Polylactic acid nanoplastics induced pyroptosis in mice testes by activating TRPM2 through mitochondrial damage

Polylactic acid (PLA) is currently one of the most widely used bio-based plastics, posing exposure risks to humans through various environmental pathways. Therefore, this study evaluated the effects of PLA nanoparticles (NPs) on the testes and the potential mechanisms involved. C57BL/6 J mice were administered PLA NPs (0.1, 1, and 10 mg/kg/day) for 4 weeks. Additionally, supplementary validation was conducted using transient receptor potential cation channel subfamily m member 2 (TRPM2) knockout models and MitoTEMPO-treated models. PLA NPs induced marked histological damage to the testes, resulting in impaired spermatogenesis and suppressed hormone synthesis. PLA NPs elevated reactive oxygen species levels, exacerbated oxidative stress, and mediated mitochondrial damage. Furthermore, PLA NPs activated TRPM2 and induced calcium ion dysregulation, leading to a significant increase in intracellular calcium levels. The study further revealed that PLA NPs markedly elevated serum IL-1β levels and activated the inflammasome pathway, thereby inducing pyroptosis in mouse testicular cells and resulting in reproductive toxicity. Collectively, these findings indicated that PLA NPs activate the TRPM2 pathway through oxidative stress-induced mitochondrial damage, subsequently inducing calcium dysregulation and causing pyroptosis in mouse testes. Our research provides new insights and evidence for the reproductive toxicity assessment of PLA NPs.