Prenatal particulate air pollution and DNA methylation in newborns: an epigenome-wide meta-analysis

Abstract

BACKGROUND: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. OBJECTIVES: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children. METHODS: We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. RESULTS: Six CpGs were significantly associated [false discovery rate (FDR) [Formula: see text]] with prenatal [Formula: see text] and 14 with [Formula: see text] exposure. Two of the [Formula: see text] CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant ([Formula: see text]) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent [Formula: see text] exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal [Formula: see text] and or [Formula: see text] exposure, of which two [Formula: see text] DMRs, including H19 and MARCH11, replicated in newborns. CONCLUSIONS: Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. https://doi.org/10.1289/EHP4522. ; The UK Medical Research Council and the Wellcome Trust (Grant ref. 102215/2/13/2) provides core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was specifically funded by a joint grant from the UK Economic & Social and Biotechnology & Biological Sciences Research Councils (Grant ref. ES/N000498/1). ALSPAC was funded by the BBSRC (BBI025751/1 and BB/I025263/1). Air pollution exposure assessment was funded by Public Health England as part of the MRC-PHE Centre for Environment and Health, funded also by the UK Medical Research Council (Grant ref. MR/L01341X/1). BAMSE was supported by a European Union (grant agreement No. 261357), Swedish Foundation for Strategic Research (SSF) (RBc08-0027). E.M. is supported by a grant from the European Research Council under the European Union (EU) Horizon 2020 (H2020) research and innovation programme (grant agreement number 757919, TRIBALCHS: This work was supported by NIEHS grants K01ES017801, R01ES022216, and P30ES007048. EARLI was supported by NIH grants R01ES016443, R01ES023780, and R01ES017646 as well as by Autism Speaks (AS 5938). The ENVIRONAGE birth cohort is funded by the European Research Counsil (ERC-2012-StG.310898) and by funds of the Flemisch Scientific Research Council (FWO, N1516112/G.0.873.11N.10). The methylation assays were funded by the European Community's Seventh Framework Programme FP7/2007-2013 project EXPOsOMICS (grant no. 308610). Z.H. is supported by the Exposomics EC FP7 grant (Grant agreement no. 308610). ZH and A.G. and the Epigenetics Group at IARC are supported by grants from the Institut National du Cancer (INCa, Plan Cancer-EVA-Inserm, France) and Association pour la Recherche sur le Cancer (ARC, France). The EWAS data was funded by a grant to VWJ from Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project no. 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC. V.W.J. also received a grant from Netherlands Organization for Health Research and Development (VIDI 016.136.361) and a Consolidator Grant from the European Research Council (ERC-2014-CoG-648916). J.F.F. has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no. 633595 (DynaHEALTH). This project received funding from the European Union's Horizon 2020 Research and Innovation Programme (733206, LIFECYCLE). HELIX was supported by funding from the European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 – the HELIX project. R.G. received the grant of the Lithuanian Agency for Science Innovation and Technology (No. 45 31V-66). The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), NIH/NINDS (grant no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1). INMA was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176), Generalitat de Catalunya-CIRIT 1999SGR 00241, and EU Commission (261357; 211250; 268479). Piccolipiù was funded by the Italian National Centre for Disease Prevention and Control (CCM grant 2010). The methylation assays were funded by the European Community's Seventh Framework Programme FP7/2007–2013 project EXPOsOMICS (grant no. 308610). Z.H. is supported by the Exposomics EC FP7 grant (Grant agreement no: 308610). Z.H. and A.G. and the Epigenetics Group at IARC are supported by grants from the Institut National du Cancer (INCa, Plan Cancer-EVA-INSERM, France) and Association pour la Recherche sur le Cancer (ARC, France). Rhea: The methylation assays were funded by the European Community's Seventh Framework Programme FP7/2007-2013 project EXPOsOMICS (grant no. 308610). Z.H. is supported by the Exposomics EC FP7 grant (grant agreement no. 308610). ZH and A.G. and the Epigenetics Group at IARC are supported by grants from the Institut National du Cancer (INCa, Plan Cancer-EVA-INSERM, France) and Association pour la Recherche sur le Cancer (ARC, France). PRISM: R.J.W. received funding for the PRISM cohort under R01 HL095606 and R01 HL1143396. A.C.J. is supported by R00 ES023450. Project Viva was supported by grants from the NIH (NIH R01 HL 111108, R01 NR013945, R01 HD 034568, K24 HD069408, K23 ES022242, P01ES009825, R01AI102960, P30 ES000002) and the U.S. Environmental Protection Agency (EPA) (R832416, RD834798). MeDALL: The methylation study of MeDALL cohorts was funded by MEDALL, a collaborative project supported by the European Union under the Health Cooperation Work Programme of the 7th Framework Programme (grant agreement no. 261357). The Biobank-Based Integrative Omics Studies (BIOS) Consortium is funded by BBMRI-NL, a research infrastructure financed by the Dutch government (NWO 184.021.007). BAMSE: was supported by the Project b2014110