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 <i>BCAT1</i> plays a key role in this process. Specifically, downregulation of <i>BCAT1</i> alleviated BPA-induced mitophagy, whereas overexpression of <i>BCAT1</i> 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 <i>in vitro</i> and <i>in vivo</i>. 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.