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AOP: 124
Title
HMG-CoA reductase inhibition leading to decreased fertility
Short name
Graphical Representation
Point of Contact
Contributors
- Kellie Fay
- Cataia Ives
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
---|---|---|---|---|
1.29 |
This AOP was last modified on May 26, 2024 20:39
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 | May 24, 2022 11:10 |
malformed, Male reproductive tract | September 16, 2017 10:16 |
Decrease, Fertility | June 29, 2017 08:09 |
Decrease, testosterone levels | May 24, 2024 12:27 |
Inhibition, HMG-CoA reductase leads to Decreased, mevalonate | December 03, 2016 16:38 |
Decreased, mevalonate leads to Decreased, cholesterol | December 03, 2016 16:38 |
malformed, Male reproductive tract leads to Decrease, Fertility | December 03, 2016 16:38 |
Decreased, cholesterol leads to Decrease, testosterone levels | April 25, 2024 17:01 |
Decrease, testosterone levels leads to malformed, Male reproductive tract | April 25, 2024 17:01 |
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.
AOP Development Strategy
Context
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 804 | Inhibition, HMG-CoA reductase | Inhibition, HMG-CoA reductase |
KE | 805 | Decreased, mevalonate | Decreased, mevalonate |
KE | 807 | Decreased, cholesterol | Decreased, cholesterol |
KE | 1690 | Decrease, testosterone levels | Decrease, testosterone levels |
KE | 809 | malformed, Male reproductive tract | malformed, Male reproductive tract |
AO | 330 | Decrease, Fertility | Decrease, Fertility |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
Fetal | Low |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Rattus rattus | Rattus rattus | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Male |
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
Essentiality of the Key Events
Evidence Assessment
Known Modulating Factors
Quantitative Understanding
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.