Decreased, Testosterone binding to androgen receptor (hypothalamus)

CHEBI:17347

CHEBI testosterone

CL:0000178

CL Leydig cell

CHEBI:81568

CHEBI Luteinizing hormone

PR:000004191

PR androgen receptor

GO:0005102

GO receptor binding

MP:0001152

MP Leydig cell hyperplasia

MP:0002006

MP neoplasm

GO:0004882

GO androgen receptor activity

WIKI decreased

WIKI increased

WikiUser_17

mammals

10116

NCBI Rattus norvegicus

Decreased, Testosterone binding to androgen receptor (hypothalamus)

Molecular

CL:2000030

CL hypothalamus native cell

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:08

Increase, Hyperplasia (Leydig cells)

Cellular

CL:0000178

CL Leydig cell

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:09

Increase, Leydig cell tumors

Cellular

CL:0000178

CL Leydig cell

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:09

Increased, Luteinizing hormone (LH)

Tissue

UBERON:0000178

UBERON blood

AOPWiki 2016-11-29T18:41:26

2017-09-16T10:16:09

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 activation 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 activation 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

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AOPWiki 2024-12-23T15:11:03

2024-12-23T15:11:03

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AOPWiki 2016-11-29T18:41:35

2016-12-03T16:37:59

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AOPWiki 2016-11-29T18:41:35

2016-12-03T16:38:00

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AOPWiki 2016-11-29T18:41:35

2016-12-03T16:38:00

Decrease in androgen receptor activity leading to Leydig cell tumors (in rat)

Decreased AR activity- Leydig cell tumors

Charles Wood

Cancer AOP group. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)

BY-SA

1.0

This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.

adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified Male Not Specified

Cook, J. C., Klinefelter, G. R., Hardisty, J. F., Sharpe, R. M., & Foster, P. M. (1999). Rodent Leydig cell tumorigenesis: a review of the physiology, pathology, mechanisms, and relevance to humans. Crit Rev Toxicol, 29(2), 169-261. doi: 10.1080/10408449991349203 AOPWiki 2016-11-29T18:41:16

2026-01-11T16:56:07