Aop: 19

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Androgen receptor antagonism leading to adverse effects in the male foetus (mammals)

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
AR antagonism leading to foetal feminisation

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Agnes Aggy   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Mukesh Patel
  • Agnes Aggy

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Open for adoption Under Development
This AOP was last modified on July 16, 2022 18:37

Revision dates for related pages

Page Revision Date/Time
N/A, Androgen receptor, Antagonism September 16, 2017 10:14
Alteration, Wnt pathway September 16, 2017 10:14
Feminisation or incomplete development, Primary and accessory male sex organs September 16, 2017 10:14
Altered, Transcription of genes by AR November 04, 2020 11:11
N/A, Impairment of reproductive capacity December 03, 2016 16:33
N/A, Androgen receptor, Antagonism leads to Alteration, Wnt pathway December 03, 2016 16:37
N/A, Androgen receptor, Antagonism leads to Altered, Transcription of genes by AR December 03, 2016 16:37
Altered, Transcription of genes by AR leads to Alteration, Wnt pathway December 03, 2016 16:37
Altered, Transcription of genes by AR leads to Feminisation or incomplete development, Primary and accessory male sex organs December 03, 2016 16:37
Alteration, Wnt pathway leads to Feminisation or incomplete development, Primary and accessory male sex organs December 03, 2016 16:37
Feminisation or incomplete development, Primary and accessory male sex organs leads to N/A, Impairment of reproductive capacity December 03, 2016 16:37

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This adverse outcome pathway details the linkage between the antagonism of the androgen receptor (AR) leading to adverse effects in the male foetus. For a more detailed explanation of this pathway, with supporting references, please refer to the project report to the OECD [1]. The AR is involved in the mediation of various cellular processes including proliferation, differentiation and apoptosis in many tissues. The two main events regulated by AR mediated gene expression are urogenital tract differentiation during gestation and sexual changes during puberty. The AR can be activated by the binding of the endogenous androgens testosterone and its metabolite 5-alpha-dihydrotestosterone (DHT), which can activate gene expression at the transcription level. In mammals, virilisation of the external genitalia is driven by DHT while the differentiation of the Wolffian duct is driven by testosterone. Chemicals which bind to the AR may cause disruption by agonism, antagonism or by both mechanisms. Agonists will mimic the action of the endogenous androgens, whilst antagonists will block the receptor and prevent activation. Androgen receptor antagonists divide into steroid-like and non-steroidal compounds. Several classes or chemical categories are indicated by the data [2][3]. These include the steroidal class (cyproterone acetate), the flutamide/ “aryl amide” class which includes bicalutamide, linuron and hydantoin analogs (such as nilutamide, vinclozin), the quinoline analog class, and the phthalimide derivatives. The best characterised class are synthetic anilides for which the model compound is flutamide.

Flutamide exhibits potent anti-androgenic activity and in animals shows dose dependent decreases in the weight of accessory sex organs at doses of 1mg/kg and above. In utero exposure to flutamide in rats has been shown to cause feminisation of external genitalia, nipple retention and alteration of androgen-dependent testicular descent in male foetuses. A number of flutamide derivatives with in vitro binding data have demonstrated in vivo activity [4][5][6][7]. In vitro the relative binding affinity (RBA) to the AR can be measured using assays which compare the competitive binding versus a control compound such as DHT or a synthetic androgen (metribolone (R1881) or mibolerone). Although this assay can measure binding it cannot distinguish between agonists and antagonists [8][9]. Transcriptional activation in cells transfected with human AR can be used to identify agonism or antagonism with respect to that induced by a known concentration of DHT [10]. Short term in vivo studies may use the Hershberger assay or acute studies involving castrated rat models [11].

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 27 N/A, Androgen receptor, Antagonism N/A, Androgen receptor, Antagonism
KE 310 Alteration, Wnt pathway Alteration, Wnt pathway
KE 240 Feminisation or incomplete development, Primary and accessory male sex organs Feminisation or incomplete development, Primary and accessory male sex organs
KE 286 Altered, Transcription of genes by AR Altered, Transcription of genes by AR
AO 337 N/A, Impairment of reproductive capacity N/A, Impairment of reproductive capacity

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Foetal

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.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. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Male

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help
  1. Project report: Developmental Toxicity Associated with the Androgen Receptor Antagonism Adverse Outcome Pathway. OECD QSAR Toolbox Report, Deliverable D6.5, 2011.
  2. Singh, S.M., Gauthier, S., Labrie, F., Current Medicinal Chemistry, 2000 (7) 211-247.
  3. Gao, W., Bohl, C.E., Dalton, J.T., Chemical Reviews, 2005 (105) 3352-3370.
  4. Morris, J.J., Hughes, L.R., Glen, A.T., Taylor, P. J., Journal of Medicinal Chemistry, 1991 (34) 447-455.
  5. Singh, S.M., Gauthier, S., Labrie, F., Current Medicinal Chemistry, 2000 (7) 211-247.
  6. Yin, D., He, Y., Perera, M.A., Hong, S.S., Marhefka, C., Stourman, N., Kirkovsky, L., Miller, D.D., Dalton, J.T., Molecular Pharmacology, 2003 (63) 211-223.
  7. Gao, W., Bohl, C.E., Dalton, J.T., Chemical Reviews, 2005 (105) 3352-3370.
  8. Singh, S.M., Gauthier, S., Labrie, F., Current Medicinal Chemistry, 2000 (7) 211-247.
  9. Yin, D., He, Y., Perera, M.A., Hong, S.S., Marhefka, C., Stourman, N., Kirkovsky, L., Miller, D.D., Dalton, J.T., Molecular Pharmacology, 2003 (63) 211-223.
  10. Yin, D., He, Y., Perera, M.A., Hong, S.S., Marhefka, C., Stourman, N., Kirkovsky, L., Miller, D.D., Dalton, J.T., Molecular Pharmacology, 2003 (63) 211-223.
  11. Lambright, C., Ostby, J., Bobseine, K., Wilson, V., Hotchkiss, A.K., Mann, P.C., Gray, L.E., Toxicological Sciences, 2000 (56) 389-399.