Air pollution, epigenetics, and asthma

Abstract

Exposure to traffic-related air pollution (TRAP) has been implicated in asthma development, persistence, and exacerbation. This exposure is highly significant as large segments of the global population resides in zones that are most impacted by TRAP and schools are often located in high TRAP exposure areas. Recent findings shed new light on the epigenetic mechanisms by which exposure to traffic pollution may contribute to the development and persistence of asthma. In order to delineate TRAP induced effects on the epigenome, utilization of newly available innovative methods to assess and quantify traffic pollution will be needed to accurately quantify exposure. This review will summarize the most recent findings in each of these areas. Although there is considerable evidence that TRAP plays a role in asthma, heterogeneity in both the definitions of TRAP exposure and asthma outcomes has led to confusion in the field. Novel information regarding molecular characterization of asthma phenotypes, TRAP exposure assessment methods, and epigenetics are revolutionizing the field. Application of these new findings will accelerate the field and the development of new strategies for interventions to combat TRAP-induced asthma.

Keywords: Asthma; Epigenetics; Traffic pollution.

Fig. 1

DNA methylation and demethylation in mammals. DNMTs methylate cytosine C to 5-methylcytosine (5mC) by transferring the methyl group from S-adenosylmethionine (SAM) to cytosine. TET enzymes oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), 5-carboxylcytosine (5caC) (together, oxi-mC). Further, oxi-mC can be restored to C through the thymine DNA glycosylase (TDG)-mediated base excision repair (BER) of 5fC:G and 5caC:G base pairs and replication-dependent passive demethylation

Fig. 2

Epigenetic mechanisms mediate DEP effects on asthma pathogenesis. Lung epithelial cells recognize polycyclic aromatic hydrocarbons present in diesel exhaust particles (DEPs) via the aryl hydrocarbon receptor (AhR), promoting cytochrome P450 family 1 A1 (CYP1A1)-mediated and iNOS-mediated detoxification through altering methylation. Failure to detoxify results in oxidative stress, which may upregulate TETs and downregulate DNMTs through the crosstalk between AhR and HIF1-α and directly lead to secretion of chemokines (eosinophils/neutrophils) and cytokines involved in TH17 and TH2 differentiation (TSLP), Treg differentiation and B cell function, all contributing to airway inflammation. The secretion of these chemokines and cytokines can also be triggered by repair cytokines (amphiregulin, TGFα) signaling through the epidermal growth factor receptor (EGFR), p38 mitogen-activated protein kinase, and NF-κB, which can be augmented by demethylation and upregulation through TET proteins and DNMTs. DEP promotes allergic airway inflammation by upregulating the expression of the Jagged1/Notch1 pathway in dendritic cells (DC) in an AhR dependent manner in concert with allergens. DEP may also regulate DNMT and TET expression in dendritic cells and macrophages through the AhR pathway, enhancing airway inflammation in presence of allergens. DEP diesel exhaust particle; OVA ovalbumin; TSLP thymic stromal lymphopoietin