title: Furan-induced transcriptomic and gene-specific DNA methylation changes in the livers of Fischer 344 rats in a 2-year carcinogenicity study.
abstract: Furan is a significant food contaminant and a potent hepatotoxicant and rodent liver carcinogen. The carcinogenic effect of furan has been attributed to genotoxic and non-genotoxic, including epigenetic, changes in the liver; however, the mechanisms of the furan-induced 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 2-year rodent tumorigenicity bioassay. High-throughput whole-genome transcriptomic analysis demonstrated distinct alterations in gene expression in liver lesions induced in male F344 rats treated with 0.92 or 2.0 mg furan/kg body weight (bw)/day for 104 weeks. Compared to normal liver tissue, 1336 and 1541 genes were found to be differentially expressed in liver lesions in rats treated with 0.92 and 2.0 mg furan/kg bw/day, respectively, among which 1001 transcripts were differentially expressed at both doses. Pairing transcriptomic and next-generation bisulfite sequencing analyses of the common differentially expressed genes identified 42 CpG island-containing genes in which the methylation level was correlated inversely with gene expression. Forty-eight percent of these genes (20 genes, including Areg, Jag1, and Foxe1) that exhibited the most significant methylation and gene expression changes were involved in key pathways associated with different aspects of liver pathology. Our findings illustrate that gene-specific DNA methylation changes have functional consequences and may be an important component of furan hepatotoxicity and hepatocarcinogenicity.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research (NCTR), 3900 NCTR Rd., Jefferson, AR, 72079, USA.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Tryndyak
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research (NCTR), 3900 NCTR Rd., Jefferson, AR, 72079, USA.
authors.forename: Aline
authors.initials: A
authors.lastname: de Conti
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research (NCTR), 3900 NCTR Rd., Jefferson, AR, 72079, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.affiliation: Toxicologic Pathology Associates, National Center for Toxicological Research (NCTR), Jefferson, AR, USA.
authors.forename: Greg R
authors.initials: GR
authors.lastname: Olson
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research (NCTR), 3900 NCTR Rd., Jefferson, AR, 72079, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research (NCTR), 3900 NCTR Rd., Jefferson, AR, 72079, USA. igor.pogribny@fda.hhs.gov.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D003596:Cytosine / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics; D005663:Furans / Q000633:toxicity*; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008297:Male; D011916:Rats, Inbred F344; D059467:Transcriptome / Q000187:drug effects
chemical_list: D051858:Forkhead Transcription Factors; C526350:FoxE1 protein, rat; D005663:Furans; D003596:Cytosine
keywords: Carcinogenicity; DNA methylation; Furan; Gene expression; Liver