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 Mg/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 genespecific 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 (À2.33% for a 10-fold increase in airborne benzene levels; P = 0.009) and AluI (À1.00%; P = 0.027) methylation. Hypermethylation in p15 (+0.35%; P = 0.018) and hypomethylation in MAGE-1 (À0.49%; 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]
BackgroundAltered patterns of gene expression mediate the effects of particulate matter (PM) on human health, but mechanisms through which PM modifies gene expression are largely undetermined.ObjectivesWe aimed at identifying short- and long-term effects of PM exposure on DNA methylation, a major genomic mechanism of gene expression control, in workers in an electric furnace steel plant with well-characterized exposure to PM with aerodynamic diameters < 10 μm (PM10).MethodsWe measured global genomic DNA methylation content estimated in Alu and long interspersed nuclear element-1 (LINE-1) repeated elements, and promoter DNA methylation of iNOS (inducible nitric oxide synthase), a gene suppressed by DNA methylation and induced by PM exposure in blood leukocytes. Quantitative DNA methylation analysis was performed through bisulfite PCR pyrosequencing on blood DNA obtained from 63 workers on the first day of a work week (baseline, after 2 days off work) and after 3 days of work (postexposure). Individual PM10 exposure was between 73.4 and 1,220 μg/m3.ResultsGlobal methylation content estimated in Alu and LINE-1 repeated elements did not show changes in postexposure measures compared with baseline. PM10 exposure levels were negatively associated with methylation in both Alu [β = −0.19 %5-methylcytosine (%5mC); p = 0.04] and LINE-1 [β = −0.34 %5mC; p = 0.04], likely reflecting long-term PM10 effects. iNOS promoter DNA methylation was significantly lower in postexposure blood samples compared with baseline (difference = −0.61 %5mC; p = 0.02).ConclusionsWe observed changes in global and gene specific methylation that should be further characterized in future investigations on the effects of PM.
Background: A growing body of evidence has associated maternal exposure to air pollution with adverse effects on fetal growth; however, the existing literature is inconsistent.Objectives: We aimed to quantify the association between maternal exposure to particulate air pollution and term birth weight and low birth weight (LBW) across 14 centers from 9 countries, and to explore the influence of site characteristics and exposure assessment methods on between-center heterogeneity in this association.Methods: Using a common analytical protocol, International Collaboration on Air Pollution and Pregnancy Outcomes (ICAPPO) centers generated effect estimates for term LBW and continuous birth weight associated with PM10 and PM2.5 (particulate matter ≤ 10 and 2.5 µm). We used meta-analysis to combine the estimates of effect across centers (~ 3 million births) and used meta-regression to evaluate the influence of center characteristics and exposure assessment methods on between-center heterogeneity in reported effect estimates.Results: In random-effects meta-analyses, term LBW was positively associated with a 10-μg/m3 increase in PM10 [odds ratio (OR) = 1.03; 95% CI: 1.01, 1.05] and PM2.5 (OR = 1.10; 95% CI: 1.03, 1.18) exposure during the entire pregnancy, adjusted for maternal socioeconomic status. A 10-μg/m3 increase in PM10 exposure was also negatively associated with term birth weight as a continuous outcome in the fully adjusted random-effects meta-analyses (–8.9 g; 95% CI: –13.2, –4.6 g). Meta-regressions revealed that centers with higher median PM2.5 levels and PM2.5:PM10 ratios, and centers that used a temporal exposure assessment (compared with spatiotemporal), tended to report stronger associations.Conclusion: Maternal exposure to particulate pollution was associated with LBW at term across study populations. We detected three site characteristics and aspects of exposure assessment methodology that appeared to contribute to the variation in associations reported by centers.
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