Epigenome-wide association studies of occupational exposure to benzene and formaldehyde

Sufficient evidence supports a relationship between certain myeloid neoplasms and exposure to benzene or formaldehyde. DNA methylation could underlie benzene- and formaldehyde-induced health outcomes, but data in exposed human populations are limited. We conducted two cross-sectional epigenome-wide association studies (EWAS), one in workers exposed to benzene and another in workers exposed to formaldehyde. Using HumanMethylation450 BeadChips, we investigated differences in blood cell DNA methylation among 50 benzene-exposed subjects and 48 controls, and among 31 formaldehyde-exposed subjects and 40 controls. We performed CpG-level and regional-level analyses. In the benzene EWAS, we found genome-wide significant alterations, i.e., FWER-controlled <i>P</i>-values &lt;0.05, in the mean and variance of methylation at 22 and 318 CpG sites, respectively, and in mean methylation of a large genomic region. Pathway analysis of genes corresponding to benzene-associated differential methylation sites revealed an impact on the AMPK signalling pathway. In formaldehyde-exposed subjects compared to controls, 9 CpGs in the <i>DUSP22</i> gene promoter had genome-wide significant decreased methylation variability and a large region of the <i>HOXA5</i> promoter with 44 CpGs was hypomethylated. Our findings suggest that DNA methylation may contribute to the pathogenesis of diseases related to benzene and formaldehyde exposure. Aberrant expression and methylation of <i>HOXA5</i> previously has been shown to be clinically significant in myeloid leukaemias. The tumour suppressor gene <i>DUSP22</i> is a potential biomarker of exposure to formaldehyde, and irregularities have been associated with multiple exposures and diseases.

足够的证据表明，某些髓系肿瘤（myeloid neoplasms）与苯或甲醛暴露存在明确关联。DNA甲基化可能是苯与甲醛暴露诱导健康损害的潜在分子机制，但针对暴露人群的相关研究数据仍较为匮乏。我们开展了两项横断面表观基因组全关联研究（epigenome-wide association studies, EWAS），一项针对苯暴露工人，另一项针对甲醛暴露工人。本研究采用HumanMethylation450 BeadChips技术，对50名苯暴露受试者与48名对照者，以及31名甲醛暴露受试者与40名对照者的血细胞DNA甲基化差异进行了分析，并开展了CpG位点水平与区域水平的关联分析。在苯暴露EWAS分析中，我们发现了全基因组水平的显著甲基化改变：在校正家族式错误率（family-wise error rate, FWER）后，P值<0.05，其中22个CpG位点的甲基化均值、318个CpG位点的甲基化变异度分别出现显著差异，同时一处大型基因组区域的甲基化均值也存在显著改变。对苯暴露相关差异甲基化位点所对应基因的通路富集分析显示，其显著富集于AMPK信号通路。与对照者相比，甲醛暴露受试者中，DUSP22基因启动子区域内的9个CpG位点出现了全基因组显著的甲基化变异度降低；同时HOXA5基因启动子的一处大型区域（包含44个CpG位点）呈现低甲基化状态。本研究结果提示，DNA甲基化可能参与苯与甲醛暴露相关疾病的发病过程。此前已有研究表明，HOXA5基因的异常表达与甲基化异常在髓系白血病中具有重要临床意义。抑癌基因DUSP22是甲醛暴露的潜在生物标志物，其表达异常与多种暴露因素及疾病密切相关。