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?:abstract
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BACKGROUND Epidemiological data show that traffic-related air pollution contributes to the increasing prevalence and severity of asthma. DNA methylation (DNAm) changes may elucidate adverse health effects of environmental exposures. OBJECTIVES To assess the effects of allergen and diesel exhaust (DE) exposures on global DNAm and its regulation enzymes in human airway epithelium. METHODS 11 participants, including 7 with and 4 without airway hyperresponsiveness (AHR), were recruited for a randomized, double-blinded crossover study. Each participant had 3 exposures: filtered air + saline (FA-S), filtered air + allergen (FA-A), and DE + allergen (DE-A). 48 hours post-exposure, endobronchial biopsies and bronchoalveolar lavages (BAL) were collected. Levels of DNA methyltransferases (DNMTs) and ten-eleven translocation enzymes (TETs), 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC) were determined by immunohistochemistry. Cytokines and chemokines in BAL were measured by electrochemiluminescence multiplex assays. RESULTS Predominant DNMT (pDNMT, the most abundant among DNMT1, DNMT3A, and DNMT3B), and predominant TET (pTET, the most abundant among TET1, TET2, and TET3) were participant-dependent. 5mC and its regulation enzymes differed between participants with and without AHR at baseline (FA-S) and in response to allergen challenge (regardless of DE exposure). pDNMT and pTET correlated with lung function. Allergen challenge effect on interleukin-8 in BAL was modified by TET2 baseline levels in the epithelium. CONCLUSIONS Response to allergen challenge is associated with key DNAm regulation enzymes. This relationship is generally unaltered by DE co-exposure but is rather dependent on AHR status. These enzymes therefore warranted further inquiry regarding their potential in diagnosis, prognosis, and treatment of asthma.
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