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Randomized Controlled Trial
. 2014 Dec 9;11:71.
doi: 10.1186/s12989-014-0071-3.

Short-term Diesel Exhaust Inhalation in a Controlled Human Crossover Study Is Associated With Changes in DNA Methylation of Circulating Mononuclear Cells in Asthmatics

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Randomized Controlled Trial

Short-term Diesel Exhaust Inhalation in a Controlled Human Crossover Study Is Associated With Changes in DNA Methylation of Circulating Mononuclear Cells in Asthmatics

Ruiwei Jiang et al. Part Fibre Toxicol. .
Free PMC article

Abstract

Background: Changes 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.

Methods: A 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.

Results: DNA 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.

Conclusion: Short-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.

Figures

Figure 1
Figure 1
Principal components were associated with demographics and biological variables. For principal components 1-22, only those with associations were included. Colors correspond to p-values where darker colors indicate higher association, and lighter colors indicate lower association. Abbreviations are as follows: basophils (BAS), lymphocytes (LYM), monocytes (MON).
Figure 2
Figure 2
Diesel exhaust-associated exposure patterns were captured in principal component 22. A) PC22 was associated with model-3 (DE6&30 hr vs. non-DE6&30 hr). Samples were sorted according to DE6&30 hr samples versus non-DE6&30 hr baseline samples and their PC22 associated principal component scores were displayed. There was a visible pattern indicative of DE-exposure with the DE6&30 hr samples showing mostly positive scores, and the baseline samples showing mostly negative scores. B) For each probe in the dataset, its loading value in association with PC22 was calculated. The +/-3SD and +/-6SD positions are marked by vertical dashed lines. And the probes harboring the largest contribution to diesel exposure methylation pattern were selected for using the +/-3SD cut off, resulting in 2827 hits.
Figure 3
Figure 3
Gene-specific methylation changes were found at CpG sites across the genome. A) Unadjusted LME model p-value distributions for the effect of pre (0 hr) versus post (6-30 hr) exposure for FA, and that for DE. The uniform distribution expected by chance is indicated with horizontal dashed lines. Lack of positive skewing in the FA distribution indicated no association between FA exposure and differential methylation, whereas positive skewing in the DE plot indicated heavy association of DE exposure with differential methylation. B) Volcano plot of 2827 PCA hits. Negative log10 of fdr 10% adjusted p-values from LME modeling of the PCA hits were visualized against their corresponding ∆β values. Probes that were significant with a high confidence fdr of 10% were indicated in red. C) Distribution of ∆β obtained from subtracting pre-FA beta values from post-FA beta values, and from subtracting pre-DE beta values from post-DE beta values for the PCA identified probes that were significantly altered by DE exposure. ∆β from DE samples were much larger in magnitude than that from FA samples.
Figure 4
Figure 4
DNA methylation of CpG sites overlapping with Alu and LINE1 repetitive elements was associated with diesel exhaust. A) Distributions of unadjusted p-values from LME modeling applied to CpG sites overlapping with Alu and LINE1 elements. The uniform distribution expected by chance is indicated with horizontal dashed lines. Positive skewing of DE p-value distributions indicated association with differential methylation, whereas lack of skewing of FA p-value distributions indicated absence of association. B) Distributions of ∆β obtained from subtracting pre-FA beta values from post-FA beta values, and from subtracting pre-DE beta values from post- DE beta values for LINE1 and Alu probes that were significantly altered in response to DE exposure. ∆β from DE samples were much larger in magnitude than that from FA samples.
Figure 5
Figure 5
A CpG site residing in the miR-21 genomic locus changed in DNA methylation in response to DE. Post and pre methylation beta values of CpG site cg07181702 (residing within miR-21) found to have significantly decrease in methylation by 3.9% in response to DE-, but not FA-, exposure.

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