This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
Event: 26
Key Event Title
Antagonism, Androgen receptor
Short name
Biological Context
Level of Biological Organization |
---|
Molecular |
Cell term
Cell term |
---|
eukaryotic cell |
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 |
---|---|---|---|---|
AR antagonism leading to short AGD | MolecularInitiatingEvent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
AR antagonism leading to NR | MolecularInitiatingEvent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
AR antagonism leading to decreased fertility | MolecularInitiatingEvent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
Androgen receptor antagonism and testicular cancer | MolecularInitiatingEvent | Chander K. Negi (send email) | Under development: Not open for comment. Do not cite | |
AR antagonism leading to hypospadias | MolecularInitiatingEvent | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | |
Adverse Outcome Pathways diagram related to PBDEs associated male reproductive toxicity | MolecularInitiatingEvent | Yue Zhang (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 Do not cite |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 |
---|---|
During development and at adulthood | High |
Sex Applicability
Term | Evidence |
---|---|
Mixed | High |
Key Event Description
The androgen receptor (AR) and its function
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. Testosterone (T) and the more biologically active dihydrotestosterone (DHT) are endogenous ligands for the AR (MacLean et al, 1993; MacLeod et al, 2010; Schwartz et al, 2019). In teleost fishes, 11-ketotestosterone is the second main ligand (Schuppe et al, 2020). Human AR mutations and mouse knock-out models have established a pivotal role for the AR in masculinization and spermatogenesis (Walters et al, 2010). Apart from the essential role for AR in 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 initiate cytoplasmic signaling pathways with other functions than the nuclear pathway, for instance rapid change in cell function by ion transport changes (Heinlein & Chang, 2002) and association with Src kinase to activate MAPK/ERK signaling and activation of the PI3K/Akt pathway (Leung & Sadar, 2017).
How It Is Measured or Detected
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 cells (Satoh et al, 2004) should be used for the assay and are freely available from 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 (Sonneveld et al, 2004; van der Burg et al, 2010), various transiently transfected reporter cell lines (Körner et al, 2004), and more.
The recently developed AR dimerization assay provides an assay with an improved ability to measure potential stressor-mediated disruption of dimerization/activation (Lee et al, 2021).
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
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). Likewise in fish, androgens are important for development of sexual characteristics (Ogino et al., 2014, 2023). One difference that must be mentioned is that in teleost fish, 11-ketotestosterone is the main androgen in addition to testosterone and DHT and that most teleosts have two ar ohnologs, ara and arb, with arb functioning in a similar manner to the AR in other vertebrates (Ogino et al., 2023).
This KE is applicable for both sexes, across developmental stages into adulthood, in numerous cells and tissues and across vertebrate taxa
References
OECD (2022). Test No. 251: Rapid Androgen Disruption Activity Reporter (RADAR) assay. Paris: OECD Publishing doi:10.1787/da264d82-en.
Ogino, Y., Ansai, S., Watanabe, E., Yasugi, M., Katayama, Y., Sakamoto, H., et al. (2023). Evolutionary differentiation of androgen receptor is responsible for sexual characteristic development in a teleost fish. Nat. Commun. 2023 141 14, 1–16. doi:10.1038/s41467-023-37026-6.
Ogino, Y., Hirakawa, I., Inohaya, K., Sumiya, E., Miyagawa, S., Denslow, N., et al. (2014). Bmp7 and Lef1 Are the Downstream Effectors of Androgen Signaling in Androgen-Induced Sex Characteristics Development in Medaka. Endocrinology 155, 449–462. doi:10.1210/EN.2013-1507.