3-MCPD and glycidol coexposure induces systemic toxicity and synergistic nephrotoxicity via NLRP3 inflammasome activation, necroptosis, and autophagic cell death.

3-Monochloropropane-1,2-diol (3-MCPD), 2,3-epoxy-1-propanol (glycidol), and their esters are well-known food contaminants mainly formed by the heat processing of certain refined oils and coexist in various kinds of foodstuffs. However, the combined health effect and the underlying mechanism of 3-MCPD and glycidol coexposure are not well-understood. In this study, we investigated the systemic toxicity effects and the nephrotoxicity mechanisms of 3-MCPD and glycidol coexposure with in vitro and in vivo models, and next-generation sequencing (NGS) analysis. It was found that 3-MCPD and glycidol coexposure for 28 days synergistically induced toxicity in the kidney, lung, testis, and heart in C57BL/6 mice. Kidney was the most sensitive organ to coexposure, and the coexposure had a synergistic effect on inflammation and cytotoxicity through activation of the NLRP3 inflammasome, and the induction of necroptosis, and autophagic cell death in NRK-52E cells. Moreover, the NGS results revealed the genes changes associated with nephrotoxicity, inflammation and with the broad toxicity effects induced by 3-MCPD or glycidol alone or in combination, which were consistent with the results of in vitro and in vivo models. In summary, we report for the first time of the comprehensive toxicity effects and the mechanisms caused by 3-MCPD and glycidol coexposure.