Ferroptosis contributing to spermatocyte injury induced by silica nanoparticles via BRCA1/GPX4 signaling

Abstract

Amorphous silica nanoparticles (SiNPs) have gradually been established to pose a threat to male reproductive health, but the underlying mechanisms are not yet fully elucidated. Ferroptosis is an emerging programmed cell death mechanism associated with spermatogenic disorders. Here, we examined how ferroptosis contributes to SiNP-induced male reproductive damage and assessed the regulatory role of the BRCA1/GPX4 axis in this context. GC-2spd cells were exposure to SiNPs with concentrations of 0, 10, and 20 μg/mL and RNA sequencing of GC-2spd cells was performed. Follow-up experiments were performed to validate the enrichment analysis findings. According to the bioinformatic analysis, after exposure to SiNPs, oxidative stress, ferroptosis and cell cycle pathway were markedly enriched. SiNPs triggered iron overload and significantly decreased the expression levels of glutathione peroxidase 4 (GPX4) and glutathione (GSH) in GC-2spd cells, while upregulating malondialdehyde (MDA) and heme oxygenase-1 (HO-1). Of particular note, the ferroptosis inhibitor Ferrostatin-1 (Fer-1) and a potent iron chelator deferoxamine (DFO) attenuated SiNPs-induced lipid peroxidation, iron overload and cytotoxicity. Of mechanistic importance, we found that BRCA1 targeted GPX4 as a pivotal factor in mediating ferroptosis triggered by SiNPs. Curcumin, the specifical activator of BRCA1, treatment significantly alleviate SiNPs-stimulated down-regulation on expressions of BRCA1 and GPX4. Our findings first emphasize that BRCA1/GPX4 signal-mediated ferroptosis was a factor in SiNPs-caused spermatocyte injury, which offers novel insights for clarifying the toxicity of SiNPs and for the safe application of SiNPs-related nanoproducts in the future.