Polystyrene microplastics induce anxiety via HRAS derived PERK-NF-B pathway

Exposure to environmentally hazardous substances is recognized as a significant risk factor for neurological associated disorders. Among these substances, polystyrene microplastics (PS -MPs), widely utilized in various consumer products, have been reported to exhibit neurotoxicity. However, the potential association of PS -MPs with abnormal anxiety behaviors, along with the underlying molecular mechanisms and key proteins involved, remains insufficiently explored. Here, we delineated the potential mechanisms of PS -MPs -induced anxiety through proteomics and molecular investigations. We characterized the PS -MPs, observed their accumulation in the brain, leading to anxiety -like behavior in mice, which is correlated with microglia activation and pro -inflammatory response. Consistent with these findings, our studies on BV2 microglia cells showed that PSMPs activated NF-kappa B-mediated inflammation resulting in the upregulation of pro -inflammatory cytokines such as TNF alpha and IL-1 beta. Of particular significance, HRAS was identified as a key factor in the PS -MPs induced proinflammatory response through whole proteomics analysis, and knockdown of H-ras effectively inhibited PSMPs induced PERK-NF-kappa B activation and associated pro -inflammatory response in microglia cells. Collectively, our findings highlight that PS -MPs induce anxiety of mice via the activation of the HRAS-derived PERK-NF-kappa B pathway in microlglia. Our results contribute valuable insights into the molecular mechanisms of PS -MPsinduced anxiety, and may offer implications for addressing neurotoxicity and prevention the adverse effects of environmentally hazardous substances, including microplastics.