Department of Occupational and Environmental Medicine, University of Milan and Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Med Lav. 2012 Mar-Apr;103(2):84-95.
Global genomic hypomethylation is a common event in cancer tissues that is frequently observed in hematopoietic malignancies, including leukemia. Benzene, an established leukemogen at high doses, has been suggested to induce hypomethylation based on investigations of DNA methylation in LINE-1 and Alu repetitive elements. Whether global genomic DNA methylation content is reduced in response to benzene exposure is still undetermined.
We measured global DNA methylation in 78 gasoline station attendants and 58 controls in peripheral blood cells using high-resolution gas chromatography-mass spectrometry. PCR-Pyrosequencing measures of DNA methylation at Alu and LINE-1 repetitive elements, representing a large proportion of methylation in non-coding regions, were also available. Exposure markers included personal airborne benzene, and urinary benzene, t,t-muconic acid (t,t-MA) and S-phelylmercapturic acid.
Mean global DNA methylation was 5.474 (+/- 0.083) %5mC in controls and 5.409 (+/- 0.142) %5mC in exposed participants (p = 0.01). All methylation markers were negatively correlated with airborne benzene. Alu and LINE-1 methylation, but not global DNA methylation, were negatively associated with t,t-MA; no association with the other urinary biomarkers was found. Multiple linear regression analysis adjusted for gender and age confirmed the results of correlation analysis and showed a 1.6% decrease in global DNA methylation associated with being gasoline station attendants. Alu and LINE-1 methylation levels were not associated with global DNA methylation.
Our results show that benzene exposure is associated with alterations in both global DNA and repetitive element methylation. Global and repetitive element methylation levels are not correlated in blood DNA, likely representing independent responses to benzene exposure.
全球基因组低甲基化是癌症组织中的一种常见事件，在包括白血病在内的血液恶性肿瘤中经常观察到。苯是一种高剂量的白血病诱导剂，基于对 LINE-1 和 Alu 重复元件的 DNA 甲基化的研究，已被认为会导致低甲基化。苯暴露是否会导致全基因组 DNA 甲基化含量降低仍不确定。
我们使用高分辨率气相色谱-质谱法测量了 78 名加油站工作人员和 58 名对照者外周血细胞中的全基因组 DNA 甲基化。也可获得 Alu 和 LINE-1 重复元件的 DNA 甲基化的 PCR-焦磷酸测序测量值，这些元件代表非编码区中很大一部分的甲基化。暴露标志物包括个人空气苯、尿苯、t,t-粘康酸（t,t-MA）和 S-苯巯基尿酸。
对照组的全基因组 DNA 甲基化平均值为 5.474（+/-0.083）%5mC，暴露组为 5.409（+/-0.142）%5mC（p=0.01）。所有甲基化标志物均与空气苯呈负相关。Alu 和 LINE-1 甲基化，但不是全基因组 DNA 甲基化，与 t,t-MA 呈负相关；与其他尿生物标志物无关联。性别和年龄调整的多元线性回归分析证实了相关分析的结果，并表明与作为加油站工作人员相关的全基因组 DNA 甲基化降低了 1.6%。Alu 和 LINE-1 甲基化水平与全基因组 DNA 甲基化无关。
我们的结果表明，苯暴露与全基因组和重复元件甲基化的改变有关。血液 DNA 中的全基因组和重复元件甲基化水平不相关，可能代表对苯暴露的独立反应。
