Synergistic nanotoxicology: Mitochondrial ROS-driven mitochondrial damage and oxidative stress underlie polylactic...

Polylactic acid (PLA) and synthetic amorphous silica (SAS), both extensively utilized in food-related applications, raise significant toxicological concern owing to their co-exposure potential to humans. Previous studies have shown that PLA and SAS can lead to reproductive toxicity. However, the combined reproductive effects and underlying mechanisms in mammalian are still indistinct. In this study, we investigate the combined toxicity of PLA nanoplastics (PLA NPs) and silica nanoparticles (SiNPs) on male reproduction. The co-exposure to PLA NPs and SiNPs significantly enhanced reproductive toxicity, including testicular structural damage, spermatogenic disturbance and sex hormone disorder. Furthermore, PLA NPs and SiNPs synergistically caused severe mitochondrial damage and generated excessive reactive oxygen species (ROS), subsequently inhibiting the Kelch-like ECH-associated protein 1/ Nuclear factor erythroid 2-related factor 2 pathway to exacerbate oxidative stress. Mitochondrial-targeted antioxidant intervention effectively normalized oxidative stress and reproductive damage. These results demonstrated that PLA NPs and SiNPs synergistically aggravated testicular toxicity in mice by inducing mitochondrial ROS production resulting in mitochondrial damage as well as enhancing oxidative stress. Our study provides a foundation for future studies on the mechanism of toxicity in mammals by synergistic exposure to PLA NPs and SiNPs.