Bisphenol S exposure before sexual maturity impairs follicular development via Cathepsin L-mediated granulosa cell death

Bisphenol S (BPS) poses potential risks to the reproductive system, but its effects during pre-sexual maturity on follicle development and its underlying mechanisms remain unclear. This study aimed to investigate the association between pre-sexual BPS exposure and follicular dysplasia, as well as to decipher the molecular mechanisms involved. Urine samples from females aged 3–16 years were first analyzed, revealing a 95.7% detection rate of BPS, with a geometric mean concentration of 51.74 ng/L. Furthermore, the pre-sexual rat model revealed that BPS (0.05, 5, and 250 mg/kg body weight/day) revealed that BPS exposure impaired follicle development (reducing ovarian reserve and increasing abnormal follicles) through mediating granulosa cell death. In vitro experiments with granulosa cells showed that BPS exposure upregulated the expression of the cathepsin family (CTSL, CTSD, and CTSB), thereby activating the caspase 3 apoptotic pathway. CTSL knockdown further confirmed its critical role as a mediator of BPS induced granulosa cell death. These results demonstrate that BPS exposure impairs follicle development via CTSL mediated granulosa cell death, providing novel mechanistic insights into environmental pollutant induced female reproductive dysfunction. • Widespread BPS exposure (95.7% detection) is revealed in female aged 3–16 years old. • BPS exposure disrupts follicle development by triggering granulosa cell apoptosis. • CTSL is identified as the key regulator of BPS-induced ovarian toxicity via mediating granulosa cell apoptosis.