Long-chain chlorinated paraffins exposure induces premature ovarian failure by disrupting the balance of mitochondrial fission.

Abstract

Long-chain chlorinated paraffins (LCCPs) accumulate in reproductive organs due to their high persistence and bioaccumulation potential; however, the molecular mechanisms underlying their ovarian toxicity remain unclear. In this study, we used primary mouse granulosa cells, a human SVOG cell line, and an oral exposure model in female mice to systematically evaluate the ovarian damage effects of LCCPs and investigate the underlying signaling pathways. The results showed that concentrations of 0.02-2 µg/mL of LCCPs concentration-dependently reduced granulosa cell survival rates (by 12%-58%, P < 0.05), while significantly upregulating oxidative stress (MDA, ROS), inflammatory cytokines (IL-6, TNF-α), and aging markers (SA-β-gal activity). In vivo exposure led to morphological degeneration of ovarian tissue and a reduction in the number of primordial follicles, accompanied by decreased serum estradiol and elevated follicle-stimulating hormone (FSH) levels; these changes resemble the phenotype of clinical ovarian dysfunction. At the mechanistic level, LCCPs induce excessive mitochondrial fission by blocking the interaction between Drp1 and Parkin, leading to the leakage of mitochondrial DNA into the cytoplasm, which in turn activates the cGAS-STING pathway and ultimately drives granulosa cell senescence. These findings reveal a novel mechanism by which LCCPs mediate ovarian toxicity via the "excessive mitochondrial fragmentation- mtDNA leakage- cGAS- STING- cellular senescence" axis, providing direct experimental evidence for assessing the risks of persistent organic pollutants to female reproductive health.