Changes in DNA methylation patterns in subjects exposed to low-dose benzene
Changes in DNA methylation patterns in subjects exposed to low-dose benzene
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DOI：
10.1158/0008-5472.can-06-2995
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Yang, Allen S.
中科院分区：
文献类型：
--
作者：
Bollati, Valentina;Baccarelli, Andrea;Yang, Allen S.
异常的DNA甲基化模式，包括整体低甲基化、基因特异性高甲基化/低甲基化和印迹缺失（LOI），在急性髓细胞性白血病（AML）和其他癌症组织中很常见。我们首次调查了这种表观遗传变化是否是由低水平暴露于苯（一种与AML风险相关的广泛污染物）引起的。血液DNA样本和暴露数据来自于不同苯暴露水平的受试者，包括意大利米兰的78名加油站服务员、77名交通警察和58名未暴露的参照物（个人空气苯范围，< 6-478 μ g/m3）。使用亚硫酸氢盐-PCR焦磷酸测序来定量长散布核元件-1（LINE-1）和DNA重复元件中的DNA甲基化作为全基因组甲基化的替代物，并检查MACE-1和p15的基因特异性甲基化。等位基因特异性焦磷酸测序的H19基因被用来检测LOI在96例杂合子的H19印迹中心G/A单核苷酸多态性。空气中的苯与LINE-1（空气中苯水平增加10倍时为-2.33%; P=0.009）和THE 1（-1.00%; P=0.027）甲基化的显著降低相关。p15基因的高甲基化（+0.35%; P=0.018）和法师-1基因的低甲基化（-0.49%; P=0.049）与空气中苯含量的增加有关。LOI仅在暴露受试者中发现（4/73，5.5%），而在参照物中未发现（0/23，0.0%）。而空气中苯含量与LOI无显著相关性（P > 0.20）。这是第一项将DNA甲基化改变（重现恶性细胞中发现的异常表观遗传模式）与低水平致癌物暴露联系起来的人类研究。
Aberrant DNA methylation patterns, including global hypomethylation, gene-specific hypermethylation/hypomethylation, and loss of imprinting (LOI), are common in acute myelogenous leukemia (AML) and other cancer tissues. We investigated for the first time whether such epigenetic changes are induced in healthy subjects by low-level exposure to benzene, a widespread pollutant associated with AML risk. Blood DNA samples and exposure data were obtained from subjects with different levels of benzene exposure, including 78 gas station attendants, 77 traffic police officers, and 58 unexposed referents in Milan, Italy (personal airborne benzene range, < 6-478 mu g/m(3)). Bisulfite-PCR pyrosequencing was used to quantitate DNA methylation in long interspersed nuclear element-1 (LINE-1) and Alul repetitive elements as a surrogate of genome-wide methylation and examine genespecific methylation of MACE-1 and p15. Allele-specific pyrosequencing of the H19 gene was used to detect LOI in 96 subjects heterozygous for the H19 imprinting center G/A single-nucleotide polymorphism. Airborne benzene was associated with a significant reduction in LINE-1 (-2.33% for a 10-fold increase in airborne benzene levels; P=0.009) and Alul (-1.00%; P=0.027) methylation. Hypermethylation in p15 (+0.35%; P=0.018) and hypomethylation in MAGE-1 (-0.49%; P=0.049) were associated with increasing airborne benzene levels. LOI was found only in exposed subjects (4 of 73, 5.5%) and not in referents (0 of 23, 0.0%). However, LOI was not significantly associated with airborne benzene (P > 0.20). This is the first human study to link altered DNA methylation, reproducing the aberrant epigenetic patterns found in malignant cells, to low-level carcinogen exposure.