Baicalin targets YTHDC2 and alleviates male reproductive toxicity caused by co-exposure to nanoplastics and manganese through m6A-dependent pathway

Nanoplastics (NPs) pollution has become a pressing global environmental issue. NPs possess the ability to adsorb heavy metals, thereby acting as vectors that facilitate the entry of these toxic substances into living organisms. However, the synergistic toxic effects of NPs and heavy metals, particularly with regard to male reproductive health, remain poorly understood. This study establishes in vivo and in vitro models to assess the effects of single and co-exposure to polystyrene nanoplastics (PS-NPs, 0.1 μm) and manganese (Mn) on male reproductive function. Our results reveal that co-exposure leads to a synergistic toxic effect, aggravating testicular damage, sperm abnormalities, and hormone disruption. Mechanistically, PS-NPs and Mn collaboratively suppress the RNA-binding protein YTHDC2, which in turn impairs Mdm2 transcription and translation in an m6A-dependent manner. This disruption results in cell cycle arrest via the Mdm2-p53 pathway, ultimately hindering spermatogenesis. Notably, baicalin, a natural compound, effectively targets YTHDC2 and mitigates the reproductive toxicity induced by co-exposure. These findings provide the novel evidence of the synergistic reproductive toxicity of PS-NPs and Mn in male mammals, offering new insights into their combined toxic effects and highlighting the potential of baicalin as a therapeutic intervention.