Hypospadias, increased

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

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

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

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

Flutamide

2016-11-29T18:42:27

Cyproterone acetate

2020-05-17T10:13:28

Vinclozolin

2020-05-14T11:28:31

WCS_9606

common toxicological species human

10090

NCBI mouse

10116

NCBI rat

WikiUser_25

Wikiuser: Cyauk human and other cells in culture

Hypospadias, increased

Hypospadias

Organ

High

Development

High High High AOPWiki 2022-12-18T10:39:05

2022-12-20T11:50:11

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

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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e97a6b90> AOPWiki 2020-05-11T07:39:00

2020-05-11T07:39:00

<upstream-id>462a05e5-64c1-4e06-8191-a05206d6776d</upstream-id> <downstream-id>f970ea58-6491-4dd5-8dae-d81095cb9791</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42e97cbf80> AOPWiki 2023-01-11T04:04:19

2023-01-11T04:04:19

Androgen receptor (AR) antagonism leading to hypospadias in male offspring

AR antagonism leading to hypospadias

Brendan Ferreri-Hanberry

BY-SA

2.5

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>).

adjacent

Not Specified

High non-adjacent

Not Specified

AOPWiki 2022-12-18T10:45:51

2023-09-25T16:27:13