Di-(2-ethylhexyl) phthalate-induced hepatotoxicity exacerbated type 2 diabetes mellitus (T2DM) in female pubertal T2DM mice.

Di-(2-ethylhexyl) phthalate (DEHP), one of the most common plasticizers, is closely associated with a high prevalence of pubertal type 2 diabetes mellitus (T2DM). Numerous studies have indicated that DEHP-induced metabolic toxicity exhibits sex differences. In this study, the sex differences in the effect of DEHP on pubertal T2DM (P-T2DM) mice, the susceptibility of female P-T2DM mice to DEHP-induced metabolic toxicity, and the underlying mechanisms were investigated. DEHP exposure exacerbated metabolic disorders in female P-T2DM mice. Factorial analysis showed that female P-T2DM mice were more sensitive to DEHP exposure than female normal mice and male P-T2DM mice. It was determined by integrated biomarker response results that female P-T2DM mice had higher risks of developing T2DM, metabolic disorders, cardiovascular events and hepatotoxicity than male P-T2DM mice. Moreover, hepatic transcriptome analysis emphasized the effects of DEHP on the expression of oxidative injury- and metabolic function-related genes. Western blotting indicated that DEHP activated Jun-N-terminal kinase (JNK) and impaired insulin sensitivity in the liver, which were the main causes of DEHP-exacerbated metabolic abnormalities in P-T2DM mice. Our study revealed that compared with normal mice and male P-T2DM mice, female P-T2DM mice tend to suffer from increased DEHP-induced metabolic toxicity, which was primarily attributed to hepatotoxicity.