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Changes in DNA Methylation Patterns in Subjects Exposed to Low-Dose Benzene

¹ Molecular Epidemiology Laboratory, Department of Environmental and Occupational Health, University of Milan and Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore Policlinico, Milan, Italy; ² Exposure, Epidemiology, and Risk Program, Harvard School of Public Health, Boston, Massachusetts; ³ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; ⁴ Department of Chemistry and Environmental Sciences, University of Insubria, Como, Italy; and ⁵ Division of Hematology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California

Requests for reprints: Valentina Bollati, Center of Molecular Epidemiology and Genetics, Department of Environmental and Occupational Health, University of Milan, Via San Barnaba 8, 20122 Milan, Italy. Phone: 39-02-503-20127; Fax: 39-02-503-20103; E-mail: valentina.bollati{at}unimi.it.

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 µg/m³). Bisulfite-PCR pyrosequencing was used to quantitate DNA methylation in long interspersed nuclear element-1 (LINE-1) and AluI repetitive elements as a surrogate of genome-wide methylation and examine gene-specific methylation of MAGE-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 AluI (–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. [Cancer Res 2007;67(3):876–80]

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