Liver immune and lipid metabolism disorders in mice induced by triphenyl phosphate with or without high fructose and high fat diet

Organophosphorus flame retardants (OPFRs) are frequently detected in food and human samples, and epidemiological studies have found that human exposure to aryl-OPFRs (triphenyl phosphate, TPP) is associated with lipid metabolism. Although toxicity studies suggest a potential obesity risk from TPP exposure, the molecular mechanism remains unclear. This study investigated the subchronic dietary effects on mouse liver significantly changed proteins (SCPs) and elucidated the underlying molecular mechanisms of TPP with or without a high-fructose and high-fat (HFF) diet. Male C57BL/6J mice were exposed to low-dose TPP (corresponding to the oral reference dose, 10 μg/kg body weight (bw)/day) and high-dose TPP (1000 μg/kg bw/day) for 12 weeks. The results showed that exposure to TPP generated changes of liver function and organelle damage as well as increases in total cholesterol and triglyceride levels. TPP exposure at a low dose damaged the liver immune system via major histocompatibility complex-related proteins involved in antigen processing and presentation. TPP exposure at a high dose caused disorders of the biosynthesis of unsaturated fatty acids and steroid hormones, thereby inducing lipid accumulation in the liver. Although 10 μg/kg TPP did not cause serious lipid metabolism disorders in the liver, significant overexpression of fatty acid-binding protein 5, malic enzyme 1, and other related SCPs was observed, which led to disorders of cholesterol metabolism and lipogenesis to activate the proliferator-activated receptor signaling pathway and thus induced potential obesity risks. In addition, lipid metabolism disorders related to TPP were aggravated under the HFF diet, impairing liver mitochondrial and endoplasmic reticulum function in mice by altering the activity of cytochrome P450 enzyme subfamilies. These findings provide an in-depth understanding of the molecular toxicity mechanisms and health risks associated with subchronic exposure to TPP under different dietary regimes.