Relationship:437

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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
Translator protein (TSPO), Decrease Cholesterol transport in mitochondria, Reduction

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
PPAR alpha activation leading to decreased fertility upon utero exposure in rodent males Directly Leads to Moderate
PPARα activation leading to impaired fertility in adult male rodents Directly Leads to Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links

How Does This Key Event Relationship Work

Translocator Protein (TSPO) mediates the first step in the delivery of cholesterol to the inner mitochondrial membrane cytochrome P-450 side chain cleavage enzyme(P450scc) (Besman et al., 1989). TSPO ligands stimulate steroidogenesis and induce cholesterol movement from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM) (Besman et al., 1989). Therefore reduced amount/activity of the TSPO will impair the cholesterol delivery necessary for the hormone biosynthesis.

Weight of Evidence

Biological Plausibility

Empirical Support for Linkage

The effects of altered TSPO are to decrease cholesterol transport into Leydig cells (Gazouli, 2002), (Borch, Metzdorff, Vinggaard, Brokken, & Dalgaard, 2006). Additionally, Thompson et al observed decreased uptake of cholesterol in Leydig cell mitochondria upon exposure to phthalates (Thompson, Ross, & Gaido, 2004).

Uncertainties or Inconsistencies

Quantitative Understanding of the Linkage

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Evidence Supporting Taxonomic Applicability

References