Predominant DNMT and TET mediate effects of allergen on the human bronchial epithelium in a controlled air pollution exposure study - 05/05/21
, Chris Carlsten, MD, MPH b, ⁎ Abstract |
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 |
We sought to assess the effects of allergen and diesel exhaust (DE) exposures on global DNAm and its regulation enzymes in human airway epithelium.
Methods |
A total of 11 participants, including 7 with and 4 without airway hyperresponsiveness, were recruited for a randomized, double-blind crossover study. Each participant had 3 exposures: filtered air + saline, filtered air + allergen, and DE + allergen. Forty-eight hours postexposure, endobronchial biopsies and bronchoalveolar lavages were collected. Levels of DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, 5-methylcytosine, and 5-hydroxymethylcytosine were determined by immunohistochemistry. Cytokines and chemokines in bronchoalveolar lavages were measured by electrochemiluminescence multiplex assays.
Results |
Predominant DNMT (the most abundant among DNMT1, DNMT3A, and DNMT3B) and predominant TET (the most abundant among TET1, TET2, and TET3) were participant-dependent. 5-Methylcytosine and its regulation enzymes differed between participants with and without airway hyperresponsiveness at baseline (filtered air + saline) and in response to allergen challenge (regardless of DE exposure). Predominant DNMT and predominant TET correlated with lung function. Allergen challenge effect on IL-8 in bronchoalveolar lavages 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 coexposure but is rather dependent on airway hyperresponsiveness status. These enzymes therefore warranted further inquiry regarding their potential in diagnosis, prognosis, and treatment of asthma.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Controlled human exposure crossover study, ten-eleven translocation (TET), DNA methylation (DNAm), asthma, allergen, diesel exhaust (DE)
Abbreviations used : 5hmC, 5mC, AHR, BAL, DE, DEP, DNAm, DNMT, FA, HBEC, IHC, LLOD, PC20, pDNMT, pTET, RT, TBS, TET, TRAP
Plan
| This study was supported by Canadian Institutes of Health Research (grant no. MOP 123319), WorkSafe BC (grant no. RG2011-OG07), AllerGen National Centre for Excellence (grant no. GxE4), the International Program Fund for doctoral students from Sun Yat-sen University and the program of China Scholarships Council (to H.L.), WorkSafe BC Research Training Award RS2016-TG08 and an NSERC Alexander Graham Bell Scholarship CGS-D (to M.H.R.), fellowships from the BC Lung Association, MITACS Accelerate, and the Michael Smith Foundation for Health Research (to C.F.R.), and the Canada Research Chairs program (to C.C.). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 5
P. 1671-1682 - mai 2021 Retour au numéro
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