Bisphenol A Disrupts Spermatogenesis via Excessive Mitophagy-Driven Ferroptosis

BPA is a globally ubiquitous industrial compound that harms male reproductive health by causing abnormal sperm development and subsequent spermatogonia loss, yet the underlying mechanisms of BPA-induced spermatogenesis disorder remain unclear. Here, we explored BPA's effects on adolescent male mice and GC-1 cells by gavaging mice with BPA at doses of 20, 200, or 2000 μg/kg/d for 4 weeks and treating GC-1 cells with 10 μM BPA for 12 h to establish a damage model. The results revealed that BPA induced spermatogenesis disorder via Ferroptosis, which was associated with the activation of excessive Mitophagy. RNA-seq analysis elucidated that upregulated BCAT1 plays a key role in this process. Specifically, downregulation of BCAT1 alleviated BPA-induced Mitophagy, whereas overexpression of BCAT1 exacerbated these effects. Moreover, the occurrence of BPA-induced spermatogenesis disorder is regulated by the binding of PINK1 via targeting SER227 to BCAT1. Additionally, quercetin, a potential BCAT1 ligand, reduced BCAT1 expression and mitigated BPA-induced Mitophagy and Ferroptosis both in vitro and in vivo. In summary, our results reveal that quercetin effectively inhibits BPA-induced Mitophagy activation, thereby reducing Ferroptosis in spermatogonia cells. This study highlights BCAT1 as a potential therapeutic target and provides novel insights into BPA-induced testicular toxicity and therapeutic strategy development.