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Event: 26

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Antagonism, Androgen receptor

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Antagonism, Androgen receptor
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
eukaryotic cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
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

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Vertebrates Vertebrates High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
During development and at adulthood High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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, 2004van 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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

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

List of the literature that was cited for this KE description. More help

Davey RA, Grossmann M (2016) Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev 37: 3-15

Heemers HV, Tindall DJ (2007) Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev 28: 778-808

Heinlein CA, Chang C (2002) The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol 16: 2181-2187

Körner W, Vinggaard AM, Térouanne B, Ma R, Wieloch C, Schlumpf M, Sultan C, Soto AM (2004) Interlaboratory comparison of four in vitro assays for assessing androgenic and antiandrogenic activity of environmental chemicals. Environ Health Perspect 112: 695-702

Lee SH, Hong KY, Seo H, Lee HS, Park Y (2021) Mechanistic insight into human androgen receptor-mediated endocrine-disrupting potentials by a stable bioluminescence resonance energy transfer-based dimerization assay. Chem Biol Interact 349: 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

MacLean HE, Chu S, Warne GL, Zajac JD (1993) Related individuals with different androgen receptor gene deletions. J Clin Invest 91: 1123-1128

MacLeod DJ, Sharpe RM, Welsh M, Fisken M, Scott HM, Hutchison GR, Drake AJ, van den Driesche S (2010) Androgen action in the masculinization programming window and development of male reproductive organs. Int J Androl 33: 279-287

OECD. (2016) Test No. 458: Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals. OECD Guidelines for the Testing of Chemicals, Section 4, Paris.

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.

Rana K, davey RA, Zajac JD (2014) Human androgen deficiency: insights gained from androgen receptor knockout mouse models. Asian J Androl 16: 169-177

Satoh K, Ohyama K, Aoki N, Iida M, Nagai F (2004) Study on anti-androgenic effects of bisphenol a diglycidyl ether (BADGE), bisphenol F diglycidyl ether (BFDGE) and their derivatives using cells stably transfected with human androgen receptor, AR-EcoScreen. Food Chem Toxicol 42: 983-993

Schuppe, E. R., Miles, M. C., and Fuxjager, M. J. (2020). Evolution of the androgen receptor: Perspectives from human health to dancing birds. Mol. Cell. Endocrinol. 499, 110577. doi:10.1016/J.MCE.2019.110577 

Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U, Svingen T (2019) Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. Arch Toxicol 93: 253-272

Sonneveld E, Jansen HJ, Riteco JA, Brouwer A, van der Burg B (2005) Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays. Toxicol Sci 83: 136-148

van der Burg B, Winter R, Man HY, Vangenechten C, Berckmans P, Weimer M, Witters H, van der Linden S (2010) Optimization and prevalidation of the in vitro AR CALUX method to test androgenic and antiandrogenic activity of compounds. Reprod Toxicol 30: 18-24

Walters KA, Simanainen U, Handelsman DJ (2010) Molecular insights into androgen actions in male and female reproductive function from androgen receptor knockout models. Hum Reprod Update 16: 543-558