title: Epigenetic events determine tissue-specific toxicity of inhalational exposure to the genotoxic chemical 1,3-butadiene in male C57BL/6J mice.
abstract: 1,3-Butadiene (BD), a widely used industrial chemical and a ubiquitous environmental pollutant, is a known human carcinogen. Although genotoxicity is an established mechanism of the tumorigenicity of BD, epigenetic effects have also been observed in livers of mice exposed to the chemical. To better characterize the diverse molecular mechanisms of BD tumorigenicity, we evaluated genotoxic and epigenotoxic effects of BD exposure in mouse tissues that are target (lung and liver) and non-target (kidney) for BD-induced tumors. We hypothesized that epigenetic alterations may explain, at least in part, the tissue-specific differences in BD tumorigenicity in mice. We evaluated the level of N-7-(2,3,4-trihydroxybut-1-yl)guanine adducts and 1,4-bis-(guan-7-yl)-2,3-butanediol crosslinks, DNA methylation, and histone modifications in male C57BL/6 mice exposed to filtered air or 425 ppm of BD by inhalation (6 h/day, 5 days/week) for 2 weeks. Although DNA damage was observed in all three tissues of BD-exposed mice, variation in epigenetic effects clearly existed between the kidneys, liver, and lungs. Epigenetic alterations indicative of genomic instability, including demethylation of repetitive DNA sequences and alterations in histone-lysine acetylation, were evident in the liver and lung tissues of BD-exposed mice. Changes in DNA methylation were insignificant in the kidneys of treated mice, whereas marks of condensed heterochromatin and transcriptional silencing (histone-lysine trimethylation) were increased. These modifications may represent a potential mechanistic explanation for the lack of tumorigenesis in the kidney. Our results indicate that differential tissue susceptibility to chemical-induced tumorigenesis may be attributed to tissue-specific epigenetic alterations.
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079 and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Grace
authors.initials: G
authors.lastname: Chappell
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079 and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455 *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079 and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Kobets
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079 and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Bridget
authors.initials: B
authors.lastname: O'Brien
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079 and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tretyakova
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079 and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Dewakar
authors.initials: D
authors.lastname: Sangaraju
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079 and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Oksana
authors.initials: O
authors.lastname: Kosyk
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079 and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Sexton
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079 and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Wanda
authors.initials: W
authors.lastname: Bodnar
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079 and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
authors.affiliation: *Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, Division of Biochemical Toxicology, National Center for Toxicological Research, FDA, Jefferson, Arkansas 72079 and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455 iir@unc.edu.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D018736:DNA Adducts; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D042822:Genomic Instability / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D019570:Inhalation Exposure; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL
chemical_list: D000393:Air Pollutants; D002070:Butadienes; D002274:Carcinogens, Environmental; D018736:DNA Adducts; D006657:Histones; C031763:1,3-butadiene
keywords: 1,3-butadiene; epigenetics; genotoxicity