Antagonism, Androgen receptor

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

90357-06-5

LKJPYSCBVHEWIU-UHFFFAOYSA-N

Bicalutamide

Casodex CDX Propanamide, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-

DTXSID2022678

PR:000004191

PR androgen receptor

GO:0004882

GO androgen receptor activity

GO:0048513

GO animal organ development

GO:0010468

GO regulation of gene expression

WIKI decreased

WIKI abnormal

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 Flutamide is a selective androgen receptor (AR) antagonist (Simard et al 1986) that has been shown to induce shorter male AGD in rats after in utero exposure (Foster & Harris 2005; Hass et al 2007; Kita et al 2016; McIntyre et al 2001; Mylchreest et al 1999; Scott et al 2007; Welsh et al 2007).

2016-11-29T18:42:27

2025-08-14T05:22:07

Cyproterone acetate

2020-05-17T10:13:28

Vinclozolin

2020-05-14T11:28:31

Bicalutamide

2020-08-07T06:55:53

Stressor:286 Tebuconazole

2020-08-07T07:00:53

Vinclozalin

2016-11-29T18:42:27

WikiUser_17

mammals

WikiUser_28

Vertebrates

Antagonism, Androgen receptor

Molecular

The androgen receptor (AR) and its function The AR is a ligand-activated transcription factor belonging to the steroid hormone nuclear receptor family (<a href="https://aopwiki.org/events/26#_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. Testosterone (T) and the more biologically active dihydrotestosterone (DHT) are endogenous ligands for 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>). In teleost fishes, 11-ketotestosterone is the second main ligand (<a href="#" title="Schuppe et al, 2020">Schuppe et al, 2020</a>). Human AR mutations and mouse knock-out models have established a pivotal role for the AR in masculinization and spermatogenesis (<a href="#_ENREF_9" title="Walters, 2010 #254">Walters et al, 2010</a>). Apart from the essential role for AR in 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 initiate cytoplasmic signaling pathways with other functions than the nuclear pathway, for instance rapid change in cell function by ion transport changes (<a href="#_ENREF_3" title="Heinlein, 2002 #256">Heinlein & Chang, 2002</a>) and association with Src kinase to activate MAPK/ERK signaling and activation of the PI3K/Akt pathway (<a href="#" title="Leung & Sadar, 2017">Leung & Sadar, 2017</a>).

AR antagonism can be measured in vitro by transient or stable transactivation assays to evaluate nuclear receptor activation. There is already a validated test guideline 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>). This test guideline contains three different methods. More information on limitations, advantages, protocols, and availability and description of cells are given in the test guideline. Besides these validated methods, other transiently or stably transfected reporter cell lines are available as well as yeast based systems (Campana et al, 2015; <a href="#_ENREF_10" title="Körner, 2004 #282">Körner et al, 2004</a>). AR nuclear translocation can be monitored by various assays (Campana et al 2015), for example by monitoring fluorescent rat AR movement in living cells (Tyagi et al 2020), with several human AR translocation assays being commercially available; e.g. Fluorescent AR Nuclear Translocation Assay (tGFP-hAR/HEK293) or Human Androgen NHR Cell Based Antagonist Translocation LeadHunter Assay. Additional information on AR interaction can be obtained employing competitive AR binding assays (Freyberger et al 2010, Shaw et al 2018), which can also inform on relative potency of the compounds, though not on downstream effect of the AR binding. The recently developed AR dimerization assay provides an assay with an improved ability to measure potential stressor-mediated disruption of 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 mammalian taxa. It is, however, acknowledged that this KE most likely has a much broader domain of applicability extending to non-mammalian vertebrates. AOP developers are encouraged to add additional relevant knowledge to expand on the applicability to also include other vertebrates.

CL:0000255

CL eukaryotic cell

High Mixed

High

During development and at adulthood

High

Campana C, Pezzi V, Rainey WE (2015) Cell based assays for screening androgen receptor ligands. Semin Reprod Med 33: 225-234. <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> Freyberger A, Weimer M, Tran HS, Ahr HJ. Assessment of a recombinant androgen receptor binding assay: initial steps towards validation. Reprod Toxicol. 2010 Aug;30(1):2-8. doi: 10.1016/j.reprotox.2009.10.001. Epub 2009 Oct 13. PMID: 19833195. <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_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 id="_ENREF_23" name="_ENREF_23">Leung, J. K., & Sadar, M. D. (2017). Non-Genomic Actions of the Androgen Receptor in Prostate Cancer. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00002</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> OECD (2022). Test No. 251: <a name="_Hlk148359154">Rapid Androgen Disruption Activity Reporter (RADAR) assay</a>. Paris: OECD Publishing doi:10.1787/da264d82-en. <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 id="_ENREF_22" name="_ENREF_22">Schuppe, E. R., Miles, M. C., and Fuxjager, M. J. (2020). Evolution of the androgen receptor: Perspectives from human health to dancing birds. Mol. Cell. Endocrinol. 499, 110577. doi:10.1016/J.MCE.2019.110577 </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> Shaw J, Leveridge M, Norling C, Karén J, Molina DM, O'Neill D, Dowling JE, Davey P, Cowan S, Dabrowski M, Main M, Gianni D. Determining direct binders of the Androgen Receptor using a high-throughput Cellular Thermal Shift Assay. Sci Rep. 2018 Jan 9;8(1):163. doi: 10.1038/s41598-017-18650-x. PMID: 29317749; PMCID: PMC5760633. Tyagi RK, Lavrovsky Y, Ahn SC, Song CS, Chatterjee B, Roy AK (2000) Dynamics of intracellular movement and nucleocytoplasmic recycling of the ligand-activated androgen receptor in living cells. Mol Endocrinol 14: 1162-1174 <a id="_ENREF_21" 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

2024-04-05T08:04:44

Decrease, androgen receptor activation

Decrease, AR activation

Tissue

This KE refers to decreased activation of the androgen receptor (AR) as occurring in complex biological systems such as tissues and organs in vivo. It is thus considered distinct from KEs describing either blocking of AR or decreased androgen synthesis. The AR is a nuclear transcription factor with canonical AR activation regulated by the binding of the androgens such as testosterone or dihydrotestosterone (DHT). Thus, AR activity can be decreased by reduced levels of steroidal ligands (testosterone, DHT) or the presence of compounds interfering with ligand binding to the receptor (Davey & Grossmann, 2016; Gao et al., 2005). In the inactive state, AR is sequestered in the cytoplasm of cells by molecular chaperones. In the classical (genomic) AR signaling pathway, AR activation causes dissociation of the chaperones, AR dimerization and translocation to the nucleus to modulate gene expression. AR binds to the androgen response element (ARE) (Davey & Grossmann, 2016; Gao et al., 2005). Notably, for transcriptional regulation the AR is closely associated with other co-factors that may differ between cells, tissues and life stages. In this way, the functional consequence of AR activation is cell- and tissue-specific. This dependency on co-factors such as the SRC proteins also means that stressors affecting recruitment of co-activators to AR can result in decreased AR activity (Heinlein & Chang, 2002), as shown for the pyrethroid cypermethrin (Wang et al., 2016). Ligand-bound AR may also associate with cytoplasmic and membrane-bound proteins to initiate cytoplasmic signaling pathways with other functions than the nuclear pathway. Non-genomic AR signaling includes association with Src kinase to activate MAPK/ERK signaling and activation of the PI3K/Akt pathway. Decreased AR activity may therefore be a decrease in the genomic and/or non-genomic AR signaling pathways (Leung & Sadar, 2017).

This KE specifically focuses on decreased in vivo activation, with most methods that can be used to measure AR activity carried out in vitro. They provide indirect information about the KE and are described in lower tier MIE/KEs (see for example MIE/KE-26 for AR antagonism, KE-1690 for decreased T levels and KE-1613 for decreased dihydrotestosterone levels). Assays may in the future be developed to measure AR activation in mammalian organisms.

This KE is considered broadly applicable across mammalian taxa as all mammals express the AR in numerous cells and tissues where it regulates gene transcription required for developmental processes and functions. It is, however, acknowledged that this KE most likely has a much broader domain of applicability extending to non-mammalian vertebrates. AOP developers are encouraged to add additional relevant knowledge to expand on the applicability to also include other vertebrates.

High Mixed

High

During development and at adulthood

High

Davey, R. A., & Grossmann, M. (2016). Androgen Receptor Structure, Function and Biology: From Bench to Bedside. The Clinical Biochemist. Reviews, 37(1), 3–15. Gao, W., Bohl, C. E., & Dalton, J. T. (2005). Chemistry and structural biology of androgen receptor. Chemical Reviews, 105(9), 3352–3370. https://doi.org/10.1021/cr020456u Heinlein, C. A., & Chang, C. (2002). Androgen Receptor (AR) Coregulators: An Overview. https://academic.oup.com/edrv/article/23/2/175/2424160 Leung, J. K., & Sadar, M. D. (2017). Non-Genomic Actions of the Androgen Receptor in Prostate Cancer. Frontiers in Endocrinology, 8. <a href="https://doi.org/10.3389/fendo.2017.00002" style="color:#0563c1; text-decoration:underline">https://doi.org/10.3389/fendo.2017.00002</a> OECD (2022). Test No. 251: Rapid Androgen Disruption Activity Reporter (RADAR) assay. Paris: OECD Publishing doi:10.1787/da264d82-en. Wang Q, Zhou JL, Wang H, Ju Q, Ding Z, Zhou XL, Ge X, Shi QM, Pan C, Zhang JP, Zhang MR, Yu HM, Xu LC. (2016). Inhibition effect of cypermethrin mediated by co-regulators SRC-1 and SMRT in interleukin-6-induced androgen receptor activation. Chemosphere. 158:24-9. doi: 10.1016/j.chemosphere.2016.05.053 <table> <tbody> <tr> <td colspan="1" rowspan="1">   </td> <td colspan="1" rowspan="1">   </td> </tr> </tbody> </table> AOPWiki 2019-04-10T05:04:18

2026-02-04T16:01:38

Malformation, cryptorchidism - maldescended testis

Malformation, cryptorchidism

Organ

Undescended testis is a testicular disorder syndrome known as  cryptorchidism. Testis migration is a major event in male fetus development, as it will directly affect his reproductive health. Cryptorchidism can defined itself as the insertion of the testis in another position than the scrotum. Although the events leading to this pathology occurred during development, cryptorchidism can only be defined after birth though clinical examination as palpation. Cryptorchidism can be either uni- or bilateral and has been reported to increase in incidence over the decades (Denmark, UK, India…). The maldescended testis will experiment heat stress (37 against 33C outside the body) interfering with testicular physiology and development of germ cells into spermatogonia. Germ cells maturation failure will induce a non-reversible reduction in fertility power of the individual. Cryptorchidism is an established risk factor for infertility and is known to increase the incidence of testicular germ cell tumors (TGCT) 123   Remark:  <table> <tbody> <tr> <td colspan="1" rowspan="1"> Cryptorchidism is the first AO of a larger list including raise in testicular cancer and germ cell tumor incidence, as well as reduced fertility due to impairment in germ cells maturation. </td> </tr> </tbody> </table>

Cryptorchidism is a birth defect that can be highlighted by a clinical examination. The aim of this palpation is to locate the gonad and determine its lowest position without causing painful traction on the spermatic cord. 4

Life Stage: Problems first can be observed during development, with adverse outcome manifesting in mature individuals. Sex: Applies to males. Taxonomic: Most representative studies have been done in mammals (humans, lab mice, lab rats) with clinical observations in humans; plausible for all vertebrates with descended testes.     NOTE: Italics symbolize edits from John Frisch

High Male

Moderate

During development and at adulthood

Moderate

1 Hutson J.M., Li R., Southwell B.R., Newgreen D., and Cousinery M. (2015) Regulation of testicular descent. Pediatric Surgery International, 31(4): 317-325. <a href="https://www.google.com/url?q=https://doi.org/10.1007/s00383-015-3673-4&sa=D&ust=1554891396648000">https://doi.org/10.1007/s00383-015-3673-4</a>  2 Boisen K.A., Kaleva M., Main K.M., Virtanen H.E., Haavisto A.M., Schmidt I.M., Chellakooty M., Damgaard I.N., Mau C., Reunanen M., Skakkebaek N.E. and Toppari J. (2004) Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet, 17;363(9417):1264-9 <a href="https://www.google.com/url?q=https://doi.org/10.1016/S0140-6736(04)15998-9&sa=D&ust=1554891396649000">https://doi.org/10.1016/S0140-6736(04)15998-9</a>  3 Acerini C.L., Miles H.L., Dunger D.B., Ong K.K. and Hughes I.A. (2009) The descriptive epidemiology of congenital and acquired cryptorchidism in a UK infant cohort. Archives of disease in childhood, 94(11):868-72 https://doi.org10.1136/adc.2008.150219  4 Hutson J.M., et al. (2015) Cryptorchidism and Hypospadias. Endotext<a href="https://www.google.com/url?q=https://www.ncbi.nlm.nih.gov/books/NBK279106/&sa=D&ust=1554891396651000">https://www.ncbi.nlm.nih.gov/books/NBK279106/</a>  AOPWiki 2019-04-10T05:06:57

2024-07-18T10:30:03

Testicular Cancer

Organ

AOPWiki 2021-02-12T12:17:36

2021-02-12T12:17:36

Altered, Transcription of genes by the androgen receptor

Altered, Transcription of genes by the AR

Tissue

This KE refers to transcription of genes by the androgen receptor (AR) as occurring in complex biological systems such as tissues and organs in vivo. Rather than measuring individual genes, this KE aims to capture patterns of effects at transcriptome level in specific target cells/tissues. In other words, it can be replaced by specific KEs for individual adverse outcomes as information becomes available, for example the transcriptional toxicity response in prostate tissue for AO: prostate cancer, perineum tissue for AO: reduced AGD, etc.  AR regulates many genes that differ between tissues and life stages and, importantly, different gene transcripts within individual cells can go in either direction since AR can act as both transcriptional activator and suppressor. Thus, the ‘directionality’ of the KE cannot be either reduced or increased, but instead describe an altered transcriptome. The Androgen Receptor and its function 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). Androgens (such as dihydrotestosterone and testosterone) are AR ligands and act by binding to the AR in androgen-responsive tissues (Davey and Grossmann 2016). Human AR mutations and mouse knockout models have established a fundamental role for 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).   Altered transcription of genes by the AR as a Key Event Upon activation by ligand-binding, the AR translocates 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 vary between cells and tissues, as well as with developmental stages and is also dependent on available co-regulators (Bevan and Parker 1999; Heemers and Tindall 2007). It should also be mentioned that the AR can work in other ‘non-canonial’ ways such as non-genomic signaling, and ligand-independent activation (Davey & Grossmann, 2016; Estrada et al, 2003; Jin et al, 2013). A large number of 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, Jin et al. 2013).

Altered 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, e.g. transcriptomics. Since this KE aims to capture AR-mediated transcriptional patterns of effect, downstream bioinformatics analyses will typically be required to identify and compare effect footprints. Clusters of genes can be statistically associated with, for example, biological process terms or gene ontology terms relevant for AR-mediated signaling. Large transcriptomics data repositories can be used to compare transcriptional patterns between chemicals, tissues, and species (e.g. TOXsIgN (Darde et al, 2018a; Darde et al, 2018b), comparisons can be made to identified sets of AR ‘biomarker’ genes (e.g. as done in (Rooney et al, 2018)), and various methods can be used e.g. connectivity mapping (Keenan et al, 2019).

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).  This KE is considered broadly applicable across mammalian taxa, sex and developmental stages, as all mammals express the AR in numerous cells and tissues where it regulates gene transcription required for developmental processes and function. It is, however, acknowledged that this KE most likely has a much broader domain of applicability extending to non-mammalian vertebrates. AOP developers are encouraged to add additional relevant knowledge to expand on the applicability to also include other vertebrates.

High Mixed

High

During development and at adulthood

High

Bevan C, Parker M (1999) The role of coactivators in steroid hormone action. Exp. Cell Res. 253:349–356 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 Darde, T. A., Gaudriault, P., Beranger, R., Lancien, C., Caillarec-Joly, A., Sallou, O., et al. (2018a). TOXsIgN: a cross-species repository for toxicogenomic signatures. Bioinformatics 34, 2116–2122. doi:10.1093/bioinformatics/bty040. Darde, T. A., Chalmel, F., and Svingen, T. (2018b). Exploiting advances in transcriptomics to improve on human-relevant toxicology. Curr. Opin. Toxicol. 11–12, 43–50. doi:10.1016/j.cotox.2019.02.001. Davey RA, Grossmann M (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev 37:3–15 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 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 Jin, Hong Jian, Jung Kim, and Jindan Yu. 2013. “Androgen Receptor Genomic Regulation.” Translational Andrology and Urology 2(3):158–77. doi: 10.3978/j.issn.2223-4683.2013.09.01 Keenan, A. B., Wojciechowicz, M. L., Wang, Z., Jagodnik, K. M., Jenkins, S. L., Lachmann, A., et al. (2019). Connectivity Mapping: Methods and Applications. Annu. Rev. Biomed. Data Sci. 2, 69–92. doi:10.1146/ANNUREV-BIODATASCI-072018-021211. Maclean HE, Chu S, Warne GL, Zajact JD Related Individuals with Different Androgen Receptor Gene Deletions 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 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<a name="_Hlk148352925"></a> Rana K, Davey RA, Zajac JD (2014) Human androgen deficiency: Insights gained from androgen receptor knockout mouse models. Asian J. Androl. 16:169–177 Rooney, J. P., Chorley, B., Kleinstreuer, N., and Corton, J. C. (2018). Identification of Androgen Receptor Modulators in a Prostate Cancer Cell Line Microarray Compendium. Toxicol. Sci. 166, 146–162. doi:10.1093/TOXSCI/KFY187. 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 AOPWiki 2016-11-29T18:41:23

2024-04-05T09:28:17

Androgen receptor antagonism leading to testicular cancer

Androgen receptor antagonism and testicular cancer

Chander K. Negi

BY-SA

2.0

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>).

AOPWiki 2021-02-12T12:12:19

2024-12-23T15:28:43