Short-term diesel exhaust inhalation in a controlled human crossover study is associated with changes in DNA methylation of circulating mononuclear cells in asthmatics

Abstract

BackgroundChanges in DNA methylation have been associated with traffic-related air pollution in observational studies, but the specific mechanisms and temporal dynamics therein have not been explored in a controlled study of asthmatics. In this study, we investigate short-term effects of diesel exhaust inhalation on DNA methylation levels at CpG sites across the genome in circulating blood in asthmatics.MethodsA double-blind crossover study of filtered air and diesel exhaust exposures was performed on sixteen non-smoking asthmatic subjects. Blood samples were collected pre-exposure, and then 6 and 30 hours post-exposure. Peripheral blood mononuclear cell DNA methylation was interrogated using the Illumina Infinium HumanMethylation450 Array. Exposure-related changes in DNA methylation were identified. In addition, CpG sites overlapping with Alu or LINE1 repetitive elements and candidate microRNA loci were also analyzed.ResultsDNA methylation at 2827 CpG sites were affected by exposure to diesel exhaust but not filtered air; these sites enriched for genes involved in protein kinase and NFkB pathways. CpG sites with significant changes in response to diesel exhaust exposure primarily became less methylated, with a site residing within GSTP1 being among the significant hits. Diesel exhaust-associated change was also found for CpG sites overlapping with Alu and LINE1 elements as well as for a site within miR-21.ConclusionShort-term exposure to diesel exhaust resulted in DNA methylation changes at CpG sites residing in genes involved in inflammation and oxidative stress response, repetitive elements, and microRNA. This provides plausibility for the role of DNA methylation in pathways by which airborne particulate matter impacts gene expression and offers support for including DNA methylation analysis in future efforts to understand the interactions between environmental exposures and biological systems.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-014-0071-3) contains supplementary material, which is available to authorized users.

Response of transposable elements to environmental stressors

“…Recent studies indicate that exposure to diesel also leads to altered methylation status of TEs, suggesting the epigenetic alterations may be also involved in lung carcinogenesis. Jiang and colleagues, in their controlled human crossover study, reported that short-term diesel exhaust inhalation was associated with changes in DNA methylation of circulating mononuclear cells in 16 asthmatics 6 and 30 hours postexposure [150]. Similar to the findings in RAW264.7 macrophages [142], the response to diesel exhaust exposure within L1 and Alu elements was not uniform, with sites of both hypo- and hypermethylation being identified [150].…”

“…Jiang and colleagues, in their controlled human crossover study, reported that short-term diesel exhaust inhalation was associated with changes in DNA methylation of circulating mononuclear cells in 16 asthmatics 6 and 30 hours postexposure [150]. Similar to the findings in RAW264.7 macrophages [142], the response to diesel exhaust exposure within L1 and Alu elements was not uniform, with sites of both hypo- and hypermethylation being identified [150]. Specifically, out of the 31 L1differentially methylated positions in the genome, 13 increased, while 18 decreased in DNA methylation after exposure.…”

Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up

“…Short-term diesel exhaust exposure (DEP), as a model of particulate air pollution, was next investigated for association with DNA methylation differences in blood samples from 16 19-to 35-year-old nonsmokers with asthma and/or airway hyper-responsiveness using linear mixed effects modeling to compare post-DEP versus pre-DEP, and postfiltered air particles versus prefiltered air particles (35). Adjustment was done using a 5% Benjamini and Hochberg false discovery rate-correction for multiple testing on the set of probes selected for the analysis.…”

“…As a marker for short-term, trafficrelated air pollution exposure, 16 adult nonsmokers with asthma were exposed to 2 hours of DEP, at an average concentration of 300 mg/m 3 , containing high levels of NO 2 (0.22 ppm) (35,37). The difference in DNA methylation level was tested in blood samples pre-exposure versus postexposure.…”

Lung cancer early detection and health disparities: the intersection of epigenetics and ethnicity

“…Emerging evidence suggests that, amongst various ethnic groups, certain epigenetic regulatory pathways respond differentially to exposure to known environmental toxins (66)(67)(68). The causal link between tobacco inhalation, the toxin most commonly associated with lung cancer development, and gene promoter methylation has been explored within the context of ethnicity and resulted in inconsistent findings.…”