Short-term airborne particulate matter exposure alters the epigenetic landscape of human genes associated with the mitogen-activated protein kinase network: a cross-sectional study

Abstract

BackgroundExposure to air particulate matter is known to elevate blood biomarkers of inflammation and to increase cardiopulmonary morbidity and mortality. Major components of airborne particulate matter typically include black carbon from traffic and sulfates from coal-burning power plants. DNA methylation is thought to be sensitive to these environmental toxins and possibly mediate environmental effects on clinical outcomes via regulation of gene networks. The underlying mechanisms may include epigenetic modulation of major inflammatory pathways, yet the details remain unclear.MethodsWe sought to elucidate how short-term exposure to air pollution components, singly and/or in combination, alter blood DNA methylation in certain inflammation-associated gene networks, MAPK and NF-κB, which may transmit the environmental signal(s) and influence the inflammatory pathway in vivo. To this end, we utilized a custom-integrated workflow—molecular processing, pollution surveillance, biostatical analysis, and bioinformatic visualization—to map novel human (epi)gene pathway-environment interactions.ResultsSpecifically, out of 84 MAPK pathway genes considered, we identified 11 whose DNA methylation status was highly associated with black carbon exposure, after adjusting for potential confounders—age, sulfate exposure, smoking, blood cell composition, and blood pressure. Moreover, after adjusting for these confounders, multi-pollutant analysis of synergistic DNA methylations significantly associated with sulfate and BC exposures yielded 14 MAPK genes. No associations were found with the NF-κB pathway.ConclusionExposure to short-term air pollution components thus resulted in quantifiable epigenetic changes in the promoter areas of MAPK pathway genes. Bioinformatic mapping of single- vs. multi-exposure-associated epigenetic changes suggests that these alterations might affect biological pathways in nuanced ways that are not simply additive or fully predictable via individual-level exposure assessments.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-069X-13-94) contains supplementary material, which is available to authorized users.

Possible Mediation by Methylation in Acute Inflammation Following Personal Exposure to Fine Particulate Air Pollution

“…Evidence also suggests effects on methylation specific to airway inflammation: nitric oxide synthase 2a methylation decreased within 24 hours of PM 2.5 exposure (22). Reduced methylation of inflammation genes.was also associated with acute or intermediate-term exposure to air pollutants (19,(21)(22)(23)(24)50).…”

“…In considering biological pathways by which PM 2.5 could induce inflammation, DNA methylation at sites regulating gene expression could play an important role (18,19). Several recent studies have reported PM 2.5 -related reductions in DNA methylation in noncoding repetitive elements, including long interspersed nuclear element-1 (20) and Alu (21), a short interspersed nuclear element, both of which are considered surrogates for global methylation.…”

“…Several recent studies have reported PM 2.5 -related reductions in DNA methylation in noncoding repetitive elements, including long interspersed nuclear element-1 (20) and Alu (21), a short interspersed nuclear element, both of which are considered surrogates for global methylation. However, few epidemiologic studies have investigated the associations between PM 2.5 and short-term changes in methylation at specific sites in the DNA, where a cytosine nucleotide is followed by a guanine nucleotide in the sequence of bases along the 5′ to 3′ direction and the nucleotides are separated by 1 phosphate (cytosine-phosphate-guanine (CpG)), that regulate inflammation responses (19,(21)(22)(23)(24). In addition, most epidemiologic studies have relied on outdoor, fixed air-quality monitoring stations, which poorly approximate individual exposures, which in turn depend on patterns of daily activity and microenvironments (25,26).…”

Differential DNA methylation and PM2.5 species in a 450K epigenome-wide association study

“…54 We have also reported that particulate air pollution was associated with changes in methylation in the MAPK pathway within the NAS cohort, but were unable to analyze metal components as in this study. 55 Earlier, we found that particles from oil combustion were associated with markers of inflammation and endothelial dysfunction, and with increased blood pressure in the NAS population. 56,57 The current study may indicate potential mechanisms of PM-related health effects on an epigenetic level: specifically, a proinflammatory stimulus such as air pollution may modify methylation in genes relevant to immune responses, inducing inflammation and endothelial dysfunction, thereby influencing cardiovascular health.…”

Is Cellular Heterogeneity Merely a Confounder to be Removed from Epigenome-Wide Association Studies?

“…Although it is possible to deconvolute these lineages, it is logistically difficult in limited samples and resource intensive. Another possibility for blood-based study is to directly measure the cell count in the DNA sample [36,37] and determine how much of the methylation signal is co-linear with the cell counts. However, such measures are not always feasible, for instance, when studying previously frozen samples, or solid tissues that are not easily fractionated.…”