API XML

Aop: 124

AOP Title

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HMG-CoA reductase inhibition leading to decreased fertility

Short name:

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HMGCR inhibition to male fertility

Graphical Representation

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Click to download graphical representation template

Authors

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Kellie Fay

Point of Contact

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Kellie Fay   (email point of contact)

Contributors

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  • Kellie Fay

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite 1.29 Under Development


This AOP was last modified on January 27, 2018 15:34

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Revision dates for related pages

Page Revision Date/Time
Inhibition, HMG-CoA reductase December 03, 2016 16:33
Decreased, mevalonate December 03, 2016 16:37
Decreased, cholesterol December 03, 2016 16:37
Decreased, Testosterone December 03, 2016 16:37
malformed, Male reproductive tract September 16, 2017 10:16
Decrease, Fertility June 29, 2017 08:09
Inhibition, HMG-CoA reductase leads to Decreased, mevalonate December 03, 2016 16:38
Decreased, mevalonate leads to Decreased, cholesterol December 03, 2016 16:38
Decreased, cholesterol leads to Decreased, Testosterone December 03, 2016 16:38
Decreased, Testosterone leads to malformed, Male reproductive tract December 03, 2016 16:38
malformed, Male reproductive tract leads to Decrease, Fertility December 03, 2016 16:38

Abstract

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During sexual differentiation and gonadal development in utero or in ovo, androgenic tissues develop, in part, under the control of testosterone (Viger et al. 2005). Reduction of circulating testosterone during this crucial time of development can result in malformed reproductive tracts in males. Exposure to drugs (e.g., statins) or other compounds may cause male reproductive tract abnormalities by inhibiting HMG-CoA reductase, which is the rate-limiting enzyme in the production of cholesteron, the precursor of testosterone.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 804 Inhibition, HMG-CoA reductase Inhibition, HMG-CoA reductase
2 KE 805 Decreased, mevalonate Decreased, mevalonate
3 KE 807 Decreased, cholesterol Decreased, cholesterol
4 KE 808 Decreased, Testosterone Decreased, Testosterone
5 KE 809 malformed, Male reproductive tract malformed, Male reproductive tract
6 AO 330 Decrease, Fertility Decrease, Fertility

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Inhibition, HMG-CoA reductase leads to Decreased, mevalonate adjacent High
Decreased, mevalonate leads to Decreased, cholesterol adjacent
malformed, Male reproductive tract leads to Decrease, Fertility adjacent
Decreased, cholesterol leads to Decreased, Testosterone non-adjacent
Decreased, Testosterone leads to malformed, Male reproductive tract non-adjacent

Network View

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Stressors

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Life Stage Applicability

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Life stage Evidence
Fetal Low

Taxonomic Applicability

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Term Scientific Term Evidence Link
Rattus rattus Rattus rattus NCBI

Sex Applicability

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Sex Evidence
Male

Overall Assessment of the AOP

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This AOP was developed primarily from one study of exposure of rats in utero to simvastatin (as well as a phthalate ester; Beverley et al., 2015) and biological plausibility. It currently should be considered putative and untested.

Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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Beverly, B. E. J., et al. (2014). "Simvastatin and Dipentyl Phthalate Lower Ex Vivo Testicular Testosterone Production and Exhibit Additive Effects on Testicular Testosterone and Gene Expression Via Distinct Mechanistic Pathways in the Fetal Rat." Toxicological Sciences.