94-26-8QFOHBWFCKVYLES-UHFFFAOYSA-NQFOHBWFCKVYLES-UHFFFAOYSA-N
ButylparabenButyl 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
DTXSID302020972-55-9UCNVFOCBFJOQAL-UHFFFAOYSA-NUCNVFOCBFJOQAL-UHFFFAOYSA-N
p,p'-DDE1,1-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
DTXSID9020374117-81-7BJQHLKABXJIVAM-UHFFFAOYNA-NBJQHLKABXJIVAM-UHFFFAOYSA-N
Di(2-ethylhexyl) phthalate1,2-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
DTXSID502060750-02-2UREBDLICKHMUKA-CXSFZGCWSA-NUREBDLICKHMUKA-CXSFZGCWSA-N
DexamethasonePregna-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
DTXSID3020384122-14-5ZNOLGFHPUIJIMJ-UHFFFAOYSA-NZNOLGFHPUIJIMJ-UHFFFAOYSA-N
FenitrothionPhosphorothioic 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
DTXSID403261313311-84-7MKXKFYHWDHIYRV-UHFFFAOYSA-NMKXKFYHWDHIYRV-UHFFFAOYSA-N
FlutamidePropanamide, 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
DTXSID703200465277-42-1XMAYWYJOQHXEEK-OZXSUGGESA-NXMAYWYJOQHXEEK-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-
DTXSID7029879330-55-2XKJMBINCVNINCA-UHFFFAOYSA-NXKJMBINCVNINCA-UHFFFAOYSA-N
LinuronUrea, 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-
DTXSID202416367747-09-5TVLSRXXIMLFWEO-UHFFFAOYSA-NTVLSRXXIMLFWEO-UHFFFAOYSA-N
Prochloraz1H-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
DTXSID402427032809-16-8QXJKBPAVAHBARF-UHFFFAOYNA-NQXJKBPAVAHBARF-UHFFFAOYSA-N
Procymidone3-(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
DTXSID9033923131983-72-7PPDBOQMNKNNODG-UHFFFAOYNA-NPPDBOQMNKNNODG-UHFFFAOYSA-N
Triticonazole5-[(4-Chlorophenyl)methylene]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol
DTXSID003265550471-44-8FSCWZHGZWWDELK-UHFFFAOYNA-NFSCWZHGZWWDELK-UHFFFAOYSA-N
Vinclozolin2,4-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
DTXSID402236184-61-7VOWAEIGWURALJQ-UHFFFAOYSA-NVOWAEIGWURALJQ-UHFFFAOYSA-N
Dicyclohexyl phthalate1,2-Benzenedicarboxylic acid, dicyclohexyl ester
DTXSID502502190357-06-5LKJPYSCBVHEWIU-UHFFFAOYSA-NLKJPYSCBVHEWIU-UHFFFAOYSA-N
BicalutamideCasodex
CDX
Propanamide, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-
DTXSID2022678427-51-0UWFYSQMTEOIJJG-FDTZYFLXSA-NUWFYSQMTEOIJJG-FDTZYFLXSA-N
Cyproterone acetate3'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
DTXSID5020366133855-98-8ZMYFCFLJBGAQRS-UHFFFAOYNA-NZMYFCFLJBGAQRS-UHFFFAOYSA-N
EpoxiconazoleDTXSID104037285509-19-9FQKUGOMFVDPBIZ-UHFFFAOYSA-NFQKUGOMFVDPBIZ-UHFFFAOYSA-N
FlusilazoleNuStar
DTXSID302423560207-90-1STJLVHWMYQXCPB-UHFFFAOYNA-NSTJLVHWMYQXCPB-UHFFFAOYSA-N
Propiconazoleppz
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
DTXSID8024280FMA:264621Musculature of male perineumPR:000004191androgen receptorGO:0030521androgen receptor signaling pathwayGO:0010468regulation of gene expression9disrupted2decreasedFinasteride2016-11-29T18:42:272016-11-29T18:42:27Butylparaben2020-05-18T12:14:362020-05-18T12:14:36p,p'-DDE2020-05-18T12:15:232020-05-18T12:15:23Bis(2-ethylhexyl) phthalate2016-11-29T18:42:082016-11-29T18:42:08Dexamethasone2019-06-01T00:56:522019-06-01T00:56:52Fenitrothion2020-05-18T12:51:252020-05-18T12:51:25Flutamide2016-11-29T18:42:272016-11-29T18:42:27Ketoconazole2017-05-02T11:08:422017-05-02T11:08:42Linuron2020-05-18T12:53:542020-05-18T12:53:54Prochloraz2016-11-29T18:42:222016-11-29T18:42:22Procymidone2020-05-18T12:55:122020-05-18T12:55:12Triticonazole2020-05-16T11:02:072020-05-16T11:09:42Vinclozolin2020-05-14T11:28:312020-05-14T11:28:31di-n-hexyl phthalate<p>CAS Number: 84-75-3;</p>
<p>Synonym: 1,2-Benzenedicarboxylic acid 1,2-dihexyl ester</p>
2020-05-18T14:34:222020-05-18T14:36:56Dicyclohexyl phthalate2020-05-18T14:41:462020-05-18T14:41:46butyl benzyl phthalate2020-05-18T14:46:292020-05-18T14:46:29monobenzyl phthalate2020-05-18T14:49:442020-05-18T14:49:44di-n-heptyl phthalate2020-05-18T15:01:032020-05-18T15:01:03Bicalutamide2020-08-07T06:55:532020-08-07T06:55:53Cyproterone acetate2020-05-17T10:13:282020-05-17T10:13:28Epoxiconazole2020-05-16T11:35:442020-05-16T11:35:44Flusilazole2020-05-16T11:15:342020-05-16T11:15:34Propiconazole2017-05-17T13:18:072017-05-17T13:18:07Stressor:286 Tebuconazole2020-08-07T07:00:532020-08-07T07:00:53Vinclozalin2016-11-29T18:42:272016-11-29T18:42:27WCS_9606human10116rat10090mouseWikiUser_17mammals5α-reductase, inhibition5α-reductase, inhibitionMolecular2019-04-18T19:48:352019-04-18T19:48:35Decrease, dihydrotestosterone (DHT) levelDecrease, DHT levelCellular<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Reduction in DHT synthesis leads to a reduction in DHT circulating levels. <sup>12</sup></span></span></p>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">DHT levels in a sample can be measured by (High Performance) Liquid Chromatography. After sample fractionation, DHT can be identify by comparison with internal standards spectrum. Quantification of DHT levels can be performed using hormones measurements kits (ELISA), instrumental techniques (LC-MS) or liquid scintillation spectrometry (after radiolabeling).<sup>3</sup></span></span></p>
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<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>1 </sup>Miller Walter L. (1988) Molecular Biology of Steroid Hormone Synthesis. Endocrine Reviews, 9(3): 295-318.<a href="https://www.google.com/url?q=https://doi.org/10.1210/edrv-9-3-295&sa=D&ust=1554891396614000">https://doi.org/10.1210/edrv-9-3-295</a> </span></span></p>
<p style="text-align: justify;"> </p>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>2 </sup>Miller W.L. and Auchus R.J. (2011) The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders. Endocrine Reviews, 32(1): 81-151.<a href="https://www.google.com/url?q=https://doi.org/10.1210/er.2010-0013&sa=D&ust=1554891396616000">https://doi.org/10.1210/er.2010-0013</a> </span></span></p>
<p style="text-align: justify;"> </p>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>3</sup> Shiraishi S., Lee P.W., Leung A., Goh V.H., Swerdloff R.S. and Wang C. (2008) Simultaneous measurement of serum testosterone and dihydrotestosterone by liquid chromatography-tandem mass spectrometry. Clinical chemistry, 54(11): 1855-63.<a href="https://www.google.com/url?q=https://doi.org/10.1373/clinchem.2008.103846&sa=D&ust=1554891396617000">https://doi.org/10.1373/clinchem.2008.103846</a></span></span></p>
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2019-04-10T05:02:292019-04-10T05:22:55Decrease, androgen receptors (AR) activationDecrease, AR activationCellular<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">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. <sup>12</sup></span></span></p>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">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.<sup>3</sup></span></span></p>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">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.<sup>4</sup></span></span></p>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">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.<sup>5</sup></span></span></p>
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<p><sup>1</sup> 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</p>
<p><sup>2 </sup>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> </p>
<p><sup>3</sup> 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> </p>
<p><sup>4</sup> 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> </p>
<p><sup>5</sup> 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> </p>
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2019-04-10T05:04:182019-04-10T05:24:20anogenital distance (AGD), decreasedAGD, decreasedTissue<p>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 <em>levator ani</em> and <em>bulbocavernosus </em>(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.</p>
<p>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>).</p>
<p>The AGD is a morphometric measurement carried out by trained technicians (rodents) or medical staff (humans).</p>
<p>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>).</p>
<p> </p>
<p>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>).</p>
<p>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>).</p>
UBERON:0002356perineumHighMaleHighFoetalModerateHighHigh<p><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. <em>Toxicol Lett</em> <strong>233:</strong> 125-137</a></p>
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<p><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. <em>Reprod Toxicol</em> <strong>17:</strong> 407-412</a></p>
<p><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. <em>Toxicol Sci</em> <strong>85:</strong> 1024-1032</a></p>
<p><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. <em>Toxicol Sci</em> <strong>58:</strong> 350-365</a></p>
<p><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. <em>Toxicol Appl Pharmacol</em> <strong>129:</strong> 46-52</a></p>
<p><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. <em>Reprod Toxicol</em> <strong>34:</strong> 261-274</a></p>
<p><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. <em>Environ Health Perspect</em> <strong>115 Suppl. 1:</strong> 122-128</a></p>
<p><a name="_ENREF_15">Hoshino N, Iwai M, Okazaki Y (2005) A two-generation reproductive toxicity study of dicyclohexyl phthalate in rats. <em>J Toxicol Sci</em> <strong>30 Spec No:</strong> 79-96</a></p>
<p><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. <em>Biol Reprod</em> <strong>71:</strong> 1852-1861</a></p>
<p><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. <em>Toxicol Sci</em> <strong>99:</strong> 190-202</a></p>
<p><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. <em>Endocrinology</em> <strong>155:</strong> 2467-2479</a></p>
<p><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. <em>Reprod Toxicol</em> <strong>19:</strong> 505-515</a></p>
<p><a name="_ENREF_20">Jost A (1953) Problems of fetal endocrinology: The gonadal and hypophyseal hormones. <em>Recent Prog Horm Res</em> <strong>8:</strong> 379-418</a></p>
<p><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. <em>Nat Rev Endocrinol</em> <strong>10:</strong> 553-562</a></p>
<p><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. <em>Toxicology</em> <strong>368-369:</strong> 152-161</a></p>
<p><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. <em>Toxicol Appl Pharmacol</em> <strong>213:</strong> 2</a></p>
<p><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. <em>Environ Toxicol Pharmacol</em> <strong>35:</strong> 55-60</a></p>
<p><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. <em>Biol Reprod</em> <strong>80:</strong> 882-888</a></p>
<p><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. <em>Toxicol Appl Pharmacol</em> <strong>154:</strong> 28-39</a></p>
<p><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. <em>Int J Androl</em> <strong>33:</strong> 279-287</a></p>
<p><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. <em>J Toxicol Sci</em> <strong>30 Spec No:</strong> 163-168</a></p>
<p><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. <em>Toxicol Sci</em> <strong>62:</strong> 236-249</a></p>
<p><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. <em>Reprod Toxicol</em> <strong>16:</strong> 131-139</a></p>
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<p><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. <em>Environ Health Perspect</em> <strong>109:</strong> 229-237</a></p>
<p><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. <em>Toxicol Appl Pharmacol</em> <strong>156:</strong> 81-95</a></p>
<p><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. <em>Reprod Toxicol</em> <strong>14:</strong> 513-532</a></p>
<p><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. <em>Sci Rep</em> <strong>7:</strong> 3862</a></p>
<p><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. <em>Biol Reprod</em> <strong>72:</strong> 1324-1335</a></p>
<p><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></p>
<p><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. <em>Toxicol Ind Health</em> <strong>15:</strong> 80-93</a></p>
<p><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. <em>J Appl Toxicol</em> <strong>29:</strong> 510-521</a></p>
<p><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. <em>Reprod Toxicol</em> <strong>32:</strong> 268-276</a></p>
<p><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. <em>Reprod Toxicol</em> <strong>28:</strong> 468-476</a></p>
<p><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. <em>Environ Health</em> <strong>3:</strong> 8</a></p>
<p><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. <em>Regulatory Toxicology and Pharmacology</em> <strong>59:</strong> 91-100</a></p>
<p><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. <em>Arch Toxicol</em> <strong>93:</strong> 253-272</a></p>
<p><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. <em>Endocrinology</em> <strong>148:</strong> 2027-2036</a></p>
<p><a name="_ENREF_46">Skakkebaek NE, Rajpert-De Meyts E, Main KM (2001) Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. <em>Hum Reprod</em> <strong>16:</strong> 972-978</a></p>
<p><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. <em>Int J Androl</em> <strong>31:</strong> 170-177</a></p>
<p><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. <em>Toxicol Sci</em> <strong>68:</strong> 174-183</a></p>
<p><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. <em>Reprod Toxicol</em> <strong>18:</strong> 241-264</a></p>
<p><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. <em>PloS one</em> <strong>7:</strong> e30111</a></p>
<p><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. <em>J Clin Invest</em> <strong>118:</strong> 1479-1490</a></p>
<p><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. <em>Endocrinology</em> <strong>148:</strong> 3185-3195</a></p>
<p><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. <em>Toxicol Sci</em> <strong>78:</strong> 135-143</a></p>
<p><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. <em>Toxicol Ind Health</em> <strong>15:</strong> 94-118</a></p>
<p><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. <em>Environ Toxicol Pharmacol</em> <strong>37:</strong> 705-717</a></p>
2019-08-30T04:20:562022-12-22T05:18:24Altered, Transcription of genes by ARAltered, Transcription of genes by ARCellular<p><u>The Androgen Receptor and its function</u></p>
<p>Androgens act by binding to the Androgen receptor (AR) in androgen-responsive tissues (Davey and Grossmann 2016). Human AR mutations and mouse knockout models have established the fundamental role of AR in masculinization and spermatogenesis (Maclean et al.; Walters et al. 2010; Rana et al. 2014). The AR is also expressed in many other tissues such as bone, muscles, ovaries and within the immune system (Rana et al. 2014).</p>
<p> </p>
<p><u>Altered transcription of genes by the AR as a Key Event</u></p>
<p>The AR belongs to the steroid hormone nuclear receptor family. It is a ligand-activated transcription factor with three domains; the N-terminal domain, the DNA-binding domain, and the ligand-binding domain with the latter being the most evolutionary conserved (Davey and Grossmann 2016). Upon activation by ligand-binding, the AR translocate from the cytoplasm to the cell nucleus, dimerizes, binds to androgen response elements in the DNA to modulate gene transcription (Davey and Grossmann 2016). The transcriptional targets varies between different cells and tissues, as well as with developmental stages and is, for instance, dependent on available co-regulators (Bevan and Parker 1999; Heemers and Tindall 2007).</p>
<p>Several known and proposed target genes of AR canonical signaling have been identified by analysis of gene expression following treatments with AR agonists (Bolton et al. 2007; Ngan et al. 2009) and can for instance be found in the Androgen-Responsive Gene Database (Jiang et al. 2009).</p>
<p><em>In vitro</em></p>
<p>Decreased transcription of genes by the AR can be measured by measuring the transcription level of known downstream target genes by RT-qPCR or other transcription analyses approaches, eg transcriptomics.</p>
<p>Indirect approaches include the use of transient or stable transactivation assays including the validated OECD test guideline assay, Test No. 458: <em>Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals </em>(OECD 2016). The stably transfected AR-EcoScreenTM cell line is freely available for the Japanese Collection of Research Bioresources (JCRB) Cell Bank under reference number JCRB1328. These cell-based transcriptional activation assays are typically used to detect AR agonists and antagonists. However, these types of assays are well suited to measure this KE as what they measure is exactly AR transcriptional activity. Other assays along this line 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 (van der Burg et al. 2010).</p>
<p><em>In vivo</em></p>
<p>Known downstream target gene transcription level can be measured in tissues by RT-qPCR or other gene expression analyses approaches.</p>
<p>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 (Davey and Grossmann 2016). Despite certain inter-species differences, AR function mediated through gene expression is highly conserved, with mutation studies from both humans and rodents showing strong correlation for AR-dependent development and function (Walters et al. 2010).</p>
<p>This KE is applicable for both sexes, across developmental stages into adulthood, in numerous cells and tissues and across taxa.</p>
CL:0000255eukaryotic cellHighMixedHighFoetalHighAdult, reproductively matureHighHighHigh<p>Bevan C, Parker M (1999) The role of coactivators in steroid hormone action. Exp. Cell Res. 253:349–356</p>
<p>Bolton EC, So AY, Chaivorapol C, et al (2007) Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21:2005–2017. doi: 10.1101/gad.1564207</p>
<p>Davey RA, Grossmann M (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev 37:3–15</p>
<p>Draskau MK, Boberg J, Taxvig C, et al (2019) In vitro and in vivo endocrine disrupting effects of the azole fungicides triticonazole and flusilazole. Environ Pollut 255:113309. doi: 10.1016/j.envpol.2019.113309</p>
<p>Estrada M, Espinosa A, Müller M, Jaimovich E (2003) Testosterone Stimulates Intracellular Calcium Release and Mitogen-Activated Protein Kinases Via a G Protein-Coupled Receptor in Skeletal Muscle Cells. Endocrinology 144:3586–3597. doi: 10.1210/en.2002-0164</p>
<p>Heemers H V., Tindall DJ (2007) Androgen receptor (AR) coregulators: A diversity of functions converging on and regulating the AR transcriptional complex. Endocr. Rev. 28:778–808</p>
<p>Jiang M, Ma Y, Chen C, et al (2009) Androgen-Responsive Gene Database: Integrated Knowledge on Androgen-Responsive Genes. Mol Endocrinol 23:1927–1933. doi: 10.1210/me.2009-0103</p>
<p>Kjærstad MB, Taxvig C, Nellemann C, et al (2010) Endocrine disrupting effects in vitro of conazole antifungals used as pesticides and pharmaceuticals. Reprod Toxicol 30:573–582. doi: 10.1016/J.REPROTOX.2010.07.009</p>
<p>Laier P, Metzdorff SB, Borch J, et al (2006) Mechanisms of action underlying the antiandrogenic effects of the fungicide prochloraz. Toxicol Appl Pharmacol 213:160–71. doi: 10.1016/j.taap.2005.10.013</p>
<p>Maclean HE, Chu S, Warne GL, Zajact JD Related Individuals with Different Androgen Receptor Gene Deletions</p>
<p>MacLeod DJ, Sharpe RM, Welsh M, et al (2010) Androgen action in the masculinization programming window and development of male reproductive organs. In: International Journal of Andrology. Blackwell Publishing Ltd, pp 279–287</p>
<p>Ngan S, Stronach EA, Photiou A, et al (2009) Microarray coupled to quantitative RT&ndash;PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells. Oncogene 28:2051–2063. doi: 10.1038/onc.2009.68</p>
<p>OECD (2016) Test No. 458: Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals, OECD Guide. OECD Publishing</p>
<p>Rana K, Davey RA, Zajac JD (2014) Human androgen deficiency: Insights gained from androgen receptor knockout mouse models. Asian J. Androl. 16:169–177</p>
<p>Sonneveld E, Jansen HJ, Riteco JAC, et al (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. doi: 10.1093/toxsci/kfi005</p>
<p>van der Burg B, Winter R, Man H yen, et al (2010) Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reprod Toxicol 30:18–24. doi: 10.1016/j.reprotox.2010.04.012</p>
<p>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. doi: 10.1093/humupd/dmq003</p>
2016-11-29T18:41:232020-11-04T11:11:013e4b80b2-fb45-40e9-b630-b184f5bfe2b295393c90-feb9-4bdd-9d7d-0dd78d37244e2019-04-18T19:54:392019-04-18T19:54:39d1395734-2907-4eb3-abb3-9382334f8b110a578d32-672f-4da8-b768-8abdb1e1e07b2022-12-22T05:20:452022-12-22T05:20:4595393c90-feb9-4bdd-9d7d-0dd78d37244ed1395734-2907-4eb3-abb3-9382334f8b11<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Dihydrotestosterone (DHT) is, together with testosterone, a primary ligand for the Androgen receptor (AR). DHT is an endogenous sex hormone that is synthesis from e.g. testosterone by the enzyme 5</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">α</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">-reductase in selected tissues, not least in the reproductive tracts of both sexes, but also other tissues and organs </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(<a href="#_ENREF_1" title="Davey, 2016 #250">Davey & Grossmann, 2016</a>; <a href="#_ENREF_3" title="Marks, 2004 #283">Marks, 2004</a>)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">. In the absence of ligand (DHT/testosterone) the AR is localized in the cytoplasm. AR is only activated and translocated into the nucleus to carry out its ‘genomic function’ upon ligand binding </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(<a href="#_ENREF_1" title="Davey, 2016 #250">Davey & Grossmann, 2016</a>)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">. Hence, AR transcriptional function is directly dependent on the presence of ligands, with DHT being a more potent AR activator (2-fold higher binding affinity) than testosterone </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(<a href="#_ENREF_2" title="Grino, 1990 #284">Grino et al, 1990</a>)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">. Reduced levels of DHT will lead to reduced AR activation. </span></span></p>
HighMaleHighFoetalHighDuring development and at adulthoodHighHighHighHigh2019-06-03T08:41:092021-02-02T05:50:185α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring5α-reductase inhibition leading to short AGD<p>Monica Kam Draskau; National Food Institute, Technical University of Denmark, Kongens Lyngby, 2800 Denmark</p>
<p>Terje Svingen; National Food Institute, Technical University of Denmark, Kongens Lyngby, 2800 Denmark</p>
Under development: Not open for comment. Do not citeUnder DevelopmentIncluded in OECD Work Plan1.90<p>This AOP links 5α-reductase inhibition 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).</p>
<p>5α-reductase is an enzyme responsible for the conversion of testosterone to DHT in target tissues. DHT is more potent agonist of the Androgen receptor (AR) than testosterone, so that DHT is necessary for proper masculinization of e.g. male external genitalia. 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 masculinization of the developing fetus, including differentiation of the levator ani/bulbocavernosus (LABC) muscle complex in males. The LABC complex does not develop in the absence, or low levels of, androgen signaling, as in female fetuses.</p>
<p>The key events in this pathway is inhibition of 5α-reductase that converts testosterone into the more potent DHT in androgen sensitive target tissues. This includes developing perineal region, which, when DHT levels are low or absent, leads to inactivation of the AR and failure to properly masculinize the perineum/LABC complex.</p>
<p>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’.</p>
adjacentHighHighadjacentNot SpecifiedNot Specifiednon-adjacentNot SpecifiedNot SpecifiedHighMaleHighPregnancyModerateHighModerateHigh<ol>
<li>Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U and <strong>Svingen T</strong> (2019), Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. <em>Arch Toxicol</em> 93: 253-272.</li>
</ol>
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