Changes in DNA methylation patterns in subjects exposed to low-dose benzene.
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 microg/m(3)). 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.
Bollati
Valentina
V
Molecular Epidemiology Laboratory, Department of Environmental and Occupational Health, University of Milan, Via San Barnaba 8, 20122 Milan, Italy. valentina.bollati@unimi.it
Baccarelli
Andrea
A
Hou
Lifang
L
Bonzini
Matteo
M
Fustinoni
Silvia
S
Cavallo
Domenico
D
Byun
Hyang-Min
HM
Jiang
Jiayi
J
Marinelli
Barbara
B
Pesatori
Angela C
AC
Bertazzi
Pier A
PA
Yang
Allen S
AS
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics; D001554:Benzene / Q000506:poisoning*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D004247:DNA / Q000097:blood; D019175:DNA Methylation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D005260:Female; D018392:Genomic Imprinting / Q000187:drug effects; D006801:Humans; D019570:Inhalation Exposure; D020084:Long Interspersed Nucleotide Elements / Q000187:drug effects; D008297:Male; D058950:Melanoma-Specific Antigens; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D016273:Occupational Exposure; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D000951:Antigens, Neoplasm; D050762:Cyclin-Dependent Kinase Inhibitor p15; C094335:H19 long non-coding RNA; C072011:MAGEA1 protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D004247:DNA; D001554:Benzene