SNAPSHOT
Created at: 2019-01-04 08:59
AOP ID and Title:
Status
Author status | OECD status | OECD project | SAAOP status |
---|---|---|---|
Under development: Not open for comment. Do not cite | 1.29 | Under Development |
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.
Summary of the AOP
Events
Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)
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 |
Key Event Relationships
Upstream Event | Relationship Type | Downstream Event | Evidence | Quantitative Understanding |
---|---|---|---|---|
Inhibition, HMG-CoA reductase | adjacent | Decreased, mevalonate | High | |
Decreased, mevalonate | adjacent | Decreased, cholesterol | ||
malformed, Male reproductive tract | adjacent | Decrease, Fertility | ||
Decreased, cholesterol | non-adjacent | Decreased, Testosterone | ||
Decreased, Testosterone | non-adjacent | malformed, Male reproductive tract |
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 ApplicabilityLife Stage | Evidence |
---|---|
Fetal | Low |
Term | Scientific Term | Evidence | Links |
---|---|---|---|
Rattus rattus | Rattus rattus | NCBI |
Sex | Evidence |
---|---|
Male |
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.
Appendix 1
List of MIEs in this AOP
Event: 804: Inhibition, HMG-CoA reductase
Short Name: Inhibition, HMG-CoA reductase
Key Event Component
Process | Object | Action |
---|---|---|
hydroxymethylglutaryl-CoA reductase activity | 3-hydroxy-3-methylglutaryl-coenzyme A reductase | decreased |
AOPs Including This Key Event
AOP ID and Name | Event Type |
---|---|
Aop:124 - HMG-CoA reductase inhibition leading to decreased fertility | MolecularInitiatingEvent |
Biological Context
Level of Biological Organization |
---|
Cellular |
How it is Measured or Detected
The activity of HMG-CoA reductase inhibition may be measured by a commercially available kit which measures a decrease in absorbance at 340 nm, which represents the oxidation of NADPH by the catalytic subunit of HMGR in the presence of the substrate HMG-CoA. Sterol Regulatory element-binding factor 1 (SREBF) is the transcription factor controlling downstream regulation of HMG-CoA reductase. The ToxCast assay ATG_SREBF1_CIS_up is one method of measuring transcriptional control of HMG-CoA reductase.
List of Key Events in the AOP
Event: 805: Decreased, mevalonate
Short Name: Decreased, mevalonate
Key Event Component
Process | Object | Action |
---|---|---|
mevalonate | decreased |
AOPs Including This Key Event
AOP ID and Name | Event Type |
---|---|
Aop:124 - HMG-CoA reductase inhibition leading to decreased fertility | KeyEvent |
Biological Context
Level of Biological Organization |
---|
Cellular |
Event: 807: Decreased, cholesterol
Short Name: Decreased, cholesterol
Key Event Component
Process | Object | Action |
---|---|---|
cholesterol | decreased |
AOPs Including This Key Event
AOP ID and Name | Event Type |
---|---|
Aop:124 - HMG-CoA reductase inhibition leading to decreased fertility | KeyEvent |
Biological Context
Level of Biological Organization |
---|
Cellular |
Event: 808: Decreased, Testosterone
Short Name: Decreased, Testosterone
Key Event Component
Process | Object | Action |
---|---|---|
testosterone | decreased |
AOPs Including This Key Event
AOP ID and Name | Event Type |
---|---|
Aop:124 - HMG-CoA reductase inhibition leading to decreased fertility | KeyEvent |
Biological Context
Level of Biological Organization |
---|
Individual |
Event: 809: malformed, Male reproductive tract
Short Name: malformed, Male reproductive tract
Key Event Component
Process | Object | Action |
---|---|---|
male reproductive system | morphological change |
AOPs Including This Key Event
AOP ID and Name | Event Type |
---|---|
Aop:124 - HMG-CoA reductase inhibition leading to decreased fertility | KeyEvent |
Biological Context
Level of Biological Organization |
---|
Individual |
Organ term
Organ term |
---|
male reproductive system |
List of Adverse Outcomes in this AOP
Event: 330: Decrease, Fertility
Short Name: Decrease, Fertility
Key Event Component
Process | Object | Action |
---|---|---|
fertility | decreased |
AOPs Including This Key Event
AOP ID and Name | Event Type |
---|---|
Aop:124 - HMG-CoA reductase inhibition leading to decreased fertility | AdverseOutcome |
Biological Context
Level of Biological Organization |
---|
Individual |
Domain of Applicability
Appendix 2
List of Key Event Relationships in the AOP
List of Adjacent Key Event Relationships
Relationship: 804: Inhibition, HMG-CoA reductase leads to Decreased, mevalonate
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding |
---|---|---|---|
HMG-CoA reductase inhibition leading to decreased fertility | adjacent | High |
Relationship: 805: Decreased, mevalonate leads to Decreased, cholesterol
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding |
---|---|---|---|
HMG-CoA reductase inhibition leading to decreased fertility | adjacent |
Relationship: 808: malformed, Male reproductive tract leads to Decrease, Fertility
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding |
---|---|---|---|
HMG-CoA reductase inhibition leading to decreased fertility | adjacent |
List of Non Adjacent Key Event Relationships
Relationship: 806: Decreased, cholesterol leads to Decreased, Testosterone
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding |
---|---|---|---|
HMG-CoA reductase inhibition leading to decreased fertility | non-adjacent |
Relationship: 807: Decreased, Testosterone leads to malformed, Male reproductive tract
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding |
---|---|---|---|
HMG-CoA reductase inhibition leading to decreased fertility | non-adjacent |