Effect Of DNA Methylation On Hepatoxicity In F344 Male Rats Treated With Trichloroethylene

Objective: Trichloroethylene(TCE),a common environmental contaminant,causes hepatocellular carcinoma in mice but not in rats.This study is aimed to understand the mechanisms of the species-specific hepatocarcinogenecity of TCE.Methods: Using MeDIP-chip,qPCR,COBRA and bisulfite sequencing,the DNA methylation status and the related mRNA expression levels were measured for the liver of rats exposed to TCE at 0 or 1000 mg/kg b.w.for 5 days.Results: Although no global DNA methylation change was detected,806 genes were hypermethylated and 186 genes were hypomethylated.The genes with hypermethylated DNA were enriched in endocytosis,MAPK,and cAMP signaling pathways.The hypermethylation of Uhrf2 DNA and the hypomethylation of Hadhb DNA were observed,however,no DNA methylation changes were detected in Ihh?Cdkn1a?Jun?Myc?Sfn and Cdkn2 a.The transcriptional levels of Gata1?Ihh?Jun?Tet2?Dnmt3a and Uhrf2 were significantly downregulated,whereas Hadhb and Cdkn1 a were overexpressed.No mRNA expression change was found for Clock?Mki67?Myc?Uhrf1 and Dnmt1.Conclusions: TCE-induced DNA methylation changes in rats appear to suppress hepatocarcinogenesis.Genes with TCE-induced rat liver DNA methylation and mRNA expression changes compared with mouse liver,which including Uhrf1,Mki67,Jun,Cdkn1 a,and Ihh,might be important in the species-specific hepatocarcinogenecity of TCE.