To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:2201

Relationship: 2201

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

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

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. 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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
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 Do not cite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

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) 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

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Male High
Female High

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
All life stages High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. 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 Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. 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
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   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
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  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.

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). 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