11-29T18:42:27

Mercaptobenzole

2016-11-29T18:42:26

Triticonazole

2020-05-16T11:02:07

2020-05-16T11:09:42

Flusilazole

2020-05-16T11:15:34

Epoxiconazole

2020-05-16T11:35:44

Prochloraz

2016-11-29T18:42:22

Propiconazole

2017-05-17T13:18:07

Tebuconazole

2017-05-17T13:17:14

Cyproterone acetate

2020-05-17T10:13:28

Vinclozolin

2020-05-14T11:28:31

Butylparaben

2020-05-18T12:14:36

p,p'-DDE

2020-05-18T12:15:23

Bis(2-ethylhexyl) phthalate

2016-11-29T18:42:08

Dexamethasone

2019-06-01T00:56:52

Fenitrothion

2020-05-18T12:51:25

Ketoconazole

2017-05-02T11:08:42

Linuron

2020-05-18T12:53:54

Procymidone

2020-05-18T12:55:12

di-n-hexyl phthalate CAS Number: 84-75-3; Synonym: 1,2-Benzenedicarboxylic acid 1,2-dihexyl ester

2020-05-18T14:34:22

2020-05-18T14:36:56

Dicyclohexyl phthalate

2020-05-18T14:41:46

butyl benzyl phthalate

2020-05-18T14:46:29

monobenzyl phthalate

2020-05-18T14:49:44

di-n-heptyl phthalate

2020-05-18T15:01:03

WCS_9606

common toxicological species human

10090

NCBI mouse

10116

NCBI rat

WikiUser_25

Wikiuser: Cyauk human and other cells in culture

Antagonism, Androgen receptor

Molecular

The androgen receptor (AR) and its function Development of the male reproductive system and secondary male characteristics is dependent on androgens (foremost testosterone (T) and dihydrotestosterone (DHT). T and the more biologically active DHT act by binding to the AR (<a href="#_ENREF_4" title="MacLean, 1993 #251">MacLean et al, 1993</a>; <a href="#_ENREF_5" title="MacLeod, 2010 #27">MacLeod et al, 2010</a>; <a href="#_ENREF_8" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>), with human AR mutations and mouse knock-out models having established its pivotal role in masculinization and spermatogenesis (<a href="#_ENREF_9" title="Walters, 2010 #254">Walters et al, 2010</a>). The AR is a ligand-activated transcription factor belonging to the steroid hormone nuclear receptor family (<a href="#_ENREF_1" title="Davey, 2016 #250">Davey & Grossmann, 2016</a>). The AR has three domains; the N-terminal domain, the DNA-binding domain and the ligand-binding domain, with the latter being most evolutionary conserved. Apart from the essential role AR plays for male reproductive development and function (<a href="#_ENREF_9" title="Walters, 2010 #254">Walters et al, 2010</a>), the AR is also expressed in many other tissues and organs such as bone, muscles, ovaries and the immune system (<a href="#_ENREF_7" title="Rana, 2014 #253">Rana et al, 2014</a>).  AR antagonism as Key Event The main function of the AR is to activate gene transcription in cells. Canonical signaling occurs by ligands (androgens) binding to AR in the cytoplasm which results in translocation to the cell nucleus, receptor dimerization and binding to specific regulatory DNA sequences (<a href="#_ENREF_2" title="Heemers, 2007 #255">Heemers & Tindall, 2007</a>). The gene targets regulated by AR activation depends on cell/tissue type and what stage of development activation occur, and is, for instance, dependent on available co-factors. Apart from the canonical signaling pathway, AR can also function through non-genomic modalities, for instance rapid change in cell function by ion transport changes (<a href="#_ENREF_3" title="Heinlein, 2002 #256">Heinlein & Chang, 2002</a>). However, with regard to this specific KE the canonical signaling pathway is what is referred to.

AR antagonism can be measured in vitro by transient or stable transactivation assays to evaluate nuclear receptor activation. There is already a validated assay for AR (ant)agonism adopted by the OECD, Test No. 458: Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals (<a href="#_ENREF_13" title="OECD, 2016 #257">OECD, 2016</a>). The stably transfected AR-EcoScreenTM cells (<a href="#_ENREF_15" title="Satoh, 2004 #280">Satoh et al, 2004</a>) should be used for the assay and is freely available for the Japanese Collection of Research Bioresources (JCRB) Cell Bank under reference number JCRB1328. Other assays include the AR-CALUX reporter gene assay that is derived from human U2-OS cells stably transfected with the human AR and an AR responsive reporter gene (<a href="#_ENREF_18" title="van der Burg, 2010 #261">van der Burg et al, 2010</a>), various transiently transfected reporter cell lines (<a href="#_ENREF_10" title="Körner, 2004 #282">Körner et al, 2004</a>), and more. Recently developed AR dimerization assay may soon be included in TGs for its improved ability to measure potential stressor-mediated dimerization/activation (<a href="#_ENREF_11" title="Lee, 2021 #288">Lee et al, 2021</a>).

Both the DNA-binding and ligand-binding domains of the AR are highly evolutionary conserved, whereas the transactivation domain show more divergence which may affect AR-mediated gene regulation across species (<a href="#_ENREF_1" title="Davey, 2016 #250">Davey & Grossmann, 2016</a>). Despite certain inter-species differences, AR function mediated through gene expression is highly conserved, with mutations studies from both humans and rodents showing strong correlation for AR-dependent development and function (<a href="#_ENREF_9" title="Walters, 2010 #254">Walters et al, 2010</a>). This KE is applicable for both sexes, across developmental stages into adulthood, in numerous cells and tissues and across taxa

CL:0000255

CL eukaryotic cell

High Mixed

High

Foetal

Moderate

Embryo

High

During development and at adulthood

High High High High <a name="_ENREF_1">Alapi EM, Fischer J (2006) Table of Selected Analogue Classes. In Analogue-based Drug Discovery, Fischer J, Ganellin CR (eds), p 515. Weinheim: Wiley-VCH Verlag GmbH & Co</a> <a name="_ENREF_2">Davey RA, Grossmann M (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev 37: 3-15</a> <a name="_ENREF_3">Draskau MK, Boberg J, Taxvig C, Pedersen M, Frandsen HL, Christiansen S, Svingen T (2019) In vitro and in vivo endocrine disrupting effects of the azole fungicides triticonazole and flusilazole. Environ Pollut 255: 113309</a> <a name="_ENREF_4">Foster PM, Harris MW (2005) Changes in androgen-mediated reproductive development in male rat offspring following exposure to a single oral dose of flutamide at different gestational ages. Toxicol Sci 85: 1024-1032</a> <a name="_ENREF_5">Hass U, Scholze M, Christiansen S, Dalgaard M, Vinggaard AM, Axelstad M, Metzdorff SB, Kortenkamp A (2007) Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. Environ Health Perspect 115 Suppl. 1: 122-128</a> <a name="_ENREF_6">Heemers HV, Tindall DJ (2007) Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev 28: 778-808</a> <a name="_ENREF_7">Heinlein CA, Chang C (2002) The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol 16: 2181-2187</a> <a name="_ENREF_8">Kita DH, Meyer KB, Venturelli AC, Adams R, Machado DL, Morais RN, Swan SH, Gennings C, Martino-Andrade AJ (2016) Manipulation of pre and postnatal androgen environments and anogenital distance in rats. Toxicology 368-369: 152-161</a> <a name="_ENREF_9">Kjærstad MB, Taxvig C, Nellemann C, Vinggaard AM, Andersen HR (2010) Endocrine disrupting effects in vitro of conazole antifungals used as pesticides and pharmaceuticals. Reprod Toxicol 30: 573-582</a> <a name="_ENREF_10">Körner W, Vinggaard AM, Térouanne B, Ma R, Wieloch C, Schlumpf M, Sultan C, Soto AM (2004) Interlaboratory comparison of four in vitro assays for assessing androgenic and antiandrogenic activity of environmental chemicals. Environ Health Perspect 112: 695-702</a> <a name="_ENREF_11">Lee SH, Hong KY, Seo H, Lee HS, Park Y (2021) Mechanistic insight into human androgen receptor-mediated endocrine-disrupting potentials by a stable bioluminescence resonance energy transfer-based dimerization assay. Chem Biol Interact 349: 109655</a> <a name="_ENREF_12">MacLean HE, Chu S, Warne GL, Zajac JD (1993) Related individuals with different androgen receptor gene deletions. J Clin Invest 91: 1123-1128</a> <a name="_ENREF_13">MacLeod DJ, Sharpe RM, Welsh M, Fisken M, Scott HM, Hutchison GR, Drake AJ, van den Driesche S (2010) Androgen action in the masculinization programming window and development of male reproductive organs. Int J Androl 33: 279-287</a> <a name="_ENREF_14">OECD. (2016) Test No. 458: Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals. OECD Guidelines for the Testing of Chemicals, Section 4, Paris.</a> <a name="_ENREF_15">Rana K, davey RA, Zajac JD (2014) Human androgen deficiency: insights gained from androgen receptor knockout mouse models. Asian J Androl 16: 169-177</a> <a name="_ENREF_16">Satoh K, Ohyama K, Aoki N, Iida M, Nagai F (2004) Study on anti-androgenic effects of bisphenol a diglycidyl ether (BADGE), bisphenol F diglycidyl ether (BFDGE) and their derivatives using cells stably transfected with human androgen receptor, AR-EcoScreen. Food Chem Toxicol 42: 983-993</a> <a name="_ENREF_17">Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U, Svingen T (2019) Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. Arch Toxicol 93: 253-272</a> <a name="_ENREF_18">Sonneveld E, Jansen HJ, Riteco JA, Brouwer A, van der Burg B (2005) Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays. Toxicol Sci 83: 136-148</a>   <a name="_ENREF_19">van der Burg B, Winter R, Man HY, Vangenechten C, Berckmans P, Weimer M, Witters H, van der Linden S (2010) Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reprod Toxicol 30: 18-24</a> <a name="_ENREF_20">Vinggaard AM, Niemelä J, Wedebye EB, Jensen GE (2008) Screening of 397 chemicals and development of a quantitative structure--activity relationship model for androgen receptor antagonism. Chem Res Toxicol 21: 813-823</a> <a name="_ENREF_21">Walters KA, Simanainen U, Handelsman DJ (2010) Molecular insights into androgen actions in male and female reproductive function from androgen receptor knockout models. Hum Reprod Update 16: 543-558</a> AOPWiki 2016-11-29T18:41:22

2022-06-15T06:17:59

Decrease, androgen receptors (AR) activation

Decrease, AR activation

Cellular

Androgen receptor activation is regulated by the binding of androgens. AR activity can be decreased by either a lack of steroidal ligands (testosterone, DHT) or the presence of antagonist compounds. 12

Significance of AR signaling in fetal development can be studied through a conditional deletion of the androgen receptor using a Cre/loxP approach. The recommended animal model for reproductive study is the mouse.3 Also, epidemiological case-studies following mouse or humans expressing a complete androgen insensitivity allow to directly assess the effects of a lack of AR activation on the development.4 Enzyme immunoassay (ELISA) kits for in vitro quantitative measurement of AR activity are available. Androgen receptors activity can be measured using bioassay such as the (Anti-)Androgen Receptor CALUX reporter gene assay.5

<table> <tbody> <tr> <td colspan="1" rowspan="1">   </td> <td colspan="1" rowspan="1"> 1 Davey R.A and Grossmann M. (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clinical Biochemist Reviews, 37(1): 3-15. PCM4810760 2 Gao W., Bohl C.E. and Dalton J.T. (2005) Chemistry and Structural Biology of Androgen Receptor. Chemical Reviews 105(9): 3352-3370<a href="https://www.google.com/url?q=https://doi.org/10.1021/cr020456u&sa=D&ust=1554891396627000">https://doi.org/10.1021/cr020456u</a>  3 Kaftanovskaya E.M., Huang Z., Barbara A.M., De Gendt K., Verhoeven G., Ivan P. Gorlov, and Agoulnik A.I. (2012) Cryptorchidism in Mice with an Androgen Receptor Ablation in Gubernaculum Testis. Molecular Endocrinology, 26(4): 598-607.<a href="https://www.google.com/url?q=https://doi.org/10.1210/me.2011-1283&sa=D&ust=1554891396628000">https://doi.org/10.1210/me.2011-1283</a>  4 Hutson J.M. (1985) A biphasic model for the hormonal control of testicular descent. Lancet, 24;2(8452): 419-21<a href="https://www.google.com/url?q=http://dx.doi.org/10.1016/S0140-6736(85)92739-4&sa=D&ust=1554891396629000">http://dx.doi.org/10.1016/S0140-6736(85)92739-4</a>  5 van der Burg B., Winter R., Man HY., Vangenechten C., Berckmans P., Weimer M., Witters M. and van der Linden S. (2010) Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reproductive Toxicology, 30(1):18-24 <a href="https://www.google.com/url?q=https://doi.org/0.1016/j.reprotox.2010.04.012&sa=D&ust=1554891396630000">https://doi.org/0.1016/j.reprotox.2010.04.012</a>  </td> </tr> </tbody> </table> AOPWiki 2019-04-10T05:04:18

2019-04-10T05:24:20

decrease, transcription of genes by AR

Cellular

AOPWiki 2019-08-30T04:19:47

2019-08-30T04:19:47

anogenital distance (AGD), decreased

AGD, decreased

Tissue

The anogenital distance (AGD) refers to the distance between anus and the external genitalia. In rodents and humans, the male AGD is approximately twice the length as the female AGD (<a href="#_ENREF_39" title="Salazar-Martinez, 2004 #8">Salazar-Martinez et al, 2004</a>; <a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). This sexual dimorphisms is a consequence of sex hormone-dependent development of secondary sexual characteristics (<a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). In males, it is believed that androgens (primarily DHT) activate AR-positive cells in non-myotic cells in the fetal perineum region to initiate differentiation of the perineal levator ani and bulbocavernosus (LABC) muscle complex (<a href="#_ENREF_18" title="Ipulan, 2014 #185">Ipulan et al, 2014</a>). This AR-dependent process occurs within a critical window of development, around gestational days 15-18 in rats (<a href="#_ENREF_26" title="MacLeod, 2010 #27">MacLeod et al, 2010</a>). In females, the absence of DHT prevents this masculinization effect from occurring. The involvement of androgens in masculinization of the male fetus, including the perineum, has been known for a very long time (<a href="#_ENREF_20" title="Jost, 1953 #151">Jost, 1953</a>), and AGD has historically been used to, for instance, sex newborn kittens. It is now well established that the AGD in newborns is a proxy readout for the intrauterine sex hormone milieu the fetus was developing. Too low androgen levels in XY fetuses makes the male AGD shorter, whereas excess (ectopic) androgen levels in XX fetuses makes the female AGD longer, in humans and rodents (<a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>).

The AGD is a morphometric measurement carried out by trained technicians (rodents) or medical staff (humans). In rodent studies AGD is assessed as the distance between the genital papilla and the anus, and measured using a stereomicroscope with a micrometer eyepiece. The AGD index (AGDi) is often calculated by dividing AGD by the cube root of the body weight.  It is important in statistical analysis to use litter as the statistical unit. This is done when more than one pup from each litter is examined. Statistical analyses is adjusted using litter as an independent, random and nested factor. AGD are analysed using body weight as covariate as recommended in Guidance Document 151 (<a href="#_ENREF_37" title="OECD, 2013 #30">OECD, 2013</a>).

A short AGD in male offspring is a marker of insufficient androgen action during critical fetal developmental stages (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>; <a href="#_ENREF_49" title="Welsh, 2008 #23">Welsh et al, 2008</a>). A short AGD is thus a sign of undervirilization, which is also associated with a series of male reproductive disorders, including genital malformations and infertility in humans (<a href="#_ENREF_21" title="Juul, 2014 #3">Juul et al, 2014</a>; <a href="#_ENREF_44" title="Skakkebaek, 2001 #9">Skakkebaek et al, 2001</a>). There are numerous human epidemiological studies showing associations with intrauterine exposure to anti-androgenic chemicals and short AGD in newborn boys alongside other reproductive disorders (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). This underscores the human relevance of this AO. However, in reproductive toxicity studies and chemical risk assessment, rodents (rats and mice) are what is tested on. The list of chemicals inducing short male AGD in male rat offspring is extensive, as evidenced by the ‘stressor’ list and reviewed by (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>).

UBERON:0002356

UBERON perineum

High Male

High

Foetal

Moderate High High

<a name="_ENREF_1">Aydoğan Ahbab M, Barlas N (2015) Influence of in utero di-n-hexyl phthalate and dicyclohexyl phthalate on fetal testicular development in rats. Toxicol Lett 233: 125-137</a> <a name="_ENREF_2">Boberg J, Axelstad M, Svingen T, Mandrup K, Christiansen S, Vinggaard AM, Hass U (2016) Multiple endocrine disrupting effects in rats perinatally exposed to butylparaben. Toxicol Sci 152: 244-256</a> <a name="_ENREF_3">Boberg J, Metzdorff S, Wortziger R, Axelstad M, Brokken L, Vinggaard AM, Dalgaard M, Nellemann C (2008) Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats. Toxicology 250: 75-81</a> <a name="_ENREF_4">Bowman CJ, Barlow NJ, Turner KJ, Wallace DG, Foster PM (2003) Effects of in utero exposure to finasteride on androgen-dependent reproductive development in the male rat. Toxicol Sci 74: 393-406</a> <a name="_ENREF_5">Christiansen S, Boberg J, Axelstad M, Dalgaard M, Vinggaard AM, Metzdorff SB, Hass U (2010) Low-dose perinatal exposure to di(2-ethylhexyl) phthalate induces anti-androgenic effects in male rats. Reprod Toxicol 30: 313-321</a> <a name="_ENREF_6">Christiansen S, Scholze M, Dalgaard M, Vinggaard AM, Axelstad M, Kortenkamp A, Hass U (2009) Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. Environ Health Perspect 117: 1839-1846</a> <a name="_ENREF_7">Draskau MK, Boberg J, Taxvig C, Pedersen M, Frandsen HL, Christiansen S, Svingen T (2019) In vitro and in vivo endocrine disrupting effects of the azole fungicides triticonazole and flusilazole. Environ Pollut 255: 113309</a> <a name="_ENREF_8">Ema M, Miyawaki E (2002) Effects on development of the reproductive system in male offspring of rats given butyl benzyl phthalate during late pregnancy. Reprod Toxicol 16: 71-76</a> <a name="_ENREF_9">Ema M, Miyawaki E, Hirose A, Kamata E (2003) Decreased anogenital distance and increased incidence of undescended testes in fetuses of rats given monobenzyl phthalate, a major metabolite of butyl benzyl phthalate. Reprod Toxicol 17: 407-412</a> <a name="_ENREF_10">Foster PM, Harris MW (2005) Changes in androgen-mediated reproductive development in male rat offspring following exposure to a single oral dose of flutamide at different gestational ages. Toxicol Sci 85: 1024-1032</a> <a name="_ENREF_11">Gray LE, Jr., Ostby J, Furr J, Price M, Veeramachaneni DN, Parks L (2000) Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol Sci 58: 350-365</a> <a name="_ENREF_12">Gray LEJ, Ostby JS, Kelce WR (1994) Developmental effects of an environmental antiandrogen: the fungicide vinclozolin alters sex differentiation of the male rat. Toxicol Appl Pharmacol 129: 46-52</a> <a name="_ENREF_13">Hass U, Boberg J, Christiansen S, Jacobsen PR, Vinggaard AM, Taxvig C, Poulsen ME, Herrmann SS, Jensen BH, Petersen A, Clemmensen LH, Axelstad M (2012) Adverse effects on sexual development in rat offspring after low dose exposure to a mixture of endocrine disrupting pesticides. Reprod Toxicol 34: 261-274</a> <a name="_ENREF_14">Hass U, Scholze M, Christiansen S, Dalgaard M, Vinggaard AM, Axelstad M, Metzdorff SB, Kortenkamp A (2007) Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. Environ Health Perspect 115 Suppl. 1: 122-128</a> <a name="_ENREF_15">Hoshino N, Iwai M, Okazaki Y (2005) A two-generation reproductive toxicity study of dicyclohexyl phthalate in rats. J Toxicol Sci 30 Spec No: 79-96</a> <a name="_ENREF_16">Hotchkiss AK, Parks-Saldutti LG, Ostby JS, Lambright C, Furr J, Vandenbergh JG, Gray LEJ (2004) A mixture of the "antiandrogens" linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. Biol Reprod 71: 1852-1861</a> <a name="_ENREF_17">Howdeshell KL, Furr J, Lambright CR, Rider CV, Wilson VS, Gray LE, Jr. (2007) Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes. Toxicol Sci 99: 190-202</a> <a name="_ENREF_18">Ipulan LA, Suzuki K, Sakamoto Y, Murashima A, Imai Y, Omori A, Nakagata N, Nishinakamura R, Valasek P, Yamada G (2014) Nonmyocytic androgen receptor regulates the sexually dimorphic development of the embryonic bulbocavernosus muscle. Endocrinology 155: 2467-2479</a> <a name="_ENREF_19">Jarfelt K, Dalgaard M, Hass U, Borch J, Jacobsen H, Ladefoged O (2005) Antiandrogenic effects in male rats perinatally exposed to a mixture of di(2-ethylhexyl) phthalate and di(2-ethylhexyl) adipate. Reprod Toxicol 19: 505-515</a> <a name="_ENREF_20">Jost A (1953) Problems of fetal endocrinology: The gonadal and hypophyseal hormones. Recent Prog Horm Res 8: 379-418</a> <a name="_ENREF_21">Juul A, Almstrup K, Andersson AM, Jensen TK, Jorgensen N, Main KM, Rajpert-De Meyts E, Toppari J, Skakkebaek NE (2014) Possible fetal determinants of male infertility. Nat Rev Endocrinol 10: 553-562</a> <a name="_ENREF_22">Kita DH, Meyer KB, Venturelli AC, Adams R, Machado DL, Morais RN, Swan SH, Gennings C, Martino-Andrade AJ (2016) Manipulation of pre and postnatal androgen environments and anogenital distance in rats. Toxicology 368-369: 152-161</a> <a name="_ENREF_23">Laier P, Metzdorff SB, Borch J, Hagen ML, Hass U, Christiansen S, Axelstad M, Kledal T, Dalgaard M, McKinnell C, Brokken LJ, Vinggaard AM (2006) Mechanisms of action underlying the antiandrogenic effects of the fungicide prochloraz. Toxicol Appl Pharmacol 213: 2</a> <a name="_ENREF_24">Li M, Qiu L, Zhang Y, Hua Y, Tu S, He Y, Wen S, Wang Q, Wei G (2013) Dose-related effect by maternal exposure to di-(2-ethylhexyl) phthalate plasticizer on inducing hypospadiac male rats. Environ Toxicol Pharmacol 35: 55-60</a> <a name="_ENREF_25">Lin H, Lian QQ, Hu GX, Jin Y, Zhang Y, Hardy DO, Chen GR, Lu ZQ, Sottas CM, Hardy MP, Ge RS (2009) In utero and lactational exposures to diethylhexyl-phthalate affect two populations of Leydig cells in male Long-Evans rats. Biol Reprod 80: 882-888</a> <a name="_ENREF_26">Loeffler IK, Peterson RE (1999) Interactive effects of TCDD and p,p'-DDE on male reproductive tract development in in utero and lactationally exposed rats. Toxicol Appl Pharmacol 154: 28-39</a> <a name="_ENREF_27">MacLeod DJ, Sharpe RM, Welsh M, Fisken M, Scott HM, Hutchison GR, Drake AJ, van den Driesche S (2010) Androgen action in the masculinization programming window and development of male reproductive organs. Int J Androl 33: 279-287</a> <a name="_ENREF_28">Matsuura I, Saitoh T, Ashina M, Wako Y, Iwata H, Toyota N, Ishizuka Y, Namiki M, Hoshino N, Tsuchitani M (2005) Evaluation of a two-generation reproduction toxicity study adding endpoints to detect endocrine disrupting activity using vinclozolin. J Toxicol Sci 30 Spec No: 163-168</a> <a name="_ENREF_29">McIntyre BS, Barlow NJ, Foster PM (2001) Androgen-mediated development in male rat offspring exposed to flutamide in utero: permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependent tissues. Toxicol Sci 62: 236-249</a> <a name="_ENREF_30">McIntyre BS, Barlow NJ, Sar M, Wallace DG, Foster PM (2002) Effects of in utero linuron exposure on rat Wolffian duct development. Reprod Toxicol 16: 131-139</a> <a name="_ENREF_31">Melching-Kollmuss S, Fussell KC, Schneider S, Buesen R, Groeters S, Strauss V, van Ravenzwaay B (2017) Comparing effect levels of regulatory studies with endpoints derived in targeted anti-androgenic studies: example prochloraz. Arch Toxicol 91: 143-162</a> <a name="_ENREF_32">Moore RW, Rudy TA, Lin TM, Ko K, Peterson RE (2001) Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate. Environ Health Perspect 109: 229-237</a> <a name="_ENREF_33">Mylchreest E, Sar M, Cattley RC, Foster PM (1999) Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. Toxicol Appl Pharmacol 156: 81-95</a> <a name="_ENREF_34">Nagao T, Ohta R, Marumo H, Shindo T, Yoshimura S, Ono H (2000) Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: a two-generation reproductive study. Reprod Toxicol 14: 513-532</a> <a name="_ENREF_35">Nardelli TC, Albert O, Lalancette C, Culty M, Hales BF, Robaire B (2017) In utero and lactational exposure study in rats to identify replacements for di(2-ethylhexyl) phthalate. Sci Rep 7: 3862</a> <a name="_ENREF_36">Noriega NC, Ostby J, Lambright C, Wilson VS, Gray LE, Jr. (2005) Late gestational exposure to the fungicide prochloraz delays the onset of parturition and causes reproductive malformations in male but not female rat offspring. Biol Reprod 72: 1324-1335</a> <a name="_ENREF_37">OECD. (2013) Guidance document in support of the test guideline on the extended one generation reproductive toxicity study No. 151.</a> <a name="_ENREF_38">Ostby J, Kelce WR, Lambright C, Wolf CJ, Mann P, Gray CLJ (1999) The fungicide procymidone alters sexual differentiation in the male rat by acting as an androgen-receptor antagonist in vivo and in vitro. Toxicol Ind Health 15: 80-93</a> <a name="_ENREF_39">Saillenfait AM, Gallissot F, Sabaté JP (2009a) Differential developmental toxicities of di-n-hexyl phthalate and dicyclohexyl phthalate administered orally to rats. J Appl Toxicol 29: 510-521</a> <a name="_ENREF_40">Saillenfait AM, Roudot AC, Gallissot F, Sabaté JP (2011) Prenatal developmental toxicity studies on di-n-heptyl and di-n-octyl phthalates in Sprague-Dawley rats. Reprod Toxicol 32: 268-276</a> <a name="_ENREF_41">Saillenfait AM, Sabaté JP, Gallissot F (2009b) Effects of in utero exposure to di-n-hexyl phthalate on the reproductive development of the male rat. Reprod Toxicol 28: 468-476</a> <a name="_ENREF_42">Salazar-Martinez E, Romano-Riquer P, Yanez-Marquez E, Longnecker MP, Hernandez-Avila M (2004) Anogenital distance in human male and female newborns: a descriptive, cross-sectional study. Environ Health 3: 8</a> <a name="_ENREF_43">Schneider S, Kaufmann W, Strauss V, van Ravenzwaay B (2011) Vinclozolin: a feasibility and sensitivity study of the ILSI-HESI F1-extended one-generation rat reproduction protocol. Regulatory Toxicology and Pharmacology 59: 91-100</a> <a name="_ENREF_44">Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U, Svingen T (2019) Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. Arch Toxicol 93: 253-272</a> <a name="_ENREF_45">Scott HM, Hutchison GR, Mahood IK, Hallmark N, Welsh M, De Gendt K, Verhoeven H, O'Shaughnessy P, Sharpe RM (2007) Role of androgens in fetal testis development and dysgenesis. Endocrinology 148: 2027-2036</a> <a name="_ENREF_46">Skakkebaek NE, Rajpert-De Meyts E, Main KM (2001) Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 16: 972-978</a> <a name="_ENREF_47">Taxvig C, Vinggaard AM, Hass U, Axelstad M, Metzdorff S, Nellemann C (2008) Endocrine-disrupting properties in vivo of widely used azole fungicides. Int J Androl 31: 170-177</a> <a name="_ENREF_48">Turner KJ, Barlow NJ, Struve MF, Wallace DG, Gaido KW, Dorman DC, Foster PM (2002) Effects of in utero exposure to the organophosphate insecticide fenitrothion on androgen-dependent reproductive development in the Crl:CD(SD)BR rat. Toxicol Sci 68: 174-183</a> <a name="_ENREF_49">Tyl RW, Myers CB, Marr MC, Fail PA, Seely JC, Brine DR, Barter RA, Butala JH (2004) Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats. Reprod Toxicol 18: 241-264</a> <a name="_ENREF_50">Van den Driesche S, Kolovos P, Platts S, Drake AJ, Sharpe RM (2012) Inter-relationship between testicular dysgenesis and Leydig cell function in the masculinization programming window in the rat. PloS one 7: e30111</a> <a name="_ENREF_51">Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM (2008) Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 118: 1479-1490</a> <a name="_ENREF_52">Welsh M, Saunders PT, Sharpe RM (2007) The critical time window for androgen-dependent development of the Wolffian duct in the rat. Endocrinology 148: 3185-3195</a> <a name="_ENREF_53">Wolf CJ, LeBlanc GA, Gray LE, Jr. (2004) Interactive effects of vinclozolin and testosterone propionate on pregnancy and sexual differentiation of the male and female SD rat. Toxicol Sci 78: 135-143</a> <a name="_ENREF_54">Wolf CJJ, Lambright C, Mann P, Price M, Cooper RL, Ostby J, Gray CLJ (1999) Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. Toxicol Ind Health 15: 94-118</a> <a name="_ENREF_55">Zhang L, Dong L, Ding S, Qiao P, Wang C, Zhang M, Zhang L, Du Q, Li Y, Tang N, Chang B (2014) Effects of n-butylparaben on steroidogenesis and spermatogenesis through changed E₂ levels in male rat offspring. Environ Toxicol Pharmacol 37: 705-717</a> AOPWiki 2019-08-30T04:20:56

2022-12-22T05:18:24

<upstream-id>511c85b5-52c4-4ad9-a4d0-bde7020c07f7</upstream-id> <downstream-id>1e465e70-b6b4-46ae-a048-04997e711ea6</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a0c58368> AOPWiki 2020-05-11T07:39:00

2020-05-11T07:39:00

<upstream-id>511c85b5-52c4-4ad9-a4d0-bde7020c07f7</upstream-id> <downstream-id>d9ec320f-fa7e-4f1a-bcd8-f2159ef945f7</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a0d983b8> AOPWiki 2020-05-11T04:12:54

2020-08-07T05:12:08

<upstream-id>1e465e70-b6b4-46ae-a048-04997e711ea6</upstream-id> <downstream-id>80eb3294-bfa3-4682-847e-402ef02adcb8</downstream-id>

High Male High Female

High

During development and at adulthood

High High High High

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a0f0f750> AOPWiki 2020-05-11T07:37:14

2020-11-02T08:12:23

<upstream-id>80eb3294-bfa3-4682-847e-402ef02adcb8</upstream-id> <downstream-id>d9ec320f-fa7e-4f1a-bcd8-f2159ef945f7</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a10f2d88> AOPWiki 2020-05-11T07:37:46

2020-05-11T07:37:46

<upstream-id>1e465e70-b6b4-46ae-a048-04997e711ea6</upstream-id> <downstream-id>d9ec320f-fa7e-4f1a-bcd8-f2159ef945f7</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a12d0268> AOPWiki 2022-12-22T05:20:45

2022-12-22T05:20:45

Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring

AR antagonism leading to short AGD

Evgeniia Kazymova

Sofie Christiansen; National Food Institute, Technical University of Denmark, Kongens Lyngby, 2800 Denmark Monica Kam Draskau; National Food Institute, Technical University of Denmark, Kongens Lyngby, 2800 Denmark Terje Svingen; National Food Institute, Technical University of Denmark, Kongens Lyngby, 2800 Denmark

BY-SA

Under Development

1.90

2.0

This AOP links Androgen receptor antagonism during fetal life with short anogenital distance (AGD) in male offspring. A short AGD around birth is a marker for feminization of male fetuses and is associated with male reproductive disorders, including reduced fertility in adulthood. Although a short AGD is not necessarily ‘adverse’ from a human health perspective, it is considered an ‘adverse outcome’ in OECD test guidelines; AGD measurements are mandatory in specific tests for developmental and reproductive toxicity in chemical risk assessment (TG 443, TG 421/422, TG 414). The AR is a nuclear receptor involved in the transcriptional regulation of various target genes during development and adulthood across species. Its main ligand is testosterone and dihydrotestosterone (DHT). Under normal physiological conditions, testosterone produced mainly by the testicles, is converted in peripheral tissues by 5α-reductase into DHT, which in turn binds AR and activates downstream target genes. AR signaling is necessary for normal masculinization of the developing fetus, including differentiation of the levator ani/bulbocavernosus (LABC) muscle complex in male fetuses. The LABC complex does not develop in the absence, or low levels of, androgen signaling, as in female fetuses. The key events in this pathway is antagonism of the AR in target cells of the primitive perineal region, which leads to inactivation of the AR and failure to properly masculinize the perineum/LABC complex. In this instance, the local levels of testosterone or DHT may be normal, but prevented from binding the AR.

A large number of drugs and chemicals have been shown to antagonise the AR using various AR reporter gene assays. The AR is specifically targeted in AR-sensitive cancers, for example the use of the anti-androgenic drug flutamide in treating prostate cancer (<a href="#_ENREF_1" title="Alapi, 2006 #262">Alapi & Fischer, 2006</a>). Flutamide has also been used in several rodent in vivo studies showing anti-androgenic effects (feminization of male offspring) evident by e.g. short anogenital distance (AGD) in males (<a href="#_ENREF_4" title="Foster, 2005 #53">Foster & Harris, 2005</a>; <a href="#_ENREF_5" title="Hass, 2007 #76">Hass et al, 2007</a>; <a href="#_ENREF_8" title="Kita, 2016 #34">Kita et al, 2016</a>). QSAR models can predict AR antagonism for a wide range of chemicals, many of which have shown in vitro antagonistic potential (<a href="#_ENREF_17" title="Vinggaard, 2008 #263">Vinggaard et al, 2008</a>).

In regulatory toxicology, the AGD is mandatory inclusions in OECD test guidelines used to test for developmental and reproductive toxicity of chemicals. Guidelines include ‘TG 443 extended one-generation study’, ‘TG 421/422 reproductive toxicity screening studies’ and ‘TG 414 developmental toxicity study’.

adjacent

High

High adjacent

Moderate

High adjacent

Low

Moderate non-adjacent

Low

Moderate non-adjacent

Not Specified

High Male

High

Pregnancy

Moderate High Moderate

High

1. Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U and Svingen T (2019), Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. Arch Toxicol 93: 253-272. AOPWiki 2019-08-30T04:27:36

2023-09-25T16:27:01