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Exposure to Traffic-Related Air Pollution and Changes in Exhaled Nitric Oxide and DNA Methylation in Arginase and Nitric Oxide Synthase in Children with Asthma N

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Exposure to Traffic-Related Air Pollution and Changes in Exhaled Nitric Oxide and DNA Methylation in Arginase and Nitric Oxide Synthase in Children with Asthma N Ji et al. Environmental Health (2021) 20:12 https://doi.org/10.1186/s12940-020-00678-8 RESEARCH Open Access Exposure to traffic-related air pollution and changes in exhaled nitric oxide and DNA methylation in arginase and nitric oxide synthase in children with asthma N. Ji1, M. Fang1, A. Baptista2, C. Cepeda1, M. Greenberg2, I. Colon Mincey3, P. Ohman-Strickland1, F. Haynes1, N. Fiedler1, H. M. Kipen1 and R. J. Laumbach1* Abstract Background: Traffic-related air pollution (TRAP) has been associated with increased risk of airway inflammation in children with asthma. While epigenetic changes could potentially modulate TRAP-induced inflammatory responses, few studies have assessed the temporal pattern of exposure to TRAP, epigenetic changes and inflammation in children with asthma. Our goal was to test the time-lag patterns of personal exposure to TRAP, airway inflammation (measured as fractional exhaled nitric oxide, FeNO), and DNA methylation in the promoter regions of genes involved in nitric oxide synthesis among children with asthma. Methods: We measured personal exposure to black carbon (BC) and FeNO for up to 30 days in a panel of children with asthma. We collected 90 buccal cell samples for DNA methylation analysis from 18 children (5 per child). Methylation in promoter regions of nitric oxide synthase (NOS1, NOS2A, NOS3) and arginase (ARG1, ARG2) was assessed by bisulfite pyrosequencing. Linear-mixed effect models were used to test the associations of BC at different lag periods, percent DNA methylation at each site and FeNO level. Results: Exposure to BC was positively associated with FeNO, and negatively associated with DNA methylation in NOS3. We found strongest association between FeNO and BC at lag 0–6 h while strongest associations between methylation at positions 1 and 2 in NOS3 and BC were at lag 13–24 h and lag 0–24 h, respectively. The strengths of associations were attenuated at longer lag periods. No significant associations between exposure to TRAP and methylation levels in other NOS and ARG isoforms were observed. Conclusions: Exposure to TRAP was associated with higher levels of FeNO and lower levels of DNA methylation in the promoter regions of the NOS3 gene, indicating that DNA methylation of the NOS3 gene could be an important epigenetic mechanism in physiological responses to TRAP in children with asthma. Keywords: Traffic-related air pollution, DNA methylation, Asthma, Exhaled nitric oxide * Correspondence: [email protected] 1Rutgers, The State University of New Jersey, 170 Frelinghuysen Rd, Room 204, Piscataway, NJ 08854, USA Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ji et al. Environmental Health (2021) 20:12 Page 2 of 11 Background none of the five studies focused on children with asthma, Exposure to traffic-related air pollution (TRAP) has been for whom respiratory inflammation plays a critical role linked to a number of adverse health outcomes, and the in the exacerbation of this disease. One cohort study Health Effect Institute (HEI) concluded that exposure to assessed the impacts of DNA methylation on FeNO in TRAP is causally associated with asthma exacerbation children [13]. They found that the strength of associ- among children [1]. Here, we define TRAP as the air ation between DNA methylation in ARG and FeNO was pollutants emitted from motor vehicle engines. Major stronger in children with asthma compared to those constituents of TRAP include carbon monoxide (CO), without asthma. oxides of nitrogen (NOx), volatile organic compounds We performed a longitudinal panel study, aimed to (VOCs), and particulate matter (PM). Black carbon (BC) assess the effects of exposure to TRAP on FeNO and is a relatively specific marker for diesel engine-derived DNA methylation in promoter regions of NOS and TRAP that is ubiquitous in urban communities and typ- ARG genes. We sampled buccal cells from children ically more intense near major roadways, seaports, and with asthma living in an urban, seaport-adjacent com- other centers of commercial activity. Airway inflamma- munity in New Jersey. Using real-time measurement tion is a key step in a hypothesized mode of action by of personal exposure to black carbon as an indicator which exposure to TRAP is thought to exacerbate for TRAP exposure, we investigated the temporal pat- asthma. Higher level of fraction of exhaled nitric oxide terns of DNA methylation and FeNO responses. We (FeNO), a marker of airway inflammation, was observed hypothesized that exposure to TRAP would be posi- after short-term exposure to TRAP [2–4]. Elevated level tively associated with the FeNO levels and methyla- of FeNO has, in turn, been associated with airway hyper- tion of ARG genes, and negatively associated with responsiveness and exacerbation of asthma [5]. These methylation of NOS genes. We further hypothesized findings suggest that nitric oxide (NO) production in the that the associations between TRAP and methylation respiratory tract plays an important role in asthmatic would occur within a shorter lag period than the as- airway’s response to TRAP. sociations between TRAP and FeNO. There is increasing evidence that TRAP-induced changes in FeNO may at least partly result from epigen- Methods etic modifications that alter the expression of genes in- Study population volved in the synthesis of NO. NO can be synthesized This study was nested in a panel study with repeated from L-arginine by three NO synthase (NOS) isoforms: measurements on TRAP and FeNO. From 2011 to 2016, (a) neuronal NOS (nNOS encoded by NOS1); (b) indu- we repeatedly sampled 36 children from non-smoking cible NOS (iNOS encoded by NOS2A); and (c) endothe- households living in Newark or Elizabeth NJ with mild lial NOS (eNOS encoded by NOS3)[6]. In addition, there intermittent to moderate asthma by The National Heart, are two isoforms of Arginase (ARG) (encoded by ARG1 Lung, and Blood Institute (NHLBI) criteria [14]. All of and ARG2), which compete with NOS for the L-arginine the participants were taking an inhaled bronchodilator substrate [7]. Therefore, epigenetic modifications that and/or inhaled corticosteroid, which was uninterrupted alter the expression of NOS and ARG may modulate during the study. Each subject was followed for up to 30 production of NO in the respiratory tract and hence days. Power calculations to examine the within-subject FeNO. association between either exposure and methylation, or Exposure to air pollution has been associated with methylation and FeNO, were conducted via simulation. changes in DNA methylation in the promoter regions of Simulations assumed 18 subjects with an average of 5 re- NOS or ARG suggesting a mode of action by which air peated measures per subject, using a sum across subjects pollution may alter NO production and FeNO. However, of the fisher-transformed correlations within subject, the current epidemiological evidence regarding exposure which follows a normal distribution. Assuming we con- to TRAP and changes in FeNO and DNA methylation ducted a two-sided hypothesis test that the correlation has three main limitations when establishing a chain of was equal to zero, we would have 75.9% power to detect causation in acute exacerbation of asthma. First, the a correlation of 0.35. For within-subject correlations of temporal sequence of TRAP, NOS and ARG methylation 0.40 and 0.45, we would have powers of 85.7 and 92.1%, and FeNO is necessary when inferring causality. How- respectively. Therefore, a subset of 18 children (5 buccal ever, only five observational studies have examined the samples per child) was randomly selected for the DNA temporality [8–12]. Second, all but one of these studies methylation study. The inclusion criteria are: subjects relied on fixed-site measurements in assessing with at least five buccal cell samples; with FeNO mea- individual-level exposure, which may have biased associ- surements, and with less than 20% missing of 24-h BC ations between TRAP and respiratory outcomes com- data. The Institutional Review Board of Rutgers Univer- pared to personal exposure measurements [12]. Third, sity approved the epigenetic study protocol. Parents or Ji et al. Environmental Health (2021) 20:12 Page 3 of 11 legal guardians provided informed consent for all methylcytosine (%5mC) was calculated and presented as subjects. the degree of methylation. For all assays, methylated and unmethylated DNA standards were used as positive and FeNO measurements negative control, respectively to validate the method of FeNO was measured using the NIOX MINO (Aerocrine, bisulfite conversion and PCR amplification. New Providence, NJ) following the manufacturer’s in- structions and the standards of the American Thoracic Air pollutants Society and the European Respiratory Society. Concen- Personal real-time BC data was recorded by micro- trations of NO were measured during 10-s exhalations aethalometer (AE51, Aethlabs, Oakland, CA) for up to – of breath at an exhalation pressure of 10 20 cmH2Oto 30 consecutive days.
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