Aop:124
Status
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AOP Title
Authors
Kellie Fay
Status
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Under development: Do not distribute or cite.
This AOP page was last modified on 12/11/2016.
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Abstract
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 |
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HMG-CoA reductase, Inhibition |
Key Events
Event | Support for Essentiality |
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mevalonate, Decreased | |
cholesterol, Decreased | |
Testosterone, Decreased | |
Male reproductive tract, malformed |
Adverse Outcome
Adverse Outcome |
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Fertility, Decreased |
Relationships Among Key Events and the Adverse Outcome
Event | Description | Triggers | Weight of Evidence | Quantitative Understanding |
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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 |
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Fetal | Weak | |
Fetal |
Taxonomic Applicability
Name | Scientific Name | Evidence | Links |
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Rattus rattus | Rattus rattus | NCBI |
Sex Applicability
Sex | Evidence | Links |
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Male |
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)
References
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.