Androgen receptor activation, increased

The androgen receptor (AR) belongs to the steroid hormone receptor family and mediates the biological effects of androgens. Increased AR activation described in this KE is occurring in complex biological systems such as tissues and organs in vivo due either to AR agonism (i.e. activation of the receptor by a compound) or to increased levels of the endogenous hormones testosterone or dihydrotestosterone (DHT). It is thus considered distinct from KEs describing either AR agonism or increased hormone levels.

In the absence of ligand, the AR resides in the cytoplasm. Upon binding of endogenous hormone or a compound acting as an agonist, the receptor is activated, forms a homodimer, translocates into the nucleus and binds to androgen-response elements and regulates target gene transcription by recruiting cofactor protein complexes. The AR can also exert rapid non-genomic action by binding to plasma membrane proteins and activating kinase signalling in the cytoplasm. Increased AR activity can have various effects in vivo, including on sexual development and reproductive function, as well as effects on other organs such as adipose tissue, bone, brain, cardiovascular system, hair, muscle and skin (Dalton et al., 2010; Davey & Grossmann, 2016; Luetjens et al., 2012; Naamneh Elzenaty et al., 2022; Sutinen et al., 2017).

This KE specifically focuses on increased in vivo activation, but most methods that can be used to measure AR activity are carried out in vitro. They provide indirect information about the KE and are described in lower tier KEs (for example KE-25 for AR agonism, KE-2272 for increased testosterone levels or KE-2273 for increased dihydrotestosterone levels). In this way, this KE is a placeholder for tissue-specific responses to AR activation that will depend on the adverse outcome (AO) for which it is included.

In fish, The Rapid Androgen Disruption Activity Reporter (RADAR) assay included in OECD test guideline no. 251 can be used to measure genomic AR activity (OECD, 2022). Employing a spg1-gfp construct under control of the AR-binding promoter spiggin1 in medaka fish embryos, any stressor activating or inhibiting the androgen axis will be detected. This includes for instance stressors that agonize or antagonize AR, as well as stressors that modulate androgen synthesis or metabolism. Non-genomic AR activity cannot be detected by the RADAR assay. Similar assays may in the future be developed to measure AR activity in mammalian organisms. 

Taxonomic applicability.

The AR is present in vertebrates. Mammals, birds and amphibians have one AR gene, whereas some fish species have two genes. AR activity has been studied in mammals, fish, birds and amphibians (Ogino et al., 2018). The biologically plausible domain of taxonomic applicability is vertebrates since the AR is present in vertebrates. The empirical domain of taxonomic applicability is human, rat and mice increased AR activity has been studied. The KE description focuses on mammals, but AOP developers are encouraged to expand the applicability to other species.

Life stage applicability

The AR is expressed from the fetal period throughout adult life and increased activity of the AR controls sexual development during the fetal period and reproductive function as well as effects in other organs during puberty and adulthood (Dalton et al., 2010; Luetjens et al., 2012; Naamneh Elzenaty et al., 2022; Sutinen et al., 2017).

Sex applicability

The AR is expressed in both males and females and has important roles for sexual development and reproduction as well as effects in other organs in both sexes (Naamneh Elzenaty et al., 2022; Sutinen et al., 2017).

Dalton, J. T., & Gao, W. (2010). Androgen Receptor. In C. M. Bunce & M. J. Campbell (Eds.), Nuclear Receptors (pp. 143–182). Springer Netherlands. https://doi.org/10.1007/978-90-481-3303-1_6

Davey, R.A., Grossmann, M. (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev. 2016 Feb;37(1):3-15. PMID: 27057074; PMCID: PMC4810760.

Luetjens, C. M., & Weinbauer, G. F. (2012). Testosterone: biosynthesis, transport, metabolism and (non-genomic) actions. In Testosterone (pp. 15–32). Cambridge University Press. https://doi.org/10.1017/CBO9781139003353.003

Naamneh Elzenaty, R., du Toit, T., & Flück ,C.E. (2022). Basics of androgen synthesis and action. Best Practice & Research. Clinical Endocrinology & Metabolism, 36(4), 101665. https://doi.org/10.1016/j.beem.2022.101665

OECD (2022). Test No. 251: Rapid Androgen Disruption Activity Reporter (RADAR) assay. OECD Guidelines for the Testing of Chemicals, Section 2, OECD Publishing, Paris, https://doi.org/10.1787/da264d82-en

Ogino, Y., Tohyama, S., Kohno, S., Toyota, K., Yamada, G., Yatsu, R., Kobayashi, T., Tatarazako, N., Sato, T., Matsubara, H., Lange, A., Tyler, C.R., Katsu, Y., Iguchi, T., & Miyagawa, S. (2018). Functional distinctions associated with the diversity of sex steroid hormone receptors ESR and AR. The Journal of Steroid Biochemistry and Molecular Biology, 184, 38–46. https://doi.org/10.1016/j.jsbmb.2018.06.002

Sutinen, P., Malinen, M., & Palvimo, J. J. (2017). Androgen Receptor. In M. Simoni & I. T. Huhtaniemi (Eds.), Endocrinology of the Testis and Male Reproduction (pp. 395–416). Springer International Publishing. https://doi.org/10.1007/978-3-319-44441-3_12