Association Studies of Environmental Exposures, DNA Methylation and Children's Cognitive, Behavioral, and Mental Health Problems.

Introduction: Prenatal environmental exposures have been associated with children's cognitive, behavioral, and mental health problems, and alterations in DNA methylation have been hypothesized as an underlying biological mechanism. However, when testing this hypothesis, it is often difficult to overcome the problem of multiple comparisons in statistical testing when evaluating a large number of developmental outcomes and DNA methylation sites as potential mediators. The objective of this study is to implement a 'meet-in-the-middle' approach with a sequential roadmap to address this concern. Methods: In the Columbia Center for Children's Environmental Health birth cohort study, we implemented a 5-step sequential process for identifying CpG sites that mediate associations between prenatal environmental exposures and cognitive, behavioral, and mental health problems as measured by the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) and the Child Behavior Checklist (CBCL). These steps include 1) the identification of biological pathways that are relevant to each outcome of interest; 2) selection of a set of genes and CpGs on genes that are significantly associated with the outcomes; 3) identification of exposures that are significantly associated with selected CpGs; 4) examination of exposure-outcome relationships among those where significant CpGs were identified; and 5) mediation analysis of the selected exposures and corresponding outcomes. In this study, we considered a spectrum of environmental exposure classes including environmental phenols, pesticides, phthalates, flame retardants and air pollutants. Results: Among all considered exposures and outcomes, we found one CpG site (cg27510182) on gene (DAB1) that potentially mediates the effect of exposure to PAH on CBCL social problems at children aged 7. Conclusion: This 'meet-in-the-middle' approach attenuates concerns regarding multiple comparisons by focusing on genes and pathways that are biologically relevant for the hypothesis.

Prenatal PM2.5 Exposure in Relation to Maternal and Newborn Telomere Length at Delivery.

Particulate matter with an aerodynamic diameter of 2.5 µm or less (PM2.5) is a ubiquitous air pollutant that is increasingly threatening the health of adults and children worldwide. One health impact of elevated PM2.5 exposure is alterations in telomere length (TL)-protective caps on chromosome ends that shorten with each cell division. Few analyses involve prenatal PM2.5 exposure, and paired maternal and cord TL measurements. Here, we analyzed the association between average and trimester-specific prenatal PM2.5 exposure, and maternal and newborn relative leukocyte TL measured at birth among 193 mothers and their newborns enrolled in a New-York-City-based birth cohort. Results indicated an overall negative relationship between prenatal PM2.5 and maternal TL at delivery, with a significant association observed in the second trimester (ß = -0.039, 95% CI: -0.074, -0.003). PM2.5 exposure in trimester two was also inversely related to cord TL; however, this result did not reach statistical significance (ß = -0.037, 95% CI: -0.114, 0.039), and no clear pattern emerged between PM2.5 and cord TL across the different exposure periods. Our analysis contributes to a limited body of research on ambient air pollution and human telomeres, and emphasizes the need for continued investigation into how PM2.5 exposure during pregnancy influences maternal and newborn health.

A methodological pipeline to generate an epigenetic marker of prenatal exposure to air pollution indicators.

A barrier in the children's environmental health field has been the lack of early-warning systems to identify risks of childhood illness and developmental disorders. We aimed to develop a methodology to identify an accessible biomarker measured in a small amount of blood to distinguish newborns at elevated risk from a toxic prenatal exposure, using air pollutants as a case study. Because air pollutants are associated with altered DNA methylation, we developed a pipeline using DNA methylation signatures measured in umbilical cord blood, which could be used as predictors of prenatal exposure. We used air pollution indicators, including modelled trimester-specific and pregnancy average NO2 and PM2.5, and DNA methylation signatures from Illumina arrays measured in two New York City-based longitudinal birth cohorts from the Columbia Centre for Children's Environmental Health. We developed a screening plus three-part pipeline that incorporates selection, testing, and validation to identify whether DNA methylation can be used to predict exposure to prenatal air pollution indicators, NO2 and PM2.5. Applying this pipeline, we found that cord blood DNA methylation could be used to predict high vs. low average pregnancy NO2 (AUC = 0.60, 95% CI: 0.52-0.68, with validation AUC = 0.60). Similar results were found for high vs. low third trimester NO2. In this proof of concept study using air pollutants as an example, we provide an approach (with a generalizable analytic pipeline) that can be used for prediction of prenatal exposure to contaminants. This approach has potential to identify children at risk of developmental disorders and illness resulting from prenatal exposure.

Neighborhood quality and positive health indicators among urban adolescents.

There is a growing epidemiologic interest to expand the scope of health research beyond disease and risk factors to a more comprehensive evaluation of all health states, including those on the positive end of the spectrum ("positive health"). Neighborhood quality (NQ) is a potentially modifiable factor that may influence positive health. We evaluated the association between perception of NQ in childhood and indicators of positive health among adolescents who live in low-income, urban neighborhoods of New York City. Mothers assessed NQ prospectively via questionnaire at child ages 5, 7, 9, and 11. Indicators of positive health domains including general health, physical health, and mental health were assessed and reported by mothers when their children were between the ages of 10-20 years and self-reported among a subset of children at 16-20 years. Children were grouped into "stressed" and "non-stressed" NQ groups based on the repeated prospective maternal report evaluating various aspects of their neighborhood. Overall, we found a general trend that those in the perceived "non-stressed" NQ groups had better Global Health compared to those in the "stressed" NQ group. In the subset of children who provided self-report, we observed significant associations between better overall NQ and NQ safety and better Global Health. We also observed a significant relationship between greater perceived neighborhood social cohesion and lower psychological stress. Our findings identify an important modifiable environmental factor in child and adolescent health that could serve as a focus for interventions to help break the cycle of children's environmental health disparities.