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.