Early-life exposure to polypropylene microplastics and DEHP induces ASD-relevant neurodevelopmental alterations involving mTOR-regulated autophagy impairment

Abstract

The health risks of polypropylene plastic, a major food-grade polymer, are often underestimated. Current evidence indicates that infants and young children may ingest millions of polypropylene microplastic particles (PP-MPs) daily, accompanied by co-exposure to di(2-ethylhexyl) phthalate (DEHP). However, the neurotoxic effects of such co-exposure, particularly the underlying molecular mechanisms, remain poorly understood. Here, we established an early-life exposure model by orally administering PP-MPs and/or DEHP to 3-week-old male ICR mice for 28 consecutive days. Based on assessments of neurobehavior, histopathology and representative biomarkers, we found that PP-MPs and/or DEHP exposure caused autism spectrum disorder (ASD)-relevant neurodevelopmental alterations in immature mice, including deficits in spontaneous exploration and social interaction, increased anxiety-like behaviors, neuronal and synaptic damage in the prefrontal cortex, and downregulated expression of the ASD-risk genes Shank3 and Nlgn1 . Proteomic analyses of the brain identified the mTOR signaling pathway as a key mechanism involved in the ASD-relevant neurodevelopmental alterations resulting from PP-MPs and/or DEHP exposure. Further quantitative analyses demonstrated activation of the mTOR signaling pathway, coupled with autophagic impairment and dysregulated expression of genes linked to synaptic plasticity following exposure. Notably, inhibiting the mTOR signaling pathway with rapamycin restored autophagic activity and ameliorated the ASD-relevant neurodevelopmental alterations induced by PP-MPs and/or DEHP. Collectively, these findings suggest that mTOR-regulated autophagic impairment may underlie the neurodevelopmental toxicity caused by early-life exposure to PP-MPs and DEHP, providing a theoretical basis for risk assessment and health protection strategies against neurodevelopmental hazards posed by plastic consumer products during early life.