Epigenetics refers to mitotically heritable changes to the DNA, which do not affect the DNA sequence, but can influence its function. Currently, DNA methylation is the most studied epigenetic phenomenon in large populations. It entails the binding of a methyl group, mainly to positions in genomic DNA where a cytosine is located next to a guanine, a cytosine-phosphate-guanine (CpG) site ( Figure 1). DNA methylation at CpG sites can influence gene expression by altering the DNA’s three-dimensional structure and interacting with methyl-binding proteins, consequently affecting the binding of the gene transcription and chromatin-modifying machinery. There are approximately 28 million CpG sites in the human genome. DNA methylation is a dynamic process that can be influenced by genetic factors, as well as by environmental factors such as diet, air pollution, toxicants or smoking. ^1–4 Hence, DNA methylation may be seen as linking the genome to the environment with respect to health and disease. Early development is a period of profound changes in DNA methylation and may, as such, be a critical period for environmentally-induced DNA methylation changes. ⁴ Hence, this period is of specific interest for DNA methylation studies in relation to specific exposures and long-term health outcomes. ^{1, 4–6}

Rationale: The timing and duration of traffic-related air pollution (TRAP) exposure may be important for childhood wheezing and asthma development. Objectives: We examined the relationship between TRAP exposure and longitudinal wheezing phenotypes and asthma at age 7 years. Methods: Children completed clinical examinations annually from age 1 year through age 4 years and age 7 years. Parental-reported wheezing was assessed at each age, and longitudinal wheezing phenotypes (early-transient, late-onset, persistent) and asthma were defined at age 7 years. Participants’ time-weighted exposure to TRAP, from birth through age 7 years, was estimated using a land-use regression model. The relationship between TRAP exposure and wheezing phenotypes and asthma was examined. Measurements and Main Results: High TRAP exposure at birth was significantly associated with both transient and persistent wheezing phenotypes (adjusted odds ratio [aOR] = 1.64; 95% confidence interval [CI], 1.04–2.57 and aOR = 2.31; 95% CI, 1.28–4.15, respectively); exposure from birth to age 1 year and age 1 to 2 years was also associated with persistent wheeze. Only children with high average TRAP exposure from birth through age 7 years were at significantly increased risk for asthma (aOR = 1.71; 95% CI, 1.01–2.88). Conclusions: Early-life exposure to TRAP is associated with increased risk for persistent wheezing, but only long-term exposure to high levels of TRAP throughout childhood was associated with asthma development.

This overview highlights recent experimental and epidemiological evidence for the programming effects of outdoor air pollution exposures during early development on lung function and chronic respiratory disorders, such as asthma and related allergic disorders. Air pollutants may impact anatomy and/or physiological functioning of the lung and interrelated systems. Programming effects may result from pollutant-induced shifts in a number of molecular, cellular, and physiological states and their interacting systems. Specific key regulatory systems susceptible to programming may influence lung development and vulnerability to respiratory diseases, including both central and peripheral components of neuroendocrine pathways and autonomic nervous system (ANS) functioning which, in turn, influence the immune system. Starting in utero, environmental factors, including air pollutants, may permanently organize these systems toward trajectories of enhanced pediatric (e.g., asthma, allergy) as well as adult disease risk (e.g., chronic obstructive pulmonary disease). Evidence supports a central role of oxidative stress in the toxic effects of air pollution. Additional research suggests xenobiotic metabolism and subcellular components, such as mitochondria are targets of ambient air pollution and play a role in asthma and allergy programming. Mechanisms operating at the level of the placenta are being elucidated. Epigenetic mechanisms may be at the roots of adaptive developmental programming. Optimal coordinated functioning of many complex processes and their networks of interaction are necessary for normal lung development and the maintenance of respiratory health. Outdoor air pollution may play an important role in early programming of respiratory health and is potentially amenable to intervention.

Psychosocial stress contributes to placental oxidative stress. Mitochondria are vulnerable to oxidative stress, which can lead to changes in mitochondrial DNA copy number (mtDNAcn). We examined associations of maternal lifetime stress, current negative life events, and depressive and posttraumatic-stress-disorder symptom scores with placental mtDNAcn in a racially/ethnically diverse sample (n = 147) from the Programming of Intergenerational Stress Mechanisms (PRISM) study (Massachusetts, March 2011 to August 2012). In linear regression analyses adjusted for maternal age, race/ethnicity, education, prenatal fine particulate matter exposure, prenatal smoking exposure, and the sex of the child, all measures of stress were associated with decreased placental mtDNAcn (all P values < 0.05). Weighted-quantile-sum (WQS) regression showed that higher lifetime stress and depressive symptoms accounted for most of the effect on mtDNAcn (WQS weights: 0.25 and 0.39, respectively). However, among white individuals, increased lifetime stress and posttraumatic stress disorder symptoms explained the majority of the effect (WQS weights: 0.20 and 0.62, respectively) while among nonwhite individuals, lifetime stress and depressive symptoms accounted for most of the effect (WQS weights: 0.27 and 0.55, respectively). These analyses are first to link increased maternal psychosocial stress with reduced placental mtDNAcn and add to literature documenting racial/ethnic differences in the psychological sequelae of chronic stress that may contribute to maternal-fetal health.