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Relationship: 3378

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Agonism, Androgen receptor leads to Androgen receptor activation, increased

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Agonism, Androgen receptor

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Androgen receptor activation, increased

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Androgen receptor agonism leading to long anogenital distance in female offspring	adjacent	High	Low	Johanna Zilliacus (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 Do not cite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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
mammals	mammals	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Mixed	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
During development and at adulthood	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

The androgen receptor (AR) belongs to the steroid hormone receptor family and mediates the biological effects of androgens. AR agonism is the activation of the receptor by an agonist, a ligand, that binds and activates the receptor function leading to increased AR activity in tissues and organs in vivo, which results in effects on sexual development and reproductive function, as well as effects on other organs and tissues (Dalton & Gao, 2010; Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022; Sutinen et al., 2017).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The KER describes a generally recognized and understood process, i.e. canonical knowledge. A literature search was therefore performed to identify review articles and book chapter that summarise the canonical knowledge.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The activation of the AR is a generally recognized process, i.e. canonical knowledge and the biological plausibility of the KER is considered high.

The AR belongs to the family of steroid hormone nuclear receptors. It contains three major domains essential for its activity: the N-terminal region, the ligand binding domain (LBD), and the DNA binding domain (DBD). In the absence of a ligand, the AR resides in the cytoplasm. Upon binding of an agonist such as endogenous hormones (testosterone or dihydrotestosterone) or a compound acting as an agonist, AR is activated, forms a homodimer, translocates into the nucleus and binds to androgen-response elements to regulate target gene transcription by recruiting cofactor protein complexes. Additionally, the AR can also have rapid non-genomic actions by binding to plasma membrane proteins and activating kinase signalling in the cytoplasm. AR agonism results in increased AR activity in vivo that can affect numerous biological processes, including 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 & Gao, 2010; Luetjens & Weinbauer, 2012; Naamneh Elzenaty et al., 2022; Sutinen et al., 2017).

The role of AR agonism is evident in diseases, for instance in prostate cancer in men, which depends on androgen activity for growth (Naamneh Elzenaty et al., 2022), and polycystic ovary syndrome (PCOS) in women, which is associated with increased AR activity (Naamneh Elzenaty et al., 2022).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The activation of the AR is a generally recognized process and is supported by empirical evidence for AR agonists.

Testosterone propionate, 17-methyl testosterone and trenbolone were identified as agonists in the US EPA Androgen receptor pathway model, which integrates in vitro assays for receptor binding, coregulator recruitment and transactivation, and these stressors have also been shown to increase AR activation in Hershberger assay or other in vivo assays (Kleinstreuer et al., 2018; Browne et al., 2018).

Compounds that act as AR agonists have been used as positive controls in validation of OECD TG 458 and in validation studies by ICCVAM (OECD, 2023; ICCVAM, 2003). Compounds acting as AR agonists have been evaluated in ToxCast in vitro assays for AR (U.S. EPA, 2022).

Synthetic androgen ligands have been developed as potential drugs for the treatment of androgen related disorders; selective AR modulator are ligands acting as tissue-specific AR agonists and are being studied for effects on anemias, osteoporosis, muscle wasting and benign hyperplasia of the prostate but have not yet been approved for clinical use (Dalton & Gao, 2010; Luetjens & Weinbauer, 2012).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

No uncertainties or inconsistences have been identified for the KER that is based on canonical knowledge.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

No specific evidence for response-response relationships has been identified for the KER.

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Agonism of the AR results rapidly in increased AR activity in vivo. Effects on activation of the receptor on cellular function can be seen after minutes to hours (Naamneh Elzenaty et al., 2022; Sutinen et al., 2017).

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

No specific evidence for feedforward or feedback loops has been identified for the KER.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

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 androgen receptor activity has been studied. The KER 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 & Gao, 2010; Luetjens & Weinbauer, 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).

References

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

Browne, P., Kleinstreuer, N.C., Ceger, P., Deisenroth, C., Baker, N., Markey, K., Thomas, R.S., Judson, R.J. & Casey, W. (2018) Development of a curated Hershberger database. Reprod Toxicol. 81:259-271. https://doi.org/10.1016/j.reprotox.2018.08.016

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

ICCVAM (2003) Binding, A. R. ICCVAM Evaluation of In Vitro Test Methods for Detecting Potential Endocrine Disruptors. https://ntp.niehs.nih.gov/sites/default/files/iccvam/docs/endo_docs/edfinalrpt0503/edfinrpt.pdf

Kleinstreuer, N. C., Ceger, P., Watt ,E.D., Martin, M., Houck, K., Browne ,P., Thomas, R.S., Casey, W.M., Dix, D.J., Allen, D., Sakamuru, S., Xia, M., Huang, R. & Judson R. (2017). Development and Validation of a Computational Model for Androgen Receptor Activity. Chemical Research in Toxicology 30 (4): 946–64. https://doi.org/10.1021/acs.chemrestox.6b00347

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.(2023). Test No. 458: Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist Activity of Chemicals. OECD. https://doi.org/10.1787/9789264264366-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

U.S EPA. 2022. Performance Summary for Estrogen Receptor and Androgen Receptor Pathway Models and Associated Assays. https://www.epa.gov/comptox-tools/exploring-toxcast-data