Integrated Metabolomic and Transcriptomic Analyses of Mouse Liver Reveals the In Vivo Toxicity and Mechanisms of Individual and Combined Toxicants Formed in the Thermal Processing of High-Fat Diets

As a part of a continuous 90 day subchronic toxicology study, integrated metabolomic and transcriptomic approaches were applied to assess the metabolic network changes in the livers of Kunming mice exposed to three typical thermally induced food toxicants, including oxidative derivatives of triacylglycerols (ox-TGs), aldehydes, and 3-monochloropropane-1,2-diol esters (3-MCPDE), as well as their mixtures. Results showed lipid metabolic dysregulation through impaired purine metabolism, PPAR signaling, and bile acid metabolism. Ox-TGs emerged as the most hazardous compound, altering over 10 genes/enzymes. 3-MCPDE exhibited gender-specific effects, significantly upregulating fatty acid metabolism and gluconeogenesis genes in males. Interestingly, toxicant mixtures attenuated the adverse metabolic effects caused by individual compounds, demonstrating complex regulatory mechanisms in fatty acid biosynthesis and oxidation. The metabolomic and transcriptomic analyses conducted in this study revealed that combined exposure to multiple toxicants generated during lipid thermal processing may induce more complex toxicity effects than the simple additive effects of individual toxicants. Certain antagonistic effects were observed when comparing individual toxicants to their mixtures, highlighting the need for further mechanistic verifications in this area.