Abstract
BackgroundDNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Further identification of specific CpG sites and the pollutants that are associated with methylation of these CpG sites in immune cells could impact our understanding of asthma pathophysiology. In this study, we sought to identify some CpG sites in specific genes that could be associated with asthma regulation (Foxp3 and IL10) and to identify the different AAPs for which exposure prior to the blood draw is linked to methylation levels at these sites. We recruited subjects from Fresno, California, an area known for high levels of AAPs. Blood samples and responses to questionnaires were obtained (n = 188), and in a subset of subjects (n = 33), repeat samples were collected 2 years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365 days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures.ResultsAsthma was significantly associated with higher differentially methylated regions (DMRs) of the Foxp3 promoter region (p = 0.030) and the IL10 intronic region (p = 0.026). Additionally, at the 90-day time period (90 days prior to the blood draw), Foxp3 methylation was positively associated with NO2, CO, and PM2.5 exposures (p = 0.001, p = 0.001, and p = 0.012, respectively). In the subset of subjects retested 2 years later (n = 33), a positive association between AAP exposure and methylation was sustained. There was also a negative correlation between the average Foxp3 methylation of the promoter region and activated Treg levels (p = 0.039) and a positive correlation between the average IL10 methylation of region 3 of intron 4 and IL10 cytokine expression (p = 0.030).ConclusionsShort-term and long-term exposures to high levels of CO, NO2, and PM2.5 were associated with alterations in differentially methylated regions of Foxp3. IL10 methylation showed a similar trend. For any given individual, these changes tend to be sustained over time. In addition, asthma was associated with higher differentially methylated regions of Foxp3 and IL10.
Highlights
DNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs)
Previous studies found that high prenatal ambient air pollutant (AAP) exposure alters epigenetic programming in utero [5] and that children are at greater risk of developing asthma when exposed to higher concentrations of AAPs [6]
We previously demonstrated that exposure in children to high levels of polycyclic aromatic hydrocarbons (PAHs), a component of AAPs, is associated with higher overall percent methylation of the transcriptional regulatory region of the forkhead box transcription factor 3 (Foxp3) locus [8]
Summary
DNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Previous studies found that high prenatal ambient air pollutant (AAP) exposure alters epigenetic programming in utero [5] and that children are at greater risk of developing asthma when exposed to higher concentrations of AAPs [6] This further raises concern and increases the urgency of understanding the relationship between AAP exposures and asthma and finding effective ways to prevent, treat, and/or cure asthma. In addition to the presence of higher Foxp methylation levels, we found that exposure to higher levels of PAHs is associated with decreased expression of IL10, an antiinflammatory cytokine These associations were stronger in children with asthma, suggesting disease-linked effects [14]. AAPs and DNA methylation have been linked to other health problems, such as cardiovascular disease [18]
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