title: Editor's Highlight: Organ-Specific Epigenetic Changes Induced by the Nongenotoxic Liver Carcinogen Methapyrilene in Fischer 344 Rats.
abstract: Continuous lifetime exposure to certain natural and man-made chemicals is a major cause of cancers in humans; therefore, evaluating the carcinogenic risks of chemicals remains important. Currently, substantial progress has been made in identification of genotoxic carcinogens; in contrast, predicting the carcinogenic potential of nongenotoxic compounds is a challenge due to many different modes of action that may lead to tumorigenesis. In the present study, we investigated the effects of the nongenotoxic liver carcinogen methapyrilene and the nongenotoxic noncarcinogen usnic acid, at doses that do not exhibit organ cytotoxicity, on epigenomic alterations in the livers and kidneys of Fischer 344 (F344) rats. We demonstrate that a repeat-dose oral treatment of male F344 rats with methapyrilene for 6 weeks caused target organ-specific epigenetic alterations in the livers. In contrast, only very slight epigenetic changes were found in the livers of F344 rats treated with hepatotoxicant, but noncarcinogen, usnic acid. The methapyrilene-induced epigenetic changes consisted of changes in histone lysine acetylation and methylation, with the greatest increase occurring in global and gene-specific histone H3 lysine 9 (H3K9) deacetylation. Importantly, the results of the present study show an association between gene-specific histone H3K9 deacetylation and a reduced expression of critical cancer-related genes, including prospero homeobox 1 (Prox1), HNF1 homebox A (Hnf1a), and peroxisome proliferator activated receptor alpha (Ppara), which provides a mechanistic link between methapyrilene-induced epigenetic aberrations and liver carcinogenesis.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Shpyleva
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
authors.forename: Kostiantyn
authors.initials: K
authors.lastname: Dreval
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
authors.forename: Aline
authors.initials: A
authors.lastname: de Conti
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
authors.forename: Iryna
authors.initials: I
authors.lastname: Kindrat
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202.
authors.forename: Stepan
authors.initials: S
authors.lastname: Melnyk
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage / Q000633:toxicity; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D008701:Methapyrilene / Q000008:administration & dosage / Q000633:toxicity*; D008745:Methylation / Q000187:drug effects; D009928:Organ Specificity; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011897:Random Allocation; D011916:Rats, Inbred F344; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D001572:Benzofurans; D002273:Carcinogens; D051538:Hepatocyte Nuclear Factor 1-alpha; D006657:Histones; C496489:Hnf1a protein, rat; D018398:Homeodomain Proteins; D047493:PPAR alpha; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; C073339:usnic acid; D008701:Methapyrilene; D008239:Lysine
keywords: epigenetics.; liver; methapyrilene; nongenotoxic carcinogens