Publication Type Journal Article
Title Genotoxic and Epigenotoxic Alterations in the Lung and Liver of Mice Induced by Acrylamide: A 28 Day Drinking Water Study
Authors Aline de Conti Volodymyr Tryndyak Linda S. VonTungeln Mona I. Churchwell Frederick A. Beland Alexandra Maria Moita Antunes Igor P. Pogribny
Groups BioMol
Journal CHEMICAL RESEARCH IN TOXICOLOGY
Year 2019
Month May
Volume 32
Number 5
Pages 869-877
Abstract Acrylamide has been classified as a Group 2A carcinogen (probably carcinogenic to humans) by the International Agency for Research on Cancer. The carcinogenicity of acrylamide is attributed to its well-recognized genotoxicity. In the present study, we investigated the effect of acrylamide on epigenetic alterations in mice. Female B6C3F1 mice received acrylamide in drinking water for 28 days, at doses previously used in a 2 year cancer bioassay (0, 0.0875, 0.175, 0.35, and 0.70 mM), and the genotoxic and epigenetic effects were investigated in lungs, a target organ for acrylamide carcinogenicity, and livers, a nontarget organ. Acrylamide exposure resulted in a dose-dependent formation of N7-(2-carbamoyl-2-hydroxyethyl)guanine and N3-(2-carbamoyl-2-hydroxyethyl)adenine in liver and lung DNA. In contrast, the profiles of global epigenetic alterations differed between the two tissues. In the lungs, acrylamide exposure resulted in a decrease of histone H4 lysine 20 trimethylation (H4K20me3), a common epigenetic feature of human cancer, while in the livers, there was increased acetylation of histone H3 lysine 27 (H3K27ac), a gene transcription activating mark. Treatment with 0.70 mM acrylamide also resulted in substantial alterations in the DNA methylation and whole transcriptome in the lungs and livers; however, there were substantial differences in the trends of DNA methylation and gene expression changes between the two tissues. Analysis of differentially expressed genes showed a marked up-regulation of genes and activation of the gene transcription regulation pathway in livers, but not lungs. This corresponded to increased histone H3K27ac and DNA hypomethylation in livers, in contrast to hypermethylation and transcription silencing in lungs. Our results demonstrate that acrylamide induced global epigenetic alterations independent of its genotoxic effects, suggesting that epigenetic events may determine the organ-specific carcinogenicity of acrylamide. Additionally this study provides strong support for the importance of epigenetic alterations, in addition to genotoxic events, in the mechanism of carcinogenesis induced by genotoxic chemical carcinogens.
DOI http://dx.doi.org/10.1021/acs.chemrestox.9b00020
ISBN
Publisher
Book Title
ISSN 0893-228X
EISSN 1520-5010
Conference Name
Bibtex ID ISI:000469293500010
Observations
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