PFOS-mediated suppression of SOX30 impairs DNA double-strand break repair leading to male reproductive dysfunction

Perfluorooctanesulfonic acid (PFOS), a persistent organic pollutant and representative per- and polyfluoroalkyl substance (PFAS), is ubiquitously detected in the environment and human tissues, and mounting evidence has implicated it in male reproductive dysfunction. However, the direct impact of PFOS on meiosis in spermatocytes and the underlying molecular mechanisms remain poorly understood. In this study, by combining chromosome spreading with high-resolution microscopy analysis of spermatocyte subtypes and morphology, we revealed that PFOS exposure decreased the proportion of pachytene spermatocytes and induced abnormal DNA double-strand break (DSB) repair, ultimately leading to a reduction in sperm density. Mechanistically, PFOS exposure suppressed the expression of SOX30, a germ-specific transcription factor, leading to downregulation of its downstream targets RPA2 and RAD51—key proteins of homologous recombination repair (HRR). This suppression resulted in unrepaired DSBs, triggering the pachytene checkpoint and leading to spermatocyte apoptosis. Critically, overexpression of SOX30 in PFOS-exposed GC2 spermatocyte cells restored RPA2/RAD51 expression and rescued DSB repair capacity. These findings identify SOX30 as a critical mediator of PFOS-induced meiotic DSB repair defects and establish it as a potential therapeutic target for mitigating PFAS-associated male infertility. This study provides novel insights into the molecular link between environmental pollutant exposure and impaired meiosis, offering a foundation for developing preventive and therapeutic strategies against PFOS-induced reproductive toxicity. • PFOS exposure decreases the proportion of pachytene spermatocytes and induces abnormal DNA double-strand break repair. • PFOS impairs homologous recombination repair in spermatocytes. • SOX30 is identified as the target gene mediating PFOS-induced homologous recombination repair defects.