Investigation of the gastric toxicity induced by exposure to tri-isobutyl phosphate

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Tri-isobutyl phosphate (TiBP), a widely used organophosphate flame retardant, has attracted increasing attention due to its environmental persistence and potential health risks. However, its impact on gastric function remains unclear. In this study, TiBP concentrations were significantly higher in the serum of gastric cancer patients than in healthy controls, indicating a potential link between environmental exposure and gastric pathology. In vitro, TiBP exposure reduced the viability of GES-1 gastric epithelial cells, increased apoptosis, and triggered oxidative stress, as evidenced by decreased SOD and GSH levels and elevated MDA. N-acetylcysteine co-treatment partially restored redox balance, confirming oxidative stress involvement. In vivo, mice orally exposed to TiBP for 30 days exhibited disrupted gastric gland structure, inflammatory infiltration, and reduced ZO-1 expression, accompanied by increased IL-6 and TNF-α levels. Integrated transcriptomic and metabolomic analyses revealed dose-dependent alterations in amino acid, lipid, and energy metabolism. Correlation analysis further demonstrated coordinated transcriptional and metabolic remodeling under TiBP exposure. Overall, TiBP induces oxidative stress, apoptosis, and inflammation, leading to gastric epithelial injury and metabolic reprogramming. These findings provide new insight into the mechanisms of organophosphate flame retardant–induced gastric toxicity and highlight TiBP as an emerging environmental risk factor to digestive health. • TiBP causes oxidative stress, apoptosis and inflammation, leading to gastric epithelial and barrier damage. • Multi-omics shows dose-dependent metabolic reprogramming affecting amino acid and lipid metabolism. • Low-dose TiBP is adaptive, while high-dose triggers oxidative injury and ferroptosis progression.

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