Combined toxicity of co-exposure to polystyrene nanoplastics and arsenic on the gut-liver axis in mice.

Plastic and heavy-metal contamination have become global environmental concerns, with evidence showing that humans and animals are exposed to multiple pollutants simultaneously. Polystyrene nanoplastics (PSNPs) and arsenic (As) are noteworthy due to their distribution, persistence, and potential to co-occur in food chains and ecosystems. However, their combined toxicity and underlying mechanisms remain largely unknown. Here, we explored the toxicological effects of co-exposure to As and PSNPs at concentrations representative of highly contaminated environments on the intestinal and hepatic systems of mice, with a focus on barrier integrity, microbiota dysbiosis, and mechanisms of cell death. Our findings revealed that co-exposure to As and PSNPs significantly disrupted intestinal morphology, suppressed the levels of ZO-1, Occludin, and MUC2, and activated the NFκB pathway. Meanwhile, 16S rRNA sequencing showed gut microbiota dysbiosis in the co-exposure group, with altered β-diversity, increased Ralstonia and reduced Bacteroides. Notably, network toxicology analysis revealed that the intestinal toxicological mechanisms of co-exposure involve multiple programmed cell death pathways, and the upregulation of ZBP1, NLRP3, Caspase-8, RIPK3, and their downstream effectors further confirmed that co-exposure to As and PSNPs triggered PANoptosis. Furthermore, hepatic injury and activation of the TLR4/NFκB pathway were observed, implying that co-exposure to As and PSNPs may promote liver inflammation via the gut-liver axis. These findings demonstrate that co-exposure to As and PSNPs exerts enhanced toxicity by compromising gut barrier function, inducing inflammatory cell death, and promoting inter-organ crosstalk. This study provides new mechanistic insights into the health risks posed by emerging combinations of environmental contaminants.