Neonatal exposure to PCB138 induces a polycystic ovary syndrome-like phenotype mediated by the aryl hydrocarbon receptor

Neonatal exposure to environmentally relevant levels of PCB138 induces a PCOS-like phenotype in adult mice. • PCB138 acts as an Aryl Hydrocarbon Receptor (AhR) agonist to activate the AhR signaling pathway in ovarian granulosa cells. • AhR activation by PCB138 disrupts steroidogenesis by upregulating the expression of key enzymes StAR and CYP11A1. • Granulosa cell-specific Ahr knockout or pharmacological antagonism effectively rescues PCB138-induced endocrine and ovarian dysfunction. Polycystic ovary syndrome (PCOS), a highly prevalent reproductive disorder affecting reproductive-age women, has been increasingly associated with exposure to environmental pollutants. Polychlorinated biphenyls (PCBs), recognized as environmentally persistent organic pollutants, have been detected in PCOS patients, yet their mechanistic contribution to the syndrome remains to be elucidated. In this study, the reproductive effects of PCB138, a congener frequently detected in the environment and human tissues, were assessed in female mice using environmentally relevant exposure levels. PCB138 exposure led to irregular estrous cycles, abnormal follicular development, and dysregulated steroidogenesis (high testosterone, low estradiol). Furthermore, we found that PCB138 exposure induced aryl hydrocarbon receptor (AhR) activation, leading to dysregulated steroidogenesis as demonstrated by both in vivo and in vitro experiments. AhR antagonist CH223191 treatment attenuated PCB138-induced abnormal steroidogenesis in human granulosa cells. Ovarian granulosa cell-specific Ahr -knockout mitigated PCB138-induced alterations in the estrus cycle, ovarian steroidogenesis, and follicle development. In summary, this study demonstrates that neonatal exposure to environmental levels of PCB138 induces hyperandrogenism and ovulatory dysfunction, leading to PCOS features through AhR activation. Investigation of AhR as a key regulator of PCB-induced PCOS uncovers new mechanistic insight and suggests potential therapeutic strategies to improve female reproduction. Download: Download high-res image (312KB) Download: Download full-size image