title: Particulate matter, DNA methylation in nitric oxide synthase, and childhood respiratory disease.
abstract: BACKGROUND
  Air pollutants have been associated with childhood asthma and wheeze. Epigenetic regulation of nitric oxide synthase--the gene responsible for nitric oxide production--may be affected by air pollutants and contribute to the pathogenesis of asthma and wheeze.
  
  
  OBJECTIVE
  Our goal was to investigate the association between air pollutants, DNA methylation, and respiratory outcomes in children.
  
  
  METHODS
  Given residential address and buccal sample collection date, we estimated 7-day, 1-month, 6-month, and 1-year cumulative average PM₂.₅ and PM₁₀ (particulate matter ≤ 2.5 and ≤ 10 µm aerodynamic diameter, respectively) exposures for 940 participants in the Children's Health Study. Methylation of 12 CpG sites in three NOS (nitric oxide synthase) genes was measured using a bisulfite-polymerase chain reaction Pyrosequencing assay. Beta regression models were used to estimate associations between air pollutants, percent DNA methylation, and respiratory outcomes.
  
  
  RESULTS
  A 5-µg/m³ increase in PM₂.₅ was associated with a 0.20% [95% confidence interval (CI): -0.32, -0.07] to 1.0% (95% CI: -1.61, -0.56) lower DNA methylation at NOS2A position 1, 0.06% (95% CI: -0.18, 0.06) to 0.58% (95% CI: -1.13, -0.02) lower methylation at position 2, and 0.34% (95% CI: -0.57, -0.11) to 0.89% (95% CI: -1.57, -0.21) lower methylation at position 3, depending on the length of exposure and CpG locus. One-year PM2.5 exposure was associated with 0.33% (95% CI: 0.01, 0.65) higher in average DNA methylation of 4 loci in the NOS2A CpG island. A 5-µg/m³ increase in 7-day and 1-year PM₂.₅ was associated with 0.6% (95% CI: 0.13, 0.99) and 2.8% (95% CI: 1.77, 3.75) higher NOS3 DNA methylation. No associations were observed for NOS1. PM₁₀ showed similar but weaker associations with DNA methylation in these genes.
  
  
  CONCLUSIONS
  PM₂.₅ exposure was associated with percent DNA methylation of several CpG loci in NOS genes, suggesting an epigenetic mechanism through which these pollutants may alter production of nitric oxide.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. Breton@usc.edu
authors.forename: Carrie V
authors.initials: CV
authors.lastname: Breton
authors.forename: Muhammad T
authors.initials: MT
authors.lastname: Salam
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
authors.forename: Hyang-Min
authors.initials: HM
authors.lastname: Byun
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Siegmund
authors.forename: Frank D
authors.initials: FD
authors.lastname: Gilliland
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D001249:Asthma / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics; D002140:California / Q000453:epidemiology; D002648:Child; D018899:CpG Islands / Q000187:drug effects*; D019175:DNA Methylation / Q000187:drug effects*; D004781:Environmental Exposure; D004784:Environmental Monitoring; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010316:Particle Size; D052638:Particulate Matter / Q000633:toxicity*; D012135:Respiratory Sounds / Q000235:genetics
chemical_list: D000393:Air Pollutants; D052638:Particulate Matter; C496320:NOS1 protein, human; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III