ROS-driven crosstalk between ferroptosis and necroptosis mediates neurotoxicity induced by maternal exposure to...

The pervasive environmental distribution of nanoplastics (NPs) raises critical concerns regarding their offspring health impacts. However, the precise mechanisms underlying neurotoxicity induced by maternal exposure to NPs remain poorly understood. In this study, adult female zebrafish were exposed to polystyrene nanoplastics (PS-NPs; 0.1 and 1 mg/L) for 28 days to investigate maternal transfer, subsequent neurotoxic effects, and associated cell death pathways in offspring. Fluorescence imaging confirmed the concentration-dependent accumulation of maternally transferred PS-NPs in embryos and larvae. Consequently, maternal exposure to PS-NPs significantly reduced fertilization and hatching rates, increased malformation incidence, and impaired larval development. Behavioral analyses revealed decreased locomotor activity and impaired light-dark responsiveness, accompanied by structural neuronal disorganization and reduced neuronal density in the telencephalon. Transcriptomic and molecular analyses indicated that maternal exposure to PS-NPs severely disrupted iron homeostasis characterized by iron overload and excessive reactive oxygen species (ROS) burst, and lipid peroxidation, which concurrently altered the expression of critical genes related to ferroptosis and necroptosis. Antioxidant intervention using N-acetylcysteine (NAC) effectively alleviated oxidative stress and rescued alterations in ferroptosis and necroptosis, while ferrostatin-1 (Fer-1) improved iron homeostasis, attenuated neuronal injury, and mitigated necroptosis-related responses. Collectively, our findings suggest that ROS-associated ferroptosis and necroptosis contribute to offspring neurotoxicity induced by maternal exposure to PS-NPs and indicate a potential functional crosstalk between these two regulated cell death pathways. This study provides new insights into the mechanisms underlying offspring neurotoxicity induced by NPs.