ABSTRACT: Effect of furan on transcriptomic and gene-specific DNA methylation changes in the livers of Fischer 344 rats in a two-year carcinogenicity study
Project description:Transcriptomic data obtained by RNA-seq from male Fischer 344 rats treated with furan and 3-methylfuran were compared and contrasted. Microarray data from the same rats treated with furan was also used to compare microarray to RNA seq analysis.
Project description:Aged male Fischer 344/N rats are prone to developing spontaneous peritoneal mesotheliomas, which arise predominantly from the tunica vaginalis of the testes. A definitive cause for the predominance of this neoplasm in F344/N rats is unknown. Investigation of the molecular alterations that occur in spontaneous rat mesotheliomas may provide insight into their pathogenesis, as well enable a better understanding regarding the mechanisms underlying chemically induced mesothelioma in rodents. Mesothelial cell function represents a complex interplay of pathways related to host defense mechanisms and maintenance of cellular homeostasis. Global gene expression profiles of spontaneous mesotheliomas from vehicle control male F344/N rats from two-year National Toxicology Program carcinogenicity bioassays were analyzed to determine the molecular features of these tumors, and elucidate tumor-specific gene expression profiles. The resulting gene expression pattern showed that spontaneous mesotheliomas are associated with upregulation various growth factors, oncogenes, cytokines, pattern recognition response receptors (PRR) and pathogen associated molecular patterns (PAMP) receptors, and the production of reactive oxygen and nitrogen species, as well as downregulation of apoptosis pathways. Alterations in these pathways in turn trigger molecular responses that stimulate cell proliferation and promote tumor survival and progression. Five spontaneous malignant mesotheliomas from two-year-old F344/N rats and six normal Fred-PE mesothelial cell culture samples (as controls).
Project description: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.