Integrated metabolomics and transcriptomics reveal di(2-ethylhexyl) phthalate-induced mitochondrial dysfunction and glucose metabolism disorder through oxidative stress in rat liver

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous pollutant that results in hepatotoxicity. However, an understanding of the systematic mechanism of hepatic injury caused by DEHP remains limited. Here, we performed a comprehensive metabolomics and transcriptomics analyses to describe hepatic responses of rats to long-term DEHP exposure and, together with pathology and functional injury of liver, systematically analyzed the pathogenesis and mechanisms of liver damage. SD rats were exposed to 0 and 600 mg/kg/day DEHP for 12 weeks. Thereafter, biochemical indicators and histopathological changes regarding liver function were detected. Metabolomics and transcriptomics profiles of rat liver samples were analyzed using a UPLC-MS/MS system and Illumina Hiseq 4000, respectively. DEHP induced hepatocyte structural alterations and edema, depressed monooxygenase activity, decreased antioxidant activities, aggravated oxidative damage, blocked the tricarboxylic acid cycle and respiratory chain, and disturbed glucose homeostasis in the liver. These findings indicate that reactive oxygen species play a major role in these events. Overall, this study systematically depicts the comprehensive mechanisms of long-term DEHP exposure to liver injury and highlights the power of metabolomics and transcriptomics platforms in the mechanistic understanding of xenobiotic hepatotoxicity.