Medium-Chain Chlorinated Paraffins Induced Reproductive Toxicity in Female Rats by Interfering with Oocyte Meiosis and Triggering DNA Damage

Medium-chain chlorinated paraffins (MCCPs) are among the most prevalent chemicals detected in human serum. As an emerging persistent organic pollutant, their toxicity mechanisms, particularly concerning the female reproductive system, remain poorly understood. In this study, we present both <i>in vivo</i> and <i>in vitro</i> evidence of ovarian toxicity induced by MCCPs and insights into their underlying molecular mechanisms. MCCP exposure induced chromatin condensation in the nucleus and mitochondria vacuolization of ovarian granulosa cells in rats and significantly increased the levels of serum gonadotropins and sex hormones, while reducing gonadotropin-releasing hormone levels. Transcriptomics analysis of ovaries revealed a predominant effect of MCCPs on the cell cycle, oocyte meiosis, and DNA damage repair pathways. Moreover, dual-omics integrative analysis indicated significant disturbance of steroid hormone biosynthesis caused by MCCPs, as well as amino acid metabolism related to TCA cycle. Furthermore, <i>in vitro</i> assays demonstrated that MCCP exposure disrupts intracellular Ca²⁺ homeostasis and generates reactive oxygen species, ultimately leading to DNA damage. In conclusion, this study revealed potential mechanisms by which MCCPs affect ovary function. These findings can provide valuable insights for the mechanism-based risk assessment of MCCPs on female reproduction.