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Microsomal epoxide hydrolase (EPHX1) polymorphisms are associated with aberrant promoter methylation of ERCC3 and hematotoxicity in benzene‐exposed workers
Author(s) -
Xing Caihong,
Chen Qi,
Li Guilan,
Zhang Linyuan,
Zheng Min,
Zou Zhengyong,
Hou Lifang,
Wang QianFei,
Liu Xin,
Guo Xinbiao
Publication year - 2013
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.21786
Subject(s) - methylation , dna methylation , carcinogen , biology , single nucleotide polymorphism , microbiology and biotechnology , gene , genetics , gene expression , genotype
Benzene is an important industrial chemical and widespread environmental pollutant known to induce leukemia and other blood disorders. To be carcinogenic, benzene must be metabolized to produce toxic metabolites. To investigate whether single nucleotide polymorphisms (SNPs) in the metabolic enzyme genes are associated with benzene‐induced alterations in DNA methylation and hematotoxicity, we genotyped four commonly studied SNPs in three metabolic enzymes genes CYP1A1 , EPHX1 and NQO1 ; and analyzed promoter DNA methylation status in 11 genes which have been reported to be associated with benzene‐induced hematotoxicity ( BLM , CYP1A1 , EPHX1 , ERCC3 , NQO1 , NUDT1 , p15 , p16 , RAD51 , TP53 and WRAP53 ) in 77 benzene‐exposed workers and 25 unexposed controls in China. ERCC3 , a DNA repair gene, showed a small but statistically significant increase of promoter DNA methylation in the exposed group compared with the unexposed group (mean ± SD: 4.73 ± 3.46% vs. 3.63 ± 1.96%, P = 0.048). We also observed that an increased number of C allele for rs1051740 in EPHX1 was associated with decreased ERCC3 methylation levels in benzene‐exposed workers ( P trend = 0.001), but not in unexposed controls ( P trend = 0.379). Interestingly, another EPHX1 SNP (rs2234922) was associated with lower white blood cell (WBC) counts ( P trend = 0.044) in benzene‐exposed workers. These associations remained the same when ERCC3 promoter methylation and WBCs were dichotomized according to the 90th percentile (≥6%) of methylation levels in controls and a leucopenia cutoff (<4 × 10 9 /L), respectively. Our findings suggest that benzene exposure may be associated with hypermethylation in ERCC3 , and that genetic variants in EPHX1 may play an important role in epigenetic changes and hematotoxicity among benzene‐exposed workers. Environ. Mol. Mutagen. 54:397–405, 2013. © 2013 Wiley Periodicals, Inc.