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

Bisphenol A is an endocrine disruptor associated with hormone synthesis and reproduction alterations. However, the initiating events underpinning these dysfunctions are still unclear. Here, we address the hypothesis that BPA interferes with the highly evolutionary conserved process of mitochondrial cholesterol transport, a crucial step in steroid hormone biosynthesis, by using the model organism C. elegans. We observed that embryonic lethality and germline apoptosis, hallmarks of BPA's reproductive toxicity in C. elegans, are fully rescued by low exogenous cholesterol supplementation. We also observed that increasing BPA concentrations proportionally reduced mitochondrial cholesterol levels. Mutants for strl-1 (ortholog of StAR), but not C41G7.9 (ortholog of TSPO), show reproductive defects similar to BPA's while BPA exposure in a strl-1 background did not worsen these effects. Finally, cholesterol supplementation rescued these defects for all strl-1 genotype/BPA combinations assessed. Together, these results uncover a novel mechanism underlying BPA's germline toxicity through the alteration of cholesterol transport.