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This is a legacy representation of this AOP. Please see the current version here:

AOP Title

HMG-CoA reductase inhibition leading to decreased fertility
Short name: HMGCR inhibition to male fertility


Kellie Fay


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OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

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This AOP page was last modified on 12/11/2016.

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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.

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Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
HMG-CoA reductase, Inhibition

Key Events

Event Support for Essentiality
mevalonate, Decreased
cholesterol, Decreased
Testosterone, Decreased
Male reproductive tract, malformed

Adverse Outcome

Adverse Outcome
Fertility, Decreased

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
HMG-CoA reductase, Inhibition Directly Leads to mevalonate, Decreased Strong
mevalonate, Decreased Directly Leads to cholesterol, Decreased
cholesterol, Decreased Indirectly Leads to Testosterone, Decreased
Testosterone, Decreased Indirectly Leads to Male reproductive tract, malformed
Male reproductive tract, malformed Directly Leads to Fertility, Decreased

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Life Stage Applicability

Life Stage Evidence Links
Fetal Weak

Taxonomic Applicability

Name Scientific Name Evidence Links
Rattus rattus Rattus rattus NCBI

Sex Applicability

Sex Evidence Links

Graphical Representation

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Overall Assessment of the AOP

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

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

Summary Table
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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)


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.