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Relationship: 2201

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

Antagonism, Androgen receptor leads to Altered, Transcription of genes by AR

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 (AR) antagonism leading to decreased fertility in females adjacent High Moderate Cataia Ives (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 Do not cite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
rat Rattus norvegicus High NCBI
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
zebrafish Danio rerio High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High
Female High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages 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 AR is a nuclear hormone receptor that functions primarily as a transcription factor. After binding of a ligand (androgens: DHT, testosterone) to the AR, the androgen-AR complex translocate to the nucleus and bind to specific hormone response elements on the DNA duplex to regulate gene transcription. The AR is expressed in various cells and tissues throughout the body in a spatiotemporal manner, with levels and activation changed in response to androgen signaling (Chang et al, 1995; Davey & Grossmann, 2016; Roy et al, 1999).

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

Evidence Supporting this KER

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

The fact that AR exert its primary function as a nuclear transcription factor is well-established and a generally accepted fact. Binding of androgens (ligands) to the AR induces receptor activation and transcriptional regulation of target genes (Chang et al, 1995; Davey & Grossmann, 2016; Heemers & Tindall, 2007). After binding to Androgen Response Elements (AREs), the AR can recruit a variety of co-regulators (activators or repressors) that will influence the transcriptional regulation of target genes and thereby achieve spatiotemporally regulated gene expression (Heemers & Tindall, 2007). Consequently, inhibition/competition of ligand binding to the AR leading to reduced activity will have an effect on downstream transcriptional function.

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 fact that AR exert its primary function as a nuclear transcription factor is well-established and a generally accepted fact. Binding of androgens (ligands) to the AR induces receptor activation and transcriptional regulation of target genes (Chang et al, 1995; Davey & Grossmann, 2016; Heemers & Tindall, 2007). After binding to Androgen Response Elements (AREs), the AR can recruit a variety of co-regulators (activators or repressors) that will influence the transcriptional regulation of target genes and thereby achieve spatiotemporally regulated gene expression (Heemers & Tindall, 2007). Consequently, inhibition/competition of ligand binding to the AR leading to reduced activity will have an effect on downstream transcriptional function.

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

The AR gene contains CAG repeats (encoding for the amino acid glutamine), which vary between individuals and will affect transcriptional function. Broadly speaking, fewer CAG repeats tend to render the AR more sensitive to androgen activation whereas more CAG repeats tend to render the AR less sensitive, albeit the functional relevance at the tissue/organ level remains less clear (Tirabassi et al, 2015; Zitzmann, 2009). It is plausible, however, that it may lead to variable sensitivity to AR antagonism.

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

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

References

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

Chang AY, Saltzman A, Yeh S, Young W, Keller E, Lee HJ, Wang HJ, Mizokami A (1995) Androgen receptor: an overview. Critical Reviews in Eukaryotic Gene Expression 5: 97-125

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

Furr BJ (1988) ICI 176,334: a novel non-steroidal, peripherally-selective antiandrogen. Prog Clin Biol Res 260: 13-26

Gray LE, Furr JR, Lambright CS, Evans N, Hartig PC, Cardon MC, Wilson VS, Hotchkiss AK, Conley JM (2020) Quantification of the Uncertainties in Extrapolating From In Vitro Androgen Receptor Antagonism to In Vivo Hershberger Assay Endpoints and Adverse Reproductive Development in Male Rats. Toxicol Sci 176: 297-311

Grosse A, Bartsch S, Baniahmad A (2012) Androgen receptor-mediated gene repression. Mol Cell Endocrinol 352: 46-56

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

Irwin RJ, Prout Jr GR (1973) A new antiprostatic agent for treatment of prostatic carcinoma. Surg Forum 24: 536-537

Kleinstreuer NC, Ceger P, Watt ED, Martin M, Houck K, Browne P, Thomas RS, Casey WM, Dix DJ, Allen D, Sakamuru S, Xia M, Huang R, Judson R (2017) Development and Validation of a Computational Model for Androgen Receptor Activity. Chem Res Toxicol 30: 946-964

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

Lamb AD, Massie CE, Neal DE (2014) The transcriptional programme of the androgen receptor (AR) in prostate cancer. BJU Int 113: 358-366

Lamont KR, Tindall DJ (2010) Androgen regulation of gene expression. Adv Cancer Res 107: 137-162

Martinović-Weigelt D, Wang RL, Villeneuve DL, Bencic DC, Lazorchak J, Ankley GT (2011) Gene expression profiling of the androgen receptor antagonists flutamide and vinclozolin in zebrafish (Danio rerio) gonads. Aquat Toxicol 101: 447-458

Matsumoto T, Sakari M, Okada M, Yokoyama A, Takahashi S, Kouzmenko A, Kato S (2013) The androgen receptor in health and disease. Annu Rev Physiol 75: 201-224

Mikkonen L, Pihlajamaa P, Sahu B, Zhang FP, Jänne OA (2010) Androgen receptor and androgen-dependent gene expression in lung. Mol Cell Endocrinol 317: 14-24

Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (2015) Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep 5: 12007

Nash C, Boufaied N, Badescu D, Wang YC, Paliouras M, Trifiro M, Ragoussis I, Thomson AA (2019) Genome-wide analysis of androgen receptor binding and transcriptomic analysis in mesenchymal subsets during prostate development. Dis Model Mech 12: dmm039297

Ngan S, Stronach EA, Photiou A, Waxman J, Ali S, Buluwela L (2009) Microarray coupled to quantitative RT–PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells. Oncogene 28: 2051-2063

Olsen JR, Azeem W, Hellem MR, Marvyin K, Hua Y, Qu Y, Li L, Lin B, Ke XS, Øyan AM, Kalland KH (2016) Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes. BMC Cancer 16: 377

Rondeau G, Abedinpour P, Chrastina A, Pelayo J, Borgstrom P, Welsh J (2018) Differential gene expression induced by anti-cancer agent plumbagin is mediated by androgen receptor in prostate cancer cells. Sci Rep 8: 2694

Roy AK, Lavrovsky Y, Song CS, Chen S, Jung MH, Velu NK, Bi BY, Chatterjee B (1999) Regulation of androgen action. Vitam Horm 55: 309-352

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

Schwartz CL, Vinggaard AM, Christiansen S, Darde TA, Chalmel F, Svingen T (2019) Distinct transcriptional profiles of the female, male and finasteride-induced feminized male anogenital region in rat fetuses. Toxicol Sci 169: 303-311

Takayam K, Inoue S (2013) Transcriptional network of androgen receptor in prostate cancer progression. Int J Urol 20: 756-768

Tirabassi G, Cignarelli A, Perrini S, Delli Muti N, Furlani G, Gallo M, Pallotti F, Paoli D, Giorgino F, Lombardo F, Gandini L, Lenzi A, Balercia G (2015) Influence of CAG Repeat Polymorphism on the Targets of Testosterone Action. Int J Endocrinol 2015: 298107

Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324: 787-790

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

Vinggaard AM, Niemelä J, Wedebye EB, Jensen GE (2008) Screening of 397 chemicals and development of a quantitative structure--activity relationship model for androgen receptor antagonism. Chem Res Toxicol 21: 813-823

Zitzmann M (2009) The role of the CAG repeat androgen receptor polymorphism in andrology. Front Horm Res 37: 52-61