Co-exposure to polystyrene nanoplastics and glyphosate promotes intestinal apoptosis in mice via intestinal barrier impairment and immunoinflammatory dysregulation

Environmental contaminants such as polystyrene nanoplastics (PSNPs, 1–1000 nm) and glyphosate pose significant environmental and public health risks. This study aimed to investigate the intestinal toxicity and molecular mechanisms induced by PSNPs and/or glyphosate. Mice were exposed to PSNPs (<100 nm), glyphosate, or a combination of both for 35 days via intragastric administration (PSNPs: 0.5 mg/d; glyphosate: 50 mg/kg-bw/day; PSNPs + glyphosate: 0.5 mg/d +50 mg/kg-bw/day). The control group received same volume of distilled water. Our findings revealed that exposure to PSNPs and/or glyphosate aggravated pathological alterations, including inflammatory cell infiltration, severe mitochondrial cristae fracture, and an approximately 50 % reduction in goblet cells in the intestine. Moreover, exposure to PSNPs and/or glyphosate caused a critical 75 % inhibition of FOXP3 and dissociation of tight junctions in the intestine (reflected by a 50 % decrease in Occludin, and a 20 %–50 % decrease in ZO-1). These changes were accompanied by significant alterations in beneficial gut microbiota, metabolic profiles, bile acid metabolism disorders, and a pronounced elevation in 3-β-deoxycholic acid, a metabolite tied to bile acid receptor signaling and barrier dysfunction. Although exposure to glyphosate led to the most significant upregulation of the pro-inflammatory factors TNF-α and the pro-apoptosis proteins Cleave-caspase-3, co-exposure did not exacerbate cell apoptosis in animal tissue experiments, which is contrasts with the cell-based findings. MODE-K (mouse intestinal epithelial) cells were treated with PSNPs (0.75 mg/mL) or glyphosate (0.5 mg/mL). In vitro experiments showed that PSNPs aggravated the disrupted Treg/Th17 immune-inflammatory balance, impaired intestinal barrier function (with a 50 % reduction in ZO-1 and Occludin), and increased cell apoptosis, caused by glyphosate. This study advances our understanding of the health risks posed by endocrine-disrupting chemical mixtures and provides critical insights into the molecular mechanisms of PSNP-glyphosate-induced intestinal toxicity. These findings lay the groundwork for future research aimed at mitigating the pathophysiological impacts of environmental pollutants.