Prenatal air pollution exposure and neurodevelopment: A review and blueprint for a harmonized approach within ECHO.

BACKGROUND: Air pollution exposure is ubiquitous with demonstrated effects on morbidity and mortality. A growing literature suggests that prenatal air pollution exposure impacts neurodevelopment. We posit that the Environmental influences on Child Health Outcomes (ECHO) program will provide unique opportunities to fill critical knowledge gaps given the wide spatial and temporal variability of ECHO participants. OBJECTIVES: We briefly describe current methods for air pollution exposure assessment, summarize existing studies of air pollution and neurodevelopment, and synthesize this information as a basis for recommendations, or a blueprint, for evaluating air pollution effects on neurodevelopmental outcomes in ECHO. METHODS: We review peer-reviewed literature on prenatal air pollution exposure and neurodevelopmental outcomes, including autism spectrum disorder, attention deficit hyperactivity disorder, intelligence, general cognition, mood, and imaging measures. ECHO meta-data were compiled and evaluated to assess frequency of neurodevelopmental assessments and prenatal and infancy residential address locations. Cohort recruitment locations and enrollment years were summarized to examine potential spatial and temporal variation present in ECHO. DISCUSSION: While the literature provides compelling evidence that prenatal air pollution affects neurodevelopment, limitations in spatial and temporal exposure variation exist for current published studies. As >90% of the ECHO cohorts have collected a prenatal or infancy address, application of advanced geographic information systems-based models for common air pollutant exposures may be ideal to address limitations of published research. CONCLUSIONS: In ECHO we have the opportunity to pioneer unifying exposure assessment and evaluate effects across multiple periods of development and neurodevelopmental outcomes, setting the standard for evaluation of prenatal air pollution exposures with the goal of improving children's health.

Metabolomics of childhood exposure to perfluoroalkyl substances: a cross-sectional study.

INTRODUCTION: Exposure to perfluoroalkyl substances (PFAS), synthetic and persistent chemicals used in commercial and industrial processes, are associated with cardiometabolic dysfunction and related risk factors including reduced birth weight, excess adiposity, and dyslipidemia. Identifying the metabolic changes induced by PFAS exposure could enhance our understanding of biological pathways underlying PFAS toxicity. OBJECTIVE: To identify metabolic alterations associated with serum concentrations of four PFAS in children using a metabolome-wide association study. METHODS: We performed untargeted metabolomic profiling by liquid chromatography with ultra-high-resolution mass spectrometry, and separately quantified serum concentrations of perfluorooctanoic acid, perfluorooctanesulfonic acid, perfluorononanoic acid, and perfluorohexanesulfonic acid (PFHxS) for 114 8-year old children from Cincinnati, OH. We evaluated associations between each serum PFAS concentration and 16,097 metabolic features using linear regression adjusted for child age, sex, and race with a false discovery rate < 20%. We annotated PFAS-associated metabolites and conducted pathway enrichment analyses. RESULTS: Serum PFAS concentrations were associated with metabolic features annotated primarily as lipids and dietary factors. Biological pathways associated with all four PFAS included arginine, proline, aspartate, asparagine, and butanoate metabolism. CONCLUSIONS: In this cross-sectional study, childhood serum PFAS concentrations were correlated with metabolic pathways related to energy production and catabolism. Future studies should determine whether these pathways mediate associations between PFAS exposure and childhood cardiometabolic health.

Variability and predictors of serum perfluoroalkyl substance concentrations during pregnancy and early childhood.

Exposure to poly- and perfluoroalkyl substances (PFAS), ubiquitous and persistent environmental contaminants, could be associated with adverse health outcomes, but there are limited longitudinal data assessing patterns and predictors of exposure during childhood. We quantified concentrations of eight different PFAS in sera collected from women during pregnancy and children at delivery and ages 3 and 8 years in 367 mother-child pairs enrolled in a prospective cohort from 2003 to 2006. In general, median childhood PFAS concentrations increased from birth to age 3 and then decreased by age 8. Maternal serum PFAS concentrations during pregnancy were strongly correlated with cord serum concentrations (0.76 < r < 0.94), but were weakly correlated with childhood concentrations (0.12 < r < 0.30). Several sociodemographic factors were associated with maternal PFAS concentrations, including income, race, and parity. In children, serum PFAS concentrations were associated with maternal age at delivery, race, parity, and child age. Breastfeeding duration was positively associated with childhood PFAS concentrations at ages 3 and 8 years. In addition, stain repellant use was associated with higher perfluorooctanoic acid and perfluorohexane sulfonic acid concentrations at age 8 years. Serum PFAS concentrations are higher during early childhood, a potentially sensitive period of development, and were highest among breastfed children.

Maternal serum PFOA concentration and DNA methylation in cord blood: A pilot study.

Perfluorooctanoic acid (PFOA), a perfluoroalkyl substance, is commonly detected in the serum of pregnant women and may impact fetal development via epigenetic re-programming. In a pilot study, we explored associations between serum PFOA concentrations during pregnancy and offspring peripheral leukocyte DNA methylation at delivery in women with high (n = 22, range: 12-26ng/mL) and low (n = 22, range: 1.1-3.1ng/mL) PFOA concentrations. After adjusting for cell type, child sex, and income, we did not find differences in CpG methylation in the two exposure groups that reached epigenome-wide significance. Among the 20 CpGs with the lowest p-values we found that seven CpG sites in three genes differed by exposure status. In a confirmatory cluster analysis, these 20 CpGs clustered into two groups that perfectly identified exposure status. Future studies with larger sample sizes should confirm these findings and determine if PFOA-associated changes in DNA methylation underlie potential health effects of PFOA.

Residential proximity to major roadways and incident hypertension in post-menopausal women.

Living near major roadways has been associated with increased risk of cardiovascular morbidity and mortality, presumably from exposure to elevated levels of traffic-related air and/or noise pollution. This association may potentially be mediated through increased risk of incident hypertension, but results from prior studies are equivocal. Using Cox proportional hazards models we examined residential proximity to major roadways and incident hypertension among 38,360 participants of the Women's Health Initiative (WHI) Clinical Trial cohorts free of hypertension at enrollment and followed for a median of 7.9 years. Adjusting for participant demographics and lifestyle, trial participation, and markers of individual and neighborhood socioeconomic status, the hazard ratios for incident hypertension were 1.13 (95% CI: 1.00, 1.28), 1.03 (0.95, 1.11), 1.05 (0.99, 1.11), and 1.05 (1.00, 1.10) for participants living ≤50, >50-200, >200-400, and >400-1000 m vs >1000 m from the nearest major roadway, respectively (ptrend=0.013). This association varied substantially by WHI study region with hazard ratios for women living ≤50 m from a major roadway of 1.61 (1.18, 2.20) in the West, 1.51 (1.22, 1.87) in the Northeast, 0.89 (0.70, 1.14) in the South, and 0.94 (0.75, 1.19) in the Midwest. In this large, national cohort of post-menopausal women, residential proximity to major roadways was associated with incident hypertension in selected regions of the U.S. If causal, these results suggest residential proximity to major roadways, as a marker for air, noise and other traffic-related pollution, may be a risk factor for hypertension.

Using phenome-wide association studies to examine the effect of environmental exposures on human health.

The field of environmental epidemiology has been using "-omics" technologies, including the exposome, metabolome, and methylome, to understand the potential effects and biological pathways of a number of environmental pollutants. However, the majority of studies have focused on a single disease or phenotype, and have not systematically considered patterns of multimorbidity and whether environmental pollutants have pleiotropic effects. These questions could be addressed by examining the relation between environmental exposures and the phenome - the patterns and profiles of human health that individuals experience from birth to death. By conducting Phenome Wide Association Studies (PheWAS), we can generate new hypotheses about new or poorly understood exposures, identify novel associations for established toxicants, and better understand biological pathways affected by environmental pollutants. In this article, we provide a conceptual framework for conducting PheWAS in environmental epidemiology and summarize some of the advantages and challenges to using the PheWAS to study environmental pollutant exposures. Ultimately, by adding the PheWAS to our "-omics" toolbox, we could substantially improve our understanding of the potential health effects of environmental pollutants.

Air pollution, land use, and complications of pregnancy.

BACKGROUND: Mounting evidence suggests that the natural and built environment can affect human health, but relatively few studies have considered links between features of the residential natural and built environment other than air pollution and complications of pregnancy. OBJECTIVES: To quantify the impact of features of the maternal residential natural and built environments on risk of gestational diabetes mellitus (GDM), gestational hypertension and preeclampsia among 61,640 women who delivered at a single hospital in Rhode Island between 2002 and 2012. METHODS: We estimated residential levels of ambient fine particulate matter (PM2.5) and black carbon (BC) using spatiotemporal models, neighborhood green space using remote sensing and proximity to recreational facilities, and neighborhood blue space using distance to coastal and fresh water. We used logistic regression to separately estimate the association between each feature and GDM, gestational hypertension, and preeclampsia, adjusting for individual and neighborhood markers of socioeconomic status. RESULTS: GDM, gestational hypertension, and preeclampsia were diagnosed in 8.0%, 5.0%, and 3.6% of women, respectively. We found 2nd trimester PM2.5 (OR = 1.08, 95% CI: 1.00, 1.15 per interquartile range increase in PM2.5) and living close to a major roadway (1.09, 95% CI: 1.00, 1.19) were associated with higher odds of GDM, while living <1 km from the coast was associated with lower odds of GDM (0.87, 95% CI: 0.78, 0.96). Living <500 m from a recreational facility was associated with lower odds of gestational hypertension (0.89, 95% CI: 0.80, 0.99). None of these features were associated with odds of preeclampsia. Results were qualitatively similar in mutually-adjusted models and sensitivity analyses. CONCLUSIONS: In this small coastal US state, risk of GDM was positively associated with PM2.5 and proximity to busy roadways, and negatively associated with proximity to blue space, highlighting the importance of the natural and built environment to maternal health.

Maternal ambient air pollution, preterm birth and markers of fetal growth in Rhode Island: results of a hospital-based linkage study.

BACKGROUND: Maternal exposure to ambient air pollution has been associated with higher risk of preterm birth and reduced fetal growth, but heterogeneity among prior studies suggests that additional studies are needed in diverse populations and settings. We examined the associations between maternal ambient air pollution levels, risk of preterm birth and markers of fetal growth in an urban population with relatively low exposure to air pollution. METHODS: We linked 61 640 mother-infant pairs who delivered at a single hospital in Providence, Rhode Island, from 2002 to 2012 to birth certificate and hospital discharge data. We used spatial-temporal models and stationary monitors to estimate exposure to fine particulate matter (PM2.5) and black carbon (BC) during pregnancy. Using generalised linear models, we evaluated the association between pollutant levels, risk of preterm birth and markers of fetal growth. RESULTS: In adjusted models, an IQR (2.5 µg/m3) increase in pregnancy-average PM2.5 was associated with ORs of preterm birth of 1.04 (95% CI 0.94 to 1.15) and 0.86 (0.76 to 0.98) when considering modelled and monitored PM2.5, respectively. An IQR increase in modelled and monitored PM2.5 was associated with a 12.1 g (95% CI -24.2 to -0.1) and 15.9 g (95% CI -31.6 to -0.3) lower birth weight. Results for BC were highly sensitive to choice of exposure metric. CONCLUSION: In a population with relatively low exposures to ambient air pollutants, PM2.5 was associated with reduced birth weight but not with risk of preterm birth.

Maternal residential air pollution and placental imprinted gene expression.

BACKGROUND: Maternal exposure to air pollution is associated with reduced fetal growth, but its relationship with expression of placental imprinted genes (important regulators of fetal growth) has not yet been studied. OBJECTIVES: To examine relationships between maternal residential air pollution and expression of placental imprinted genes in the Rhode Island Child Health Study (RICHS). METHODS: Women-infant pairs were enrolled following delivery between 2009 and 2013. We geocoded maternal residential addresses at delivery, estimated daily levels of fine particulate matter (PM2.5; n=355) and black carbon (BC; n=336) using spatial-temporal models, and estimated residential distance to nearest major roadway (n=355). Using linear regression models we investigated the associations between each exposure metric and expression of nine candidate genes previously associated with infant birthweight in RICHS, with secondary analyses of a panel of 108 imprinted genes expressed in the placenta. We also explored effect measure modification by infant sex. RESULTS: PM2.5 and BC were associated with altered expression for seven and one candidate genes, respectively, previously linked with birthweight in this cohort. Adjusting for multiple comparisons, we found that PM2.5 and BC were associated with changes in expression of 41 and 12 of 108 placental imprinted genes, respectively. Infant sex modified the association between PM2.5 and expression of CHD7 and between proximity to major roadways and expression of ZDBF2. CONCLUSIONS: We found that maternal exposure to residential PM2.5 and BC was associated with changes in placental imprinted gene expression, which suggests a plausible line of investigation of how air pollution affects fetal growth and development.

Current and Projected Heat-Related Morbidity and Mortality in Rhode Island.

BACKGROUND: Climate change is expected to cause increases in heat-related mortality, especially among the elderly and very young. However, additional studies are needed to clarify the effects of heat on morbidity across all age groups and across a wider range of temperatures. OBJECTIVES: We aimed to estimate the impact of current and projected future temperatures on morbidity and mortality in Rhode Island. METHODS: We used Poisson regression models to estimate the association between daily maximum temperature and rates of all-cause and heat-related emergency department (ED) admissions and all-cause mortality. We then used downscaled Coupled Model Intercomparison Project Phase 5 (CMIP5; a standardized set of climate change model simulations) projections to estimate the excess morbidity and mortality that would be observed if this population were exposed to the temperatures projected for 2046-2053 and 2092-2099 under two representative concentration pathways (RCP): RCP 8.5 and 4.5. RESULTS: Between 2005 and 2012, an increase in maximum daily temperature from 75 to 85°F was associated with 1.3% and 23.9% higher rates of all-cause and heat-related ED visits, respectively. The corresponding effect estimate for all-cause mortality from 1999 through 2011 was 4.0%. The association with all-cause ED admissions was strongest for those < 18 or ≥ 65 years of age, whereas the association with heat-related ED admissions was most pronounced among 18- to 64-year-olds. If this Rhode Island population were exposed to temperatures projected under RCP 8.5 for 2092-2099, we estimate that there would be 1.2% (range, 0.6-1.6%) and 24.4% (range, 6.9-41.8%) more all-cause and heat-related ED admissions, respectively, and 1.6% (range, 0.8-2.1%) more deaths annually between April and October. CONCLUSIONS: With all other factors held constant, our findings suggest that the current population of Rhode Island would experience substantially higher morbidity and mortality if maximum daily temperatures increase further as projected. CITATION: Kingsley SL, Eliot MN, Gold J, Vanderslice RR, Wellenius GA. 2016. Current and projected heat-related morbidity and mortality in Rhode Island. Environ Health Perspect 124:460-467; http://dx.doi.org/10.1289/ehp.1408826.

Maternal residential proximity to major roadways, birth weight, and placental DNA methylation.

BACKGROUND: Exposure to traffic pollution during fetal development has been associated with reduced fetal growth, and there is evidence to suggest that epigenetic mechanisms in the placenta in the form of variant DNA methylation may be a potential mechanism underlying this effect. OBJECTIVES: To examine the association between residential proximity to nearest major roadway, as a marker of traffic-related pollution, fetal growth and placental DNA methylation. METHODS: We obtained residential addresses, placenta samples, and demographic data from 471 women following delivery of term infants. Using generalized linear models we evaluated the association between living close to a major roadway (defined as living ≤150m from a primary highway or primary road or ≤50m from a secondary road) and fetal growth and DNA methylation of repetitive elements (LINE-1 and AluYb8). We evaluated epigenome-wide methylation in a subset of 215 women to further investigate specific variation in DNA methylation associated with proximity to major roadways. RESULTS: Living close to a major roadway was associated with a 175.9g (95% CI: -319.4, -32.5; p=0.016) lower birth weight, 1.8 (95% CI: 0.9, 3.8; p=0.09) times the odds of being small for gestational age, and 0.82 percentage points (95% CI: -1.57, -0.07; p=0.03) lower mean placental LINE-1 methylation levels in fully adjusted models. In epigenome-wide analyses, 7 CpG sites were significantly associated with residential proximity to major roadways. Additional adjustment for placental methylation did not attenuate the association between roadway proximity and birth weight. CONCLUSIONS: Living close to major roadways was associated with both lower fetal growth and significant placental epigenetic changes. However, the observed epigenetic changes appear insufficient to explain the observed association between roadway proximity and fetal growth.

Proximity of US schools to major roadways: a nationwide assessment.

Long-term exposure to traffic pollution has been associated with adverse health outcomes in children and adolescents. A significant number of schools may be located near major roadways, potentially exposing millions of children to high levels of traffic pollution, but this hypothesis has not been evaluated nationally. We obtained data on the location and characteristics of 114,644 US public and private schools, grades prekindergarten through 12, and calculated their distance to the nearest major roadway. In 2005-2006, 3.2 million students (6.2%) attended 8,424 schools (7.3%) located within 100 m of a major roadway, and an additional 3.2 million (6.3%) students attended 8,555 (7.5%) schools located 100-250 m from a major roadway. Schools serving predominantly Black students were 18% (95% CI, 13-23%) more likely to be located within 250 m of a major roadway. Public schools eligible for Title I programs and those with a majority of students eligible for free/reduced price meals were also more likely to be near major roadways. In conclusion, 6.4 million US children attended schools within 250 m of a major roadway and were likely exposed to high levels of traffic pollution. Minority and underprivileged children were disproportionately affected, although some results varied regionally.