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Created at: 2019-01-04 08:59

AOP ID and Title:


AOP 124: HMG-CoA reductase inhibition leading to decreased fertility
Short Title: HMGCR inhibition to male fertility

Authors


Kellie Fay


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 Do not cite 1.29 Under Development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 Applicability
Life Stage Evidence
Fetal Low
Taxonomic Applicability
Term Scientific Term Evidence Links
Rattus rattus Rattus rattus NCBI
Sex Applicability
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


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


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


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


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


Biological Context

Level of Biological Organization
Individual

Domain of Applicability


Taxonomic Applicability
Term Scientific Term Evidence Links
mice Mus sp. High NCBI
human Homo sapiens High NCBI

Appendix 2

List of Key Event Relationships in the AOP