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Event: 1614
Key Event Title
Decrease, androgen receptor activation
Short name
Biological Context
Level of Biological Organization |
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Tissue |
Organ term
Key Event Components
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
Cyp17A1 inhibition leads to undescended testes in mammals | KeyEvent | Bérénice COLLET (send email) | Open for citation & comment | |
5α-reductase inhibition leading to short AGD | KeyEvent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
AR antagonism leading to short AGD | KeyEvent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
Decreased testosterone synthesis leading to short AGD | KeyEvent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
AR antagonism leading to NR | KeyEvent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
Androgen receptor antagonism and testicular cancer | KeyEvent | Chander K. Negi (send email) | Under development: Not open for comment. Do not cite | |
AR antagonism leading to hypospadias | KeyEvent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Vertebrates | Vertebrates | High | NCBI |
Life Stages
Life stage | Evidence |
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During development and at adulthood | High |
Sex Applicability
Term | Evidence |
---|---|
Mixed | High |
Key Event Description
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 (Davey & Grossmann, 2016; Gao et al., 2005). AR does not, however, act alone in regulating gene transcription, but together with other co-factors that may differ between cells and tissues and life stages. In this way, the functional consequence of AR activation is cell- and tissue-dependent.
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).
How It Is Measured or Detected
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 MIE/KE-26 for AR antagonism, KE-1690 for decreased T levels and KE-1613 for decreased dihydrotestosterone levels). In this way, this KE is a placeholder for tissue-specific responses to AR activation or inactivation that will depend on the adverse outcome (AO) for which it is included.
It should be mentioned that the Rapid Androgen Disruption Activity Reporter (RADAR) assay included in OECD test guideline no. 251 detects AR antagonism in vivo in fish (OECD 2022).
Domain of Applicability
This KE is considered broadly applicable across vertebrate taxa as all vertebrate animals express the AR in numerous cells and tissues where it regulates gene transcription required for developmental processes and functions.
References
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
Hutson, J. M. (1985). A biphasic model for the hormonal control of testicular descent. The Lancet, 24, 419–421. https://doi.org/https://doi.org/10.1016/S0140-6736(85)92739-4
Kaftanovskaya, E. M., Huang, Z., Barbara, A. M., de Gendt, K., Verhoeven, G., Gorlov, I. P., & Agoulnik, A. I. (2012). Cryptorchidism in mice with an androgen receptor ablation in gubernaculum testis. Molecular Endocrinology, 26(4), 598–607. https://doi.org/10.1210/me.2011-1283
Lee, S. H., Hong, K. Y., Seo, H., Lee, H. S., & Park, Y. (2021). Mechanistic insight into human androgen receptor-mediated endocrine-disrupting potentials by a stable bioluminescence resonance energy transfer-based dimerization assay. Chemico-Biological Interactions, 349. https://doi.org/10.1016/j.cbi.2021.109655
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
OECD (2022). Test No. 251: Rapid Androgen Disruption Activity Reporter (RADAR) assay. Paris: OECD Publishing doi:10.1787/da264d82-en.
Pang, T. P. S., Clarke, M. v., Ghasem-Zadeh, A., Lee, N. K. L., Davey, R. A., & MacLean, H. E. (2012). A physiological role for androgen actions in the absence of androgen receptor DNA binding activity. Molecular and Cellular Endocrinology, 348(1), 189–197. https://doi.org/10.1016/j.mce.2011.08.017