Continuous exposure to low concentrations of antimony(III) induces inflammation, apoptosis, oxidative and endoplasmic reticulum stress in Caco-2 intestinal epithelial cells

Antimony (Sb) is a metalloid widely used in industrial applications, particularly as a catalyst in the manufacturing of polyethylene terephthalate (PET), which is used in food packaging, water bottles, and household items. Human exposure to Sb may occur via oral, cutaneous, and inhalation routes. Under stress conditions, such as prolonged storage or high temperatures, Sb can migrate from plastic into food or beverages, causing health concerns. Once absorbed in the intestine, Sb compounds interact with biomolecules, potentially affecting physiological functions. Despite Sb classification as a pollutant of priority interest, its toxic molecular mechanisms remain poorly understood. In this study, the effects of very low concentrations of Sb(III) (0.5, 5, 50, 100 nM) were evaluated on human intestinal epithelial Caco-2 cells throughout the whole cell differentiation period, simulating continuous human exposure. Sb(III) exposure affected the intestinal epithelial barrier, activating the pro-inflammatory NF-κB signaling pathway and apoptotic cell death, confirmed by Bcl-2, Bax, and Caspase-3 protein levels. Sb(III) exposure triggered oxidative stress, evidenced by increased intracellular reactive oxygen species (ROS) levels, and endoplasmic reticulum (ER) stress, as indicated by increased levels of key unfolded protein response (UPR) markers (XBP-1s, p-eIF2α, GRP78, ATF4, CHOP). Additionally, Sb-induced ER stress activated SIRT1 signaling pathway. Treatment with ER-stress specific inhibitor tauroursodeoxycholic acid (TUDCA) demonstrated the central role of ER stress in Sb-induced injury. These findings provide new insights in the intestinal epithelial toxicity of low concentrations of Sb(III), suggesting that it would be recommendable to limit Sb use in industrial processes to minimise human health hazards.