Dietary exposure of deoxynivalenol affected cytochrome P450 and growth related-gene expression via DNA methylation in piglet liver
Background Deoxynivalenol (DON) is an inevitable contaminant in animal feed and human food and can lead to decreased appetite and growth retardation in children and piglets, which are often used as models for children. Hepatotoxicity induced by DON is closely related to growth inhibition. Although many molecular mechanisms are related to the liver damage caused by DON, few studies have been done on cytochrome P450 (CYP450s) and DNA methylation, and the role of DNA methylation in growth
... in growth inhibition of piglets was also unclear. Results In the present study, piglets were randomly assigned to the following three different dietary treatments for 4 weeks: control diet, diet containing 1 mg DON/kg feed, and diet containing 3 mg DON/kg feed. Compared to the control group, elevated alanine aminotransferase activity and globulin level were observed in DON groups; however, aspartate aminotransferase activity was decreased in 3 mg/kg DON group. DON exposure increased the mRNA expression of CYP450s including CYP1A1, CYP1A2, CYP2B22, CYP2C33, CYP2D25, CYP2E1, CYP3A22 and CYP3A39, in which DNA methylation was involved in the regulation of the expression of these enzymes. By estimating the benchmark dose value of the metabolic enzymes, CYP1A1 was found to be the most sensitive metabolic enzyme to evaluate the clinical liver injury caused by DON. DON upregulated the expression of DNA methyltransferases (DNMT1 and DNMT3B) in a dose-dependent manner, thus increasing the level of 5-mC in the whole genome. Notably, DON downregulated the expression of nicotinamide n-methyltransferase, possibly reducing the weight of the piglets. Additionally, 1 mg/kg DON decreased the expression of galanin-like peptide (GALP), while 3 mg/kg DON significantly increased the level of GALP through DNA methylation, thus affecting the appetite of the piglets. DON can significantly reduce the methylation level of insulin-like growth factor 1 (IGF-1) promoter and thus increase its expression. Conclusions Taken together, increased CYP450 expression and DNA methylation are important mechanisms of liver injury and growth inhibition induced by DON, which provide future reference values determination of antagonistic toxicity.