Early-life exposure to polystyrene nanoplastics at ambient doses induces neurotoxicity via mTOR-mediated autophagy-lysosomal dysfunction and proteostasis imbalance

Nanoplastics are an emerging global environmental concern, with increasing evidence of their neurotoxic effects. Recent findings suggest that abnormal aggregation of pathogenic proteins within the nervous system may contribute to the neurotoxicity induced by nanoplastics, yet the molecular mechanisms regulating this pathological cascade remain unclear. Here, we used immature mice as an experimental model to represent infants and young children who are at higher risk of nanoplastics exposure, to elucidate the molecular mechanisms underlying neurotoxicity induced by exposure to polystyrene nanoplastics (PS-NPs) during early life. The results showed that environmentally relevant doses of PS-NPs penetrated the brains of immature mice and induced behavioral and emotional disorders. Proteomic analysis identified the mTOR signaling pathway as a candidate pathway responding to PS-NPs exposure in the immature mouse brain. Rapamycin intervention and quantitative validation further demonstrated that PS-NPs exposure upregulated mTOR signaling, thereby leading to lysosomal dysfunction and a blockade of autophagic flux, which in turn disrupted proteostasis and ultimately caused neurotoxicity. Furthermore, treatment with sodium 4-phenylbutyrate (4-PBA) confirmed that proteostasis imbalance, characterized by activation of the unfolded protein response, was a direct driver of this neurotoxicity. Notably, both rapamycin and 4-PBA treatments alleviated neurotoxicity resulting from PS-NPs exposure by restoring proteostasis. Together, these findings highlight dysregulation of the autophagy-lysosome pathway mediated by mTOR as a central mechanism of PS-NPs-induced neurotoxicity in immature mice and suggest lysosomal regulation for proteostasis remodeling as a prospective therapeutic strategy against neurological hazards related to nanoplastics.