Bisphenol A Disrupts Spermatogenesis via Excessive Mitophagy-Driven Ferroptosis

Area of Science:

• Reproductive Toxicology
• Cellular Biology
• Biochemistry

Background:

• Bisphenol A (BPA) is a widespread industrial chemical linked to male reproductive health issues.
• The precise mechanisms behind BPA-induced spermatogenesis disorder are not fully understood.
• Spermatogonia loss and abnormal sperm development are key concerns.

Purpose of the Study:

• To investigate the molecular mechanisms underlying BPA-induced male reproductive toxicity.
• To explore the role of ferroptosis, mitophagy, and BCAT1 in BPA's effects.
• To evaluate quercetin as a potential therapeutic agent against BPA toxicity.

Main Methods:

• Adolescent male mice were gavaged with BPA at varying doses (20, 200, 2000 μg/kg/d) for 4 weeks.
• GC-1 cells were treated with 10 μM BPA for 12 hours to model damage.
• RNA-sequencing (RNA-seq) was employed to analyze gene expression changes.
• The interaction between PINK1, SER227, and BCAT1 was investigated.
• In vitro and in vivo efficacy of quercetin was assessed.

Main Results:

• BPA exposure induced spermatogenesis disorder via ferroptosis, associated with excessive mitophagy.
• Upregulation of BCAT1 was identified as a key factor in BPA-induced toxicity.
• Downregulating BCAT1 ameliorated BPA effects, while its overexpression worsened them.
• PINK1 binding to SER227 on BCAT1 regulates BPA-induced spermatogenesis disorder.
• Quercetin treatment reduced BCAT1 expression, mitigating mitophagy and ferroptosis.

Conclusions:

• BPA induces male reproductive toxicity through BCAT1-mediated ferroptosis and mitophagy.
• BCAT1 plays a critical role in the pathogenesis of BPA-induced testicular damage.
• Quercetin demonstrates therapeutic potential by inhibiting BCAT1 activation and subsequent cellular damage.
• This study identifies BCAT1 as a potential therapeutic target for BPA-induced reproductive toxicity.