丙烯酰胺诱导的小鼠肺和肝的遗传毒性和表观遗传毒性变化：一项为期28天的饮用水研究。,Chemical Research in Toxicology

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丙烯酰胺诱导的小鼠肺和肝的遗传毒性和表观遗传毒性变化：一项为期28天的饮用水研究。
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2019-03-12 , DOI: 10.1021/acs.chemrestox.9b00020
Aline de Conti ₁ , Volodymyr Tryndyak ₁ , Linda S VonTungeln ₁ , Mona I Churchwell ₁ , Frederick A Beland ₁ , Alexandra M M Antunes ₂ , Igor P Pogribny ₁

Affiliation

国际癌症研究机构已将丙烯酰胺列为“ 2A类致癌物”（可能对人类致癌）。丙烯酰胺的致癌性归因于其公认的遗传毒性。在本研究中，我们调查了丙烯酰胺对小鼠表观遗传学改变的影响。雌性B6C3F1小鼠在饮用水中接受了丙烯酰胺28天，剂量为之前在2年的癌症生物测定中使用的剂量（0、0.0875、0.175、0.35和0.70 mM），并且在目标器官的肺部研究了遗传毒性和表观遗传作用对丙烯酰胺具有致癌性，而肝脏则是非目标器官。丙烯酰胺暴露导致肝和肺DNA中N7-（2-氨基甲酰基-2-羟乙基）鸟嘌呤和N3-（2-氨基甲酰基-2-羟乙基）腺嘌呤的剂量依赖性形成。相比之下，两种组织之间的整体表观遗传学改变的概况是不同的。在肺中，丙烯酰胺暴露导致组蛋白H4赖氨酸20三甲基化（H4K20me3）减少，这是人类癌症的常见表观遗传特征；而在肝脏中，组蛋白H3赖氨酸27（H3K27ac）的乙酰化增加，这是一种激活基因转录的基因标记。用0.70 mM丙烯酰胺处理也导致肺和肝中DNA甲基化和整个转录组的实质性改变。但是，在两种组织之间，DNA甲基化和基因表达变化的趋势存在实质性差异。对差异表达基因的分析表明，肝脏（而非肺）中的基因显着上调并激活了基因转录调控途径。与肺中的高甲基化和转录沉默相反，这对应于肝脏中组蛋白H3K27ac和DNA低甲基化的增加。我们的结果表明，丙烯酰胺诱导的全局表观遗传学改变与其遗传毒性效应无关，表明表观遗传事件可能决定了丙烯酰胺的器官特异性致癌性。此外，这项研究为遗传毒性化学致癌物诱导的致癌机理中除了遗传毒性事件外，表观遗传学改变的重要性提供了有力的支持。这表明表观遗传事件可能决定丙烯酰胺的器官特异性致癌性。此外，这项研究为遗传毒性化学致癌物诱导的致癌机理中除了遗传毒性事件外，表观遗传学改变的重要性提供了有力的支持。这表明表观遗传事件可能决定丙烯酰胺的器官特异性致癌性。此外，这项研究为遗传毒性化学致癌物诱导的致癌机理中除了遗传毒性事件外，表观遗传学改变的重要性提供了有力的支持。

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Genotoxic and Epigenotoxic Alterations in the Lung and Liver of Mice Induced by Acrylamide: A 28 Day Drinking Water Study.

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.

更新日期：2019-02-26

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