Bisphenol F induces spermatogenic cell ferroptosis via FTO-mediated m6A regulation of FTH1

Area of Science:

• Reproductive Biology
• Toxicology
• Molecular Biology

Background:

• Bisphenol F (BPF) is an emerging risk factor impacting male reproductive health.
• The precise molecular mechanisms underlying BPF's adverse effects on semen quality remain largely unknown.
• Ferroptosis and m6A RNA methylation are potential pathways involved in BPF toxicity.

Purpose of the Study:

• To investigate the role of ferroptosis and m6A RNA methylation in BPF-induced male reproductive damage.
• To elucidate the specific mechanism by which BPF affects male semen quality.

Main Methods:

• In vivo studies in mice to assess BPF effects on testicular structure and semen quality.
• In vitro experiments using GC-2 cells to evaluate BPF-induced cytotoxicity and ferroptosis.
• Analysis of fat mass and obesity-associated gene (FTO) expression and its role in BPF-induced ferroptosis.
• Methylated RNA immunoprecipitation (MeRIP) and RNA immunoprecipitation (RIP) assays to examine m6A modification and protein-RNA interactions.

Main Results:

• BPF exposure damaged seminiferous tubules, reduced spermatogenic cell layers, and impaired semen quality in mice.
• BPF induced ferroptosis and reduced cell viability in GC-2 cells, accompanied by inhibited FTO expression.
• FTO was found to be critical in preventing BPF-induced ferroptosis.
• m6A modification of ferritin heavy chain 1 (FTH1) mRNA increased upon FTO interference, and YTHDF1/YTHDF2 proteins were involved in regulating FTH1 expression.

Conclusions:

• BPF exposure negatively impacts male reproductive health through ferroptosis in spermatogenic cells.
• The FTO/m6A/FTH1 pathway, mediated by YTHDF1 and YTHDF2, plays a protective role against BPF-induced reproductive damage.
• Targeting the FTO pathway may offer a therapeutic strategy to alleviate BPF-induced male infertility.