Combined effect of arsenic and polystyrene-nanoplastics at environmentally relevant concentrations in mice liver: Activation of apoptosis, pyroptosis and excessive autophagy.

The ecological risks caused by the coexistence of pollutants such as arsenic (As) and polystyrene-nanoplastics (PSNPs) in the environment have become a non-negligible problem. However, the effects of As and PSNPs co-exposure on mammals and the underlying toxicity mechanisms have remained unclear. Therefore, the present study established mouse models of As and/or PSNPS exposure to systematically analyze the underlying role of autophagy, apoptosis and pyroptosis in hepatotoxicity induced by co-exposure of As and PSNPs. Our findings demonstrated for the first time that mice co-exposure to As and PSNPs displayed significant pathological changes in the liver, while exposure to As or PSNPs alone did not produce significant toxic effects. More importantly, As and PSNPs co-exposure activated excessive autophagy through altered expression levels of PI3K, mTOR, Beclin-1, ATG5, LC3 and P62. Meanwhile, co-treatment with As and PSNPs induced apoptosis in the liver, which was confirmed by ultrastructure observation and changes in the expression of apoptosis indicators (P53, Bax, Bcl-2, Caspase-3, Caspase-9, Cleaved-Caspase-3 and Cytc). Additionally, co-exposure of As and PSNPs induced pyroptosis in the liver through NLRP3/Caspase-1 pathway via targeting NLRP3, ASC, Pro-Caspase-1, GSDMD and Cleaved-Caspase-1 expressions. Overall, our findings provide deeper insight into the roles of apoptosis, pyroptosis and excessive autophagy in the aggravation of liver injury, which could contribute to a better understanding of the interactions between As and PSNPS exposure and the molecular mechanisms of hepatotoxicity.