This is a legacy representation of this AOP. Please see the current version here:
Please follow the link to snapshots page to view and create Snapshots of this AOP.
Under development: Do not distribute or cite.
This AOP page was last modified on 12/11/2016.
Click here to show/hide revision dates for related pages
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.
Summary of the AOP
Please follow link to widget page to edit this section.
If you manually enter text in this section, it will get automatically altered or deleted in subsequent edits using the widgets.
Molecular Initiating Event
|Molecular Initiating Event||Support for Essentiality|
|HMG-CoA reductase, Inhibition|
|Event||Support for Essentiality|
|Male reproductive tract, malformed|
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|
Cytoscape Web will replace the contents of this div with your graph.
Click nodes or edges.
Life Stage Applicability
|Rattus rattus||Rattus rattus||NCBI|
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,
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.
Essentiality of the Key Events
Molecular Initiating Event Summary,
Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.
Weight of Evidence Summary
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.
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.