Aopwiki

Event: 26

Key Event Title
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Antagonism, Androgen receptor

Short name
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Antagonism, Androgen receptor

Biological Context
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Level of Biological Organization
Molecular

Cell term
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Cell term
eukaryotic cell

Organ term
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Key Event Components
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Process	Object	Action

Key Event Overview

AOPs Including This Key Event
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AOP Name	Role of event in AOP
AR antagonism leading to short AGD	MolecularInitiatingEvent
AR antagonism leading to NR	MolecularInitiatingEvent
AR antagonism leading to decreased fertility	MolecularInitiatingEvent

Stressors
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Name
Mercaptobenzole
Triticonazole
Flusilazole
Epoxiconazole
Prochloraz
Propiconazole
Tebuconazole
Flutamide
Cyproterone acetate
Vinclozolin

Taxonomic Applicability
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Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI
human and other cells in culture	human and other cells in culture	High	NCBI

Life Stages
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Life stage	Evidence
Foetal	High
Embryo	Moderate
During development and at adulthood	High

Sex Applicability
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Term	Evidence
Mixed	High

Key Event Description
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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 (MacLean et al, 1993; MacLeod et al, 2010; Schwartz et al, 2019), with human AR mutations and mouse knock-out models having established its pivotal role in masculinization and spermatogenesis (Walters et al, 2010). The AR is a ligand-activated transcription factor belonging to the steroid hormone nuclear receptor family (Davey & Grossmann, 2016). 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 (Walters et al, 2010), the AR is also expressed in many other tissues and organs such as bone, muscles, ovaries and the immune system (Rana et al, 2014).

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 (Heemers & Tindall, 2007). 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 (Heinlein & Chang, 2002). However, with regard to this specific KE the canonical signaling pathway is what is referred to.

How It Is Measured or Detected
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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 (OECD, 2016). The stably transfected AR-EcoScreenTM cell line 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 (van der Burg et al, 2010).

Domain of Applicability
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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 & Grossmann, 2016). 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 (Walters et al, 2010).

This KE is applicable for both sexes, across developmental stages into adulthood, in numerous cells and tissues and across taxa

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event
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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 (Alapi & Fischer, 2006). 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 (Foster & Harris, 2005; Hass et al, 2007; Kita et al, 2016). QSAR models can predict AR antagonism for a wide range of chemicals, many of which have shown in vitro antagonistic potential (Vinggaard et al, 2008).