Asthma and lower airway disease
Inhalation of diesel exhaust and allergen alters human bronchial epithelium DNA methylation

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Background

Allergic disease affects 30% to 40% of the world's population, and its development is determined by the interplay between environmental and inherited factors. Air pollution, primarily consisting of diesel exhaust emissions, has increased at a similar rate to allergic disease. Exposure to diesel exhaust may play a role in the development and progression of allergic disease, in particular allergic respiratory disease. One potential mechanism underlying the connection between air pollution and increased allergic disease incidence is DNA methylation, an epigenetic process with the capacity to integrate gene-environment interactions.

Objective

We sought to investigate the effect of allergen and diesel exhaust exposure on bronchial epithelial DNA methylation.

Methods

We performed a randomized crossover-controlled exposure study to allergen and diesel exhaust in humans, and measured single-site (CpG) resolution global DNA methylation in bronchial epithelial cells.

Results

Exposure to allergen alone, diesel exhaust alone, or allergen and diesel exhaust together (coexposure) led to significant changes in 7 CpG sites at 48 hours. However, when the same lung was exposed to allergen and diesel exhaust but separated by approximately 4 weeks, significant changes in more than 500 sites were observed. Furthermore, sites of differential methylation differed depending on which exposure was experienced first. Functional analysis of differentially methylated CpG sites found genes involved in transcription factor activity, protein metabolism, cell adhesion, and vascular development, among others.

Conclusions

These findings suggest that specific exposures can prime the lung for changes in DNA methylation induced by a subsequent insult.

Section snippets

Study demographics

Seventeen white participants (see Tables I and II) were recruited to the Air Pollution Exposure Laboratory in Vancouver, British Columbia, Canada. Written consent was obtained from all subjects, and the protocols were approved by the institutional review board for human studies at the University of British Columbia. Participants were 20 to 46 years old (median = 27, SD = 7.8), all nonsmokers, and 47% had asthma (Table I). We excluded individuals with any of the following: (1)

Study cohort and samples

To evaluate the effects of allergen and DE exposure on DNA methylation in the human lung, we performed a rigorous randomized crossover-controlled exposure study. Specifically, 17 individuals were randomized into 2 study groups (group I and group II), defined by whether FA or DE was inhaled first (Fig 1, A). Following inhalation of FA or DE, allergen was instilled into one lung and saline into the other. The process was repeated approximately 4 weeks later with opposite exposures. This resulted

Discussion

The molecular mechanisms regulating the interaction between air pollution and allergic disease are poorly understood. Defining these mechanisms is critical for creating strategies to reduce susceptibility and severity of airways disease,8 especially given dynamics associated with both air pollution and allergens associated with global climate change.35 DNA methylation may be one of the mechanisms by which environmental exposures, including DE, can exert lasting effects on gene expression, cell

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  • Cited by (0)

    This project was supported by funding from the Canadian Institutes for Health Research (MOP 123319), WorkSafe BC (RG2011-OG07), AllerGen NCE (GxE2; GxE4), the European Respiratory Society (ERS) and the Canadian Thoracic Surgery (CTS)/Canadian Lung Association, joint ERS/CTS Long-Term Research Fellowship LTRF 2013 (to R.L.C.), and a Mining for Miracles postdoctoral fellowship (to M.J.J.). C.C. is the Canada Research Chair in Occupational and Environmental Lung Disease. M.S.K. is the Canada Research Chair in Social Epigenetics and a Senior Fellow of the Canadian Institute for Advanced Research (CIFAR). S.M. is the Canada Research Chair in Computational Biology and a Fellow of CIFAR. The funding bodies had no involvement in the study design; collection, analysis, or interpretation of the data; the writing of the report; or the decision to submit the article for publication.

    Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

    Rachel L. Clifford, PhD, is currently affiliated with the Department of Respiratory Medicine and Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.

    These authors contributed equally to this work as senior authors.

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