Chronic oral exposure to chlorpyrifos disrupts hepatic epigenetic regulation and induces metabolic dysfunction in mice

Abstract

Organophosphate pesticides (OPs) have found extensive use in agriculture due to their short half-lives and relatively low persistence in the environment. In recent years, a growing body of evidence has linked OPs, including chlorpyrifos (CPF), to endocrine, reproductive, and metabolic dysfunction, raising significant public health concerns. Although CPF has been linked to various toxic effects, the epigenetic mechanisms underlying CPF-induced hepatotoxicity remain poorly understood. In the present study, mice were orally exposed to CPF (2 or 20 mg/kg body weight), and the effects on hepatic function were assessed. CPF exposure resulted in pronounced hepatotoxicity characterized by increased oxidative stress, impaired mitochondrial function and dysregulated expression of genes involved in oxidative phosphorylation. Notably, CPF exposure significantly depleted hepatic choline levels and downregulated the expression of genes involved in the regulation of DNA methylation, including Dnmt1, Mthfr and Tet2. The decline in hepatic choline was correlated with hypomethylation of the hepatic genome in CPF-exposed mice. CPF also elevated serum corticosterone in mice, reinforcing its role as an endocrine disruptor. This hormonal disruption was associated with dysregulated glucose homeostasis as evidenced by glucose intolerance, elevated hepatic glycogen and altered hepatic expression of the glucose transporter Glut2. Together, the findings from this study provide novel mechanistic insights into the epigenetic and metabolic effects of CPF-induced hepatotoxicity.