API

Aop: 19

AOP Title

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

Short name:

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AR antagonism leading to foetal feminisation

Authors

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Point of Contact

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Mukesh Patel

Contributors

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  • Mukesh Patel

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development


This AOP was last modified on June 07, 2017 09:57

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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
Decreased, Transcription of genes by AR September 16, 2017 10:14
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 Decreased, Transcription of genes by AR December 03, 2016 16:37
Decreased, Transcription of genes by AR leads to Alteration, Wnt pathway December 03, 2016 16:37
Decreased, 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

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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].


Background (optional)

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Summary of the AOP

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Stressors

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Molecular Initiating Event

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Title Short name
N/A, Androgen receptor, Antagonism N/A, Androgen receptor, Antagonism

Key Events

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Title Short name
Alteration, Wnt pathway Alteration, Wnt pathway
Feminisation or incomplete development, Primary and accessory male sex organs Feminisation or incomplete development, Primary and accessory male sex organs
Decreased, Transcription of genes by AR Decreased, Transcription of genes by AR

Adverse Outcome

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Title Short name
N/A, Impairment of reproductive capacity N/A, Impairment of reproductive capacity

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Life Stage Applicability

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Life stage Evidence
Foetal

Taxonomic Applicability

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Sex Applicability

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Sex Evidence
Male

Graphical Representation

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Click to download graphical representation template

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

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References

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  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.