BioProject

The carcinogenic effect of furan, a potent hepatotoxicant and rodent liver carcinogen, has been attributed to genotoxic and non-genotoxic, including epigenetic, changes in the liver; however, the mechanisms of the furan liver tumorigenicity are still unclear. More...

The carcinogenic effect of furan, a potent hepatotoxicant and rodent liver carcinogen, has been attributed to genotoxic and non-genotoxic, including epigenetic, changes in the liver; however, the mechanisms of the furan liver tumorigenicity are still unclear.  The goal of the present study was to investigate the role of transcriptomic and epigenetic events in the development of hepatic lesions in Fischer (F344) rats induced by furan treatment in a classic two-year rodent tumorigenicity bioassay.  Male F344 rats were distributed randomly into control and experimental groups.  Rats from the experimental groups were treated by gavage 5 days/week with either 0.92 or 2.0 mg furan/kg body weight (bw) in corn oil for 104 weeks.  Rats from control group received corn oil only.  High-throughput whole genome microarray analyses demonstrated distinctive dose-dependent alterations in gene expression in the furan-induced liver lesions.  A total of 2073 and 2422 genes was found to be differentially expressed in the furan-induced liver lesions in rats treated with 0.92 and 2.0 mg furan/kg bw, respectively, as compared to normal liver tissue.  Approximately 60% (1340) of the differentially expressed genes were common to both treatment groups.  In silico analysis of the common differentially expressed genes revealed the presence of CpG island in 51% (679) of the genes, suggesting that they may be epigenetically regulated.  Promoter methylation analysis of individual differentially expressed CpG island-containing genes demonstrated dose-dependent gene-specific methylation changes that were highly correlated with gene expression.  Our findings illustrate that gene-specific DNA methylation changes have functional consequences and may contribute to the development of furan-induced pathologic liver lesions. Overall design: Male F344 rats were treated by gavage 5 days/week with 0.92 and 2 mg furan/kg bw for 104 weeks.  Gene expression profiles in the livers from vehicle-treated rats and non-lesion liver tissue (NT), adjacent non-lesion liver tissue (ANT) and cholangiofibrotic liver tissue (TRT) of furan-treated rats were investigated. Less...