Tri-ortho-cresyl phosphate induces hepatic steatosis by mTOR activation and ER stress induction

• Published in: Ecotoxicology and environmental safety 2024-02, Vol.271, p.116010-116010, Article 116010
• Main Authors: Li, Jing, Wu, Yi-Jun
• Format: Article
• Language: English
• Subjects: 4-phenylbutyric acid; Endoplasmic reticulum stress; Hepatic steatosis; Mouse; MTOR; Organophosphorus compound; Rapamycin; SREBPs
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2024.116010

Tri-ortho-cresyl phosphate (TOCP), an organophosphorus compound (OP), which is widely used as plasticizer, flame retardant and other industrial products, has been reported to cause multiple toxicities including neurotoxicity and reproductive toxicity. However, it remains to be elusive whether TOCP induces hepatotoxicity. The purpose of this study was to investigate the effect of TOCP on hepatocytes and the lipid metabolism in particular. The adult mice were given a single dose of TOCP (800 mg/kg, p.o.) and the histological changes in liver tissue and lipid content in serum were determined. The results showed that more vacuoles and lipid droplets were observed in the liver of the mice exposed to TOCP. And triglyceride concentrations in serum and liver tissue significantly increased. However, the histopathological changes of the liver and the elevated triglyceride levels in the exposed mice can be reversed by endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid and mTOR signal inhibitor rapamycin. It was also found that the changes of expression levels of the biomarkers of ER stress and mTOR signaling pathway, such as GRP78, CHOP, and p-mTOR, in the exposed mice were consistent with those observed in the cultured primary hepatocytes treated with the same chemicals. These results showed that TOCP activated mTOR signal and ER stress to induce de novo lipid synthesis, which led to the hepatic steatosis in mouse. •TOCP induces hepatic steatosis through activating de novo lipogenesis.•TOCP affects lipid metabolism by the sterol regulatory element binding protein.•mTOR signals and ER stress participate in the TOCP-induced hepatic steatosis.