BPA interferes with StAR-mediated mitochondrial cholesterol transport to induce germline dysfunctions

Area of Science:

• Endocrinology
• Toxicology
• Developmental Biology
• Molecular Biology

Background:

• Bisphenol A (BPA) is an endocrine disruptor linked to reproductive and hormone synthesis alterations.
• The precise molecular mechanisms initiating BPA-induced reproductive dysfunction remain largely unknown.
• Mitochondrial cholesterol transport is a critical, evolutionarily conserved step in steroid hormone biosynthesis.

Purpose of the Study:

• To investigate the hypothesis that BPA disrupts mitochondrial cholesterol transport.
• To elucidate the role of cholesterol transport in BPA's reproductive toxicity using *C. elegans*.

Main Methods:

• Utilized *C. elegans* as a model organism to study BPA toxicity.
• Assessed embryonic lethality and germline apoptosis in response to BPA exposure.
• Quantified mitochondrial cholesterol levels under varying BPA concentrations.
• Examined the effects of BPA on mutants of *strl-1* (StAR ortholog) and *C41G7.9* (TSPO ortholog).

Main Results:

• Embryonic lethality and germline apoptosis caused by BPA were fully rescued by exogenous cholesterol supplementation.
• BPA exposure led to a dose-dependent reduction in mitochondrial cholesterol levels.
• Mutants for *strl-1* exhibited reproductive defects similar to BPA exposure, and BPA did not exacerbate these defects in the *strl-1* background.
• Cholesterol supplementation rescued reproductive defects in all *strl-1* genotype/BPA combinations.

Conclusions:

• Bisphenol A exerts germline toxicity by interfering with mitochondrial cholesterol transport.
• This study uncovers a novel mechanism of BPA-induced endocrine disruption impacting steroidogenesis.
• Targeting cholesterol transport pathways may offer strategies to mitigate BPA's reproductive effects.