Di-(2-ethylhexyl) phthalate increases plasma glucose and induces lipid metabolic disorders via FoxO1 in adult mice

Di-(2-ethylhexyl) phthalate (DEHP), an endocrine-disrupting chemical (EDC) commonly used as a plasticizer, is responsible for widespread environmental pollution. Epidemiological and experimental data implicate DEHP and its metabolite mono(2-ethylhexyl) phthalate (MEHP) in the occurrence and development of metabolic syndrome. However, the specific effects and potential mechanisms of action of DEHP on glucose and lipid metabolism in adults are currently unclear. In the current study, adult male mice were continuously exposed to DEHP (0, 5, and 25 mg/kg/day) via oral administration and changes in glucose and lipid metabolism explored. Notably, exposure to DEHP led to a significant increase in plasma glucose and hepatic lipid accumulation but had no effect on insulin secretion. Western blot and real-time quantitative PCR showed that DEHP induced insulin resistance and promoted gluconeogenesis and lipid accumulation via overexpression of forkhead box protein O1 (FoxO1), in keeping with hepatic RNA sequencing data. Variations in gut microbiota aggravated these effects while inhibition of FoxO1 reversed the adverse effects of DEHP. Our findings support a key role of FoxO1 in disorders of glucose and lipid metabolism caused by DEHP.