Academic journal article Environmental Health Perspectives

Particulate Matter, DNA Methylation in Nitric Oxide Synthase, and Childhood Respiratory Disease

Academic journal article Environmental Health Perspectives

Particulate Matter, DNA Methylation in Nitric Oxide Synthase, and Childhood Respiratory Disease

Article excerpt

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 P[M.sub.2.5] and P[M.sub.10] (particulate matter [less than or equal to] 2.5 and [less than or equal to] 10 [micro]m 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-[micro]g/[m.sup.3] increase in P[M.sub.2.5] 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 P[M.sub.2.5] 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-[micro]g/[m.sup.3] increase in 7-day and 1-year P[M.sub.2.5] 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. P[M.sub.10] showed similar but weaker associations with DNA methylation in these genes.

CONCLUSIONS: P[M.sub.2.5] 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.

KEY WORDS: air pollution, asthma, DNA methylation, epigenetics, P[M.sub.2.5], wheeze. Environ Health Perspect 120:1320-1326 (2012). http://dx.doi.org/10.1289/ehp.1104439 [Online 16 May 2012]

Air pollution exposures have been implicated as important risk factors for respiratory health. Air pollution has been associated with decreases in lung function growth in childhood and lung function level in adulthood, asthma exacerbation and onset, and asthma symptoms (Ackermann-Liebrich et al. 1997; Forbes et al. 2009; Gauderman et al. 2004, 2007; Islam et al. 2007; McConnell et al. 2003, 2010; Peters et al. 1999; Sarnat and Holguin 2007). One way in which air pollution, and P[M.sub.2.5] (particulate matter [less than or equal to] 2.5 [micro]m aerodynamic diameter) in particular, might affect health outcomes is by altering nitric oxide homeostasis, an important player in the modulation of airway and vascular smooth muscle tone and inflammation (Batra et al. 2007). Nitrosative stress and regulation of nitric oxide play a key role in the pathophysiology of allergic airway diseases (Fitzpatrick et al. 2009; Sugiura et al. 2008). For example, fractional concentration of exhaled nitric oxide ([Fe.sub.NO]) is measurably higher in children with eosinophilic airway inflammation and active asthma or allergic airway diseases, conditions in which airway inflammation plays a prominent role (Bastain et al. 2011; Fitzpatrick et al. 2009; Pijnenburg and De Jongste 2008). Short term PM exposure is also associated with higher [Fe.sub.NO] (Berhane et al. 2011).

Production of nitric oxide (NO) is regulated via the nitric oxide synthase pathway. NO is synthesized from l-arginine by three NO synthase (NOS) isoforms, neuronal NOS (nNOS; encoded by NOS1), inducible NOS (iNOS; encoded by NOS2A), and endothelial NOS (eNOS; encoded by NOS3). …

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