Controlled human exposures to diesel exhaust: a human epigenome-wide experiment of target bronchial epithelial cells

Abstract

Diesel exhaust (DE) is a major contributor to ambient air pollution around the world. It is a known human carcinogen that targets the respiratory system and increases risk for many diseases, but there is limited research on the effects of DE exposure on the epigenome of human bronchial epithelial cells. Understanding the epigenetic impact of this environmental pollutant can elucidate biological mechanisms involved in the pathogenesis of harmful DE-related health effects. To estimate the causal effect of short-term DE exposure on the bronchial epithelial epigenome, we conducted a controlled single-blinded randomized crossover human experiment of exposure to DE and used bronchoscopy and Illumina 450K arrays for data collection and analysis, respectively. Of the 13 participants, 11 (85%) were male and 2 (15%) were female, and 12 (92%) were White and one (8%) was Hispanic; the mean age was 26 years (SD = 3.8 years). Eighty CpGs were differentially methylated, achieving the minimum possible exact P-value of P = 2.44 × 10−4 (i.e. 2/213). In regional analyses, we found two differentially methylated regions (DMRs) annotated to the chromosome 5 open reading frame 63 genes (C5orf63; 7-CpGs) and unc-45 myosin chaperone A gene (UNC45A; 5-CpGs). Both DMRs showed increased DNA methylation after DE exposure. The average causal effects for the DMRs ranged from 1.5% to 6.0% increases in DNA methylation at individual CpGs. In conclusion, we found that short-term DE alters DNA methylation of genes in target bronchial epithelial cells, demonstrating epigenetic level effects of exposure that could be implicated in pulmonary pathologies.

The Role of Defective Epithelial Barriers in Allergic Lung Disease and Asthma Development

“…154 Also, short-term exposure of bronchial epithelial cells to diesel exhaust, a significant contributor to air pollution, alters DNA methylation and could be implicated in pulmonary pathologies. 155 DNA-methyltransferases (Dnmts) play a crucial role in the methylation process. Qin et al showed that the bronchial epithelial Dnmt3b impairs the host defense during Pseudomonas-induced pneumonia, at least in part, by dampening the mucosal responses to flagellin.…”

Persistent DNA methylation changes associated with prenatal NO2exposure in a Canadian prospective birth study

“…For example, glycosylation of the Fc region of IgG1 can impact antibody function and decreases in IgG1 glycosylation are associated with immune activation and have been observed in asthmatic compared to non-asthmatic children, as well as in murine models of allergic asthma 96–98 . Two previous studies have reported DMRs in C5orf63 associated with diesel exhaust inhalation in bronchial epithelial cells and with smoking in peripheral blood samples obtained from a Korean cohort 99, 100 . The C5orf63 DMR observed in this study overlaps with both previously identified C5orf63 DMRs, implying this DMR represents a robust DNAm change across development stages, tissues, and human populations in response to inhaled pollutant exposure.…”

“…. Two previous studies have reported DMRs in C5orf63 associated with diesel exhaust inhalation in bronchial epithelial cells and with smoking in peripheral blood samples obtained from a Korean cohort99,100 . The C5orf63 DMR observed in this study overlaps with both previously identified C5orf63 DMRs, implying this DMR represents a robust DNAm change across development stages, tissues, and human populations in response to inhaled pollutant exposure.…”

A Functional Genomics Pipeline to Identify High-Value Asthma and Allergy CpGs in the Human Methylome

“…The epigenome plays a critical role in regulating gene expression in a context-specific manner, such as in specific cell types or in the presence of environmental exposures or disease states. DNA methylation, for example, is responsive to disease promoting exposures in both in vitro cell models 24,[42][43][44] and ex vivo cells from individuals who are healthy and with disease 1,[45][46][47][48] . Yet the DNA methylome has been underexplored and largely limited to the CpGs on commercial arrays.…”