Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

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Background: There is evidence for adverse effects of outdoor air pollution on lung function of children. Quantitative summaries of the effects of air pollution on lung function, however, are lacking due to large differences among studies.Objectives: We aimed to study the association between residential exposure to air pollution and lung function in five European birth cohorts with a standardized exposure assessment following a common protocol.Methods: As part of the European Study of Cohorts for Air Pollution Effects (ESCAPE) we analyzed data from birth cohort studies situated in Germany, Sweden, the Netherlands, and the United Kingdom that measured lung function at 6–8 years of age (n = 5,921). Annual average exposure to air pollution [nitrogen oxides (NO2, NOx), mass concentrations of particulate matter with diameters < 2.5, < 10, and 2.5–10 μm (PM2.5, PM10, and PMcoarse), and PM2.5 absorbance] at the birth address and current address was estimated by land-use regression models. Associations of lung function with estimated air pollution levels and traffic indicators were estimated for each cohort using linear regression analysis, and then combined by random effects meta-analysis.Results: Estimated levels of NO2, NOx, PM2.5 absorbance, and PM2.5 at the current address, but not at the birth address, were associated with small decreases in lung function. For example, changes in forced expiratory volume in 1 sec (FEV1) ranged from –0.86% (95% CI: –1.48, –0.24%) for a 20-μg/m3 increase in NOx to –1.77% (95% CI: –3.34, –0.18%) for a 5-μg/m3 increase in PM2.5.Conclusions: Exposure to air pollution may result in reduced lung function in schoolchildren.Citation: Gehring U, Gruzieva O, Agius RM, Beelen R, Custovic A, Cyrys J, Eeftens M, Flexeder C, Fuertes E, Heinrich J, Hoffmann B, de Jongste JC, Kerkhof M, Klümper C, Korek M, Mölter A, Schultz ES, Simpson A, Sugiri D, Svartengren M, von Berg A, Wijga AH, Pershagen G, Brunekreef B. 2013. Air pollution exposure and lung function in children: the ESCAPE project. Environ Health Perspect 121:1357–1364; http://dx.doi.org/10.1289/ehp.1306770

PM 2.5 : mass concentration of particles less than 2.5 µm in size PM 10 : mass concentration of particles less than 10 µm in size RB: Regional Background site SOP: Standard Operating Procedure ST: Street site TRAPCA: Traffic-Related Air Pollution and Childhood Asthma UB: Urban Background site ABSTRACT The ESCAPE study (European Study of Cohorts for Air Pollution Effects) investigates long-term effects on human health of exposure to air pollution in Europe. Various health endpoints are analysed by using prospective cohort studies in the study areas. This paper documents the spatial variation of measured NO 2 and NO x concentrations between and within 36 study areas across Europe. In 36 study areas NO 2 and NO x were measured using standardized methods between October 2008 and April 2011. In each study area 14 to 80 sites were selected, which represented a wide range of regional, urban and nearby traffic related pollution contrast. The measurements were conducted for two weeks per site in three different seasons, using Ogawa badges. Results for each site were adjusted for temporal variation using data obtained from a routine monitor background site, which operated continuously, and averaged. Substantial spatial variability was found in NO 2 and NO x concentrations between and within study areas. Analysis of variance showed that 40% of the overall NO 2 variance is attributable to the variability between the study areas and 60% is caused by the variability within the study areas. The corresponding values for NO x are 30% (between the study areas) and 70% (within the study areas). The within-area spatial variability was mostly determined by the differences between traffic and urban background concentrations. The traffic/urban background concentration ratio varied between 1.09 and 3.16 across Europe. The NO 2 / NO x ratio varied between 0.47 (Verona) and 0.72 (Heraklion) across study areas. In study areas in southern Europe the highest median concentrations were observed (Barcelona: NO 2 55 µg/m³), followed by densely populated areas in Western Europe (Ruhr area, The Netherlands). The lowest concentrations were observed in all areas in Northern Europe (e.g. Umeå: NO 2 7 µg/m³). In conclusion, we found significant contrast in annual average NO 2 and NO x concentration between and especially within 36 study areas across Europe. Epidemiological studies should therefore characterize intra-urban contrasts. The use of traffic indicators such as "living close to major road" as an exposure variable in epidemiological studies results in different actual NO 2 contrasts. We would like to thank Kees Meliefste, Geert de Vrieze, Marjan Tewis (IRAS, Utrecht University, The Netherlands) for the sampler preparation, analysis and data management. Furthermore, we thank all those who were responsible for air pollution measurements, data management and project supervision in all study areas and especially:

EU and the Seventh Framework Programme (the MeDALL project).