Effects of Benzene and Its Metabolites on Global DNA Methylation in Human Normal Hepatic L02 Cells
Effects of Benzene and Its Metabolites on Global DNA Methylation in Human Normal Hepatic L02 Cells
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苯及其代谢物对人正常肝L02细胞整体DNA甲基化的影响
DOI：
10.1002/tox.20777
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发表时间：
2014-01-01
影响因子：
4.5
通讯作者：
Fu, Jiamo
中科院分区：
文献类型：
--
作者：
Hu, Junjie;Ma, Huimin;Fu, Jiamo
苯是一种重要的工业化学品，也广泛存在于香烟烟雾、汽车尾气和汽油中。据悉，苯可导致造血功能紊乱，已被公认为人类致癌物。然而，它增加致癌风险的机制仅部分了解。DNA甲基化异常是与致癌物毒性相关的主要表观遗传机制。为了解苯的致癌作用，本研究采用HaeIII DNA甲基转移酶（DNMT）介导的体外甲基化检测方法，观察苯及其代谢产物对人正常肝细胞L02 DNA甲基化状态的影响，以及DNMT活性的变化是否引起苯及其代谢产物的甲基化改变。结果显示，氢醌和1，4-苯醌可诱导L02细胞DNA甲基化水平降低，与对照组相比差异有统计学意义（p < 0.05），而苯、苯酚和1，2，4-三羟基苯对L02细胞DNA甲基化水平无明显影响。苯代谢产物对HaeIII DNMT活性无影响，但1，4-苯醌在5 M浓度下对酶促甲基化反应有显著抑制作用（p < 0.05）。这些结果表明，苯的代谢产物，氢醌，和1，4-苯醌可以破坏整体DNA甲基化，和潜在的表观遗传机制，其中整体DNA低甲基化诱导的1，4-苯醌可能通过DNMT活性的抑制作用在10 M（p < 0.05）。(c)2011 Wiley Periodicals，Inc.环境毒理学29：108-116，2014年。
Benzene is an important industrial chemical that is also widely present in cigarette smoke, automobile exhaust, and gasoline. It is reported that benzene can cause hematopoietic disorders and has been recognized as a human carcinogen. However, the mechanisms by which it increases the risk of carcinogenesis are only partially understood. Aberrant DNA methylation is a major epigenetic mechanism associated with the toxicity of carcinogens. To understand the carcinogenic capacity of benzene, experiments were designed to investigate whether exposure to benzene and its metabolites would change the global DNA methylation status in human normal hepatic L02 cells and then to evaluate whether the changes would be induced by variation of DNA methyltransferase (DNMT) activity in HaeIII DNMT-mediated methylation assay in vitro. Our results showed that hydroquinone and 1,4-benzoquinone could induce global DNA hypomethylation with statistically significant difference from control (p < 0.05), but no significant global DNA methylation changes were observed in L02 cells with benzene, phenol, and 1,2,4-trihydroxybenzene exposure. Benzene metabolites could not influence HaeIII DNMT activity except that 1,4-benzoquinone shows significantly inhibiting effect on enzymatic methylation reaction at concentrations of 5 M (p < 0.05). These results suggest that benzene metabolites, hydroquinone, and 1,4-benzoquinone can disrupt global DNA methylation, and the potential epigenetic mechanism by which that global DNA hypomethylation induced by 1,4-benzoquinone may work through the inhibiting effects of DNMT activity at 10 M (p < 0.05). (c) 2011 Wiley Periodicals, Inc. Environ Toxicol 29: 108-116, 2014.