Epigenome-Wide Meta-Analysis of Methylation in Children Related to Prenatal NO2 Air Pollution Exposure

Gruzieva, Olena; Xu, Cheng-Jian; Breton, Carrie V.; Annesi-Maesano, Isabella; Antó, Josep M.; Auffray, Charles; Ballereau, Stephane; Bellander, Tom; Bousquet, Jean; Bustamante, Mariona; Charles, Marie-Aline; de Kluizenaar, Yvonne; den Dekker, Herman T.; Duijts, Liesbeth; Felix, Janine F.; Gehring, Ulrike; Guxens, Mònica; Jaddoe, Vincent V.W.; Jankipersadsing, Soesma A; Merid, Simon Kebede; Kere, Juha; Kumar, Ashish; Lemonnier, Nathanaël; Lepeule, Johanna; Nystad, Wenche; Page, Christian Magnus; Panasevich, Sviatlana; Postma, Dirkje S.; Slama, Rémy; Sunyer, Jordi; Söderhäll, Cilla; Yao, Jin-Guang; London, Stephanie J; Pershagen, Göran; Koppelman, Gerard H.; Melén, Erik

doi:10.1289/EHP36

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Epigenome-Wide Meta-Analysis of Methylation in Children Related to Prenatal NO ₂ Air Pollution Exposure

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Author(s): Olena Gruzieva ¹ ^, ^† , Cheng-Jian Xu ² ^, ³ , Carrie V. Breton ⁴ , Isabella Annesi-Maesano ⁵ , Josep M. Antó ⁶ ^, ⁷ ^, ⁸ ^, ⁹ , Charles Auffray ¹⁰ , Stéphane Ballereau ¹⁰ , Tom Bellander ¹ ^, ¹¹ , Jean Bousquet ¹² , Mariona Bustamante ⁶ ^, ⁸ ^, ⁹ ^, ¹³ , Marie-Aline Charles ¹⁴ , Yvonne de Kluizenaar ¹⁵ , Herman T. den Dekker ¹⁶ ^, ¹⁷ ^, ¹⁸ , Liesbeth Duijts ¹⁶ ^, ¹⁷ ^, ¹⁸ , Janine F. Felix ¹⁶ ^, ¹⁷ ^, ¹⁸ , Ulrike Gehring ¹⁹ , Mònica Guxens ⁶ ^, ⁸ ^, ⁹ ^, ²⁰ , Vincent V.W. Jaddoe ¹⁶ ^, ¹⁷ ^, ¹⁸ , Soesma A. Jankipersadsing ² ^, ³ , Simon Kebede Merid ¹ , Juha Kere ²¹ , Ashish Kumar ¹ ^, ²² ^, ²³ , Nathanael Lemonnier ¹⁰ , Johanna Lepeule ²⁴ , Wenche Nystad ²⁵ , Christian Magnus Page ²⁵ , Sviatlana Panasevich ²⁵ , Dirkje Postma ² , Rémy Slama ²⁴ , Jordi Sunyer ⁶ ^, ⁷ ^, ⁸ ^, ⁹ , Cilla Söderhäll ²¹ ^, ²⁶ , Jin Yao ⁴ , Stephanie J. London ²⁷ , Göran Pershagen ¹ ^, ¹¹ , Gerard H. Koppelman ²⁸ , Erik Melén ¹ ^, ¹¹ ^, ²⁹

Publication date (Electronic): 22 July 2016

Journal: Environmental Health Perspectives

Publisher: National Institute of Environmental Health Sciences

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Abstract

Background:

Prenatal exposure to air pollution is considered to be associated with adverse effects on child health. This may partly be mediated by mechanisms related to DNA methylation.

Objectives:

We investigated associations between exposure to air pollution, using nitrogen dioxide (NO2) as marker, and epigenome-wide cord blood DNA methylation.

Methods:

We meta-analyzed the associations between NO2 exposure at residential addresses during pregnancy and cord blood DNA methylation (Illumina 450K) in four European and North American studies (n = 1,508) with subsequent look-up analyses in children ages 4 (n = 733) and 8 (n = 786) years. Additionally, we applied a literature-based candidate approach for antioxidant and anti-inflammatory genes. To assess influence of exposure at the transcriptomics level, we related mRNA expression in blood cells to NO2 exposure in 4- (n = 111) and 16-year-olds (n = 239).

Results:

We found epigenome-wide significant associations [false discovery rate (FDR) p < 0.05] between maternal NO2 exposure during pregnancy and DNA methylation in newborns for 3 CpG sites in mitochondria-related genes: cg12283362 (LONP1), cg24172570 (3.8 kbp upstream of HIBADH), and cg08973675 (SLC25A28). The associations with cg08973675 methylation were also significant in the older children. Further analysis of antioxidant and anti-inflammatory genes revealed differentially methylated CpGs in CAT and TPO in newborns (FDR p < 0.05). NO2 exposure at the time of biosampling in childhood had a significant impact on CAT and TPO expression.

Conclusions:

NO2 exposure during pregnancy was associated with differential offspring DNA methylation in mitochondria-related genes. Exposure to NO2 was also linked to differential methylation as well as expression of genes involved in antioxidant defense pathways.

Citation:

Gruzieva O, Xu CJ, Breton CV, Annesi-Maesano I, Antó JM, Auffray C, Ballereau S, Bellander T, Bousquet J, Bustamante M, Charles MA, de Kluizenaar Y, den Dekker HT, Duijts L, Felix JF, Gehring U, Guxens M, Jaddoe VV, Jankipersadsing SA, Merid SK, Kere J, Kumar A, Lemonnier N, Lepeule J, Nystad W, Page CM, Panasevich S, Postma D, Slama R, Sunyer J, Söderhäll C, Yao J, London SJ, Pershagen G, Koppelman GH, Melén E. 2017. Epigenome-wide meta-analysis of methylation in children related to prenatal NO2 air pollution exposure. Environ Health Perspect 125:104–110; http://dx.doi.org/10.1289/EHP36

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The endocannabinoid system functions through two well characterized receptor systems, the CB1 and CB2 receptors. Work by a number of groups in recent years has provided evidence that the system is more complicated and additional receptor types should exist to explain ligand activity in a number of physiological processes. Cells transfected with the human cDNA for GPR55 were tested for their ability to bind and to mediate GTPgammaS binding by cannabinoid ligands. Using an antibody and peptide blocking approach, the nature of the G-protein coupling was determined and further demonstrated by measuring activity of downstream signalling pathways. We demonstrate that GPR55 binds to and is activated by the cannabinoid ligand CP55940. In addition endocannabinoids including anandamide and virodhamine activate GTPgammaS binding via GPR55 with nM potencies. Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB1 or CB2 activity and are believed to function at a novel cannabinoid receptor, also showed activity at GPR55. GPR55 couples to Galpha13 and can mediate activation of rhoA, cdc42 and rac1. These data suggest that GPR55 is a novel cannabinoid receptor, and its ligand profile with respect to CB1 and CB2 described here will permit delineation of its physiological function(s).

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Nizar Touleimat, Jörg Tost (2012)

Huge progress has been made in the development of array- or sequencing-based technologies for DNA methylation analysis. The Illumina Infinium(®) Human Methylation 450K BeadChip (Illumina Inc., CA, USA) allows the simultaneous quantitative monitoring of more than 480,000 CpG positions, enabling large-scale epigenotyping studies. However, the assay combines two different assay chemistries, which may cause a bias in the analysis if all signals are merged as a unique source of methylation measurement. We confirm in three 450K data sets that Infinium I signals are more stable and cover a wider dynamic range of methylation values than Infinium II signals. We evaluated the methylation profile of Infinium I and II probes obtained with different normalization protocols and compared these results with the methylation values of a subset of CpGs analyzed by pyrosequencing. We developed a subset quantile normalization approach for the processing of 450K BeadChips. The Infinium I signals were used as 'anchors' to normalize Infinium II signals at the level of probe coverage categories. Our normalization approach outperformed alternative normalization or correction approaches in terms of bias correction and methylation signal estimation. We further implemented a complete preprocessing protocol that solves most of the issues currently raised by 450K array users. We developed a complete preprocessing pipeline for 450K BeadChip data using an original subset quantile normalization approach that performs both sample normalization and efficient Infinium I/II shift correction. The scripts, being freely available from the authors, will allow researchers to concentrate on the biological analysis of data, such as the identification of DNA methylation signatures.

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Author and article information

Journal

Journal ID (nlm-ta): Environ Health Perspect

Journal ID (iso-abbrev): Environ. Health Perspect

Journal ID (publisher-id): EHP

Title: Environmental Health Perspectives

Publisher: National Institute of Environmental Health Sciences

ISSN (Print): 0091-6765

ISSN (Electronic): 1552-9924

Publication date (Electronic): 22 July 2016

Publication date (Print): January 2017

Volume: 125

Issue: 1

Pages: 104-110

Affiliations

[1 ]Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

[2 ]Groningen Research Institute for Asthma and COPD (GRIAC), Department of Pulmonology, and

[3 ]Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

[4 ]Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA

[5 ]Department of Epidemiology of Allergic and Respiratory Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France

[6 ]ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain

[7 ]IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain

[8 ]Universitat Pompeu Fabra (UPF), Barcelona, Spain

[9 ]CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain

[10 ]European Institute for Systems Biology and Medicine, Université de Lyon, Lyon, France

[11 ]Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden

[12 ]CHU (Centre Hospitalier Universitaire) Montpellier, University of Montpellier, Montpellier, France

[13 ]Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain

[14 ]Early Origin of the Child’s Health And Development (ORCHAD) team, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS-UMR1153) Inserm, Université Paris Descartes, Villejuif, France

[15 ]The Netherlands Organization for Applied Scientific Research (TNO), Delft, the Netherlands

[16 ]Generation R Study Group,

[17 ]Department of Epidemiology, and

[18 ]Department of Pediatrics, Erasmus MC (Medical Centre), University Medical Center, Rotterdam, the Netherlands

[19 ]Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands

[20 ]Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre–Sophia Children’s Hospital, Rotterdam, the Netherlands

[21 ]Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

[22 ]Unit of Chronic Disease Epidemiology, Department of Public Health Epidemiology, Swiss Tropical and Public Health Institute, Basel, Switzerland

[23 ]University of Basel, Basel, Switzerland

[24 ]Team of Environmental Epidemiology, Inserm and University Grenoble-Alpes, IAB (U1209), Grenoble, France

[25 ]Division for Physical and Mental health, Norwegian Institute of Public Health, Oslo, Norway

[26 ]Department of Women´s and Children´s Health, Karolinska Institutet, Stockholm, Sweden

[27 ]Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA

[28 ]Groningen Research Institute for Asthma and COPD (GRIAC), Beatrix Children’s Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

[29 ]Sachs Children’s Hospital, Stockholm, Sweden

Author notes

[*]

These authors contributed equally to this work.

[† ]Address corresponence to O. Gruzieva, Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, SE-17177 Stockholm, Sweden. Telephone: 46852480022. E-mail: olena.gruzieva@ 123456ki.se

Article

Publisher ID: EHP36

DOI: 10.1289/EHP36

PMC ID: 5226705

PubMed ID: 27448387

SO-VID: 5c9dc8f5-4de8-4f1d-a2de-ca445ca88f7a

License:

Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, “Reproduced with permission from Environmental Health Perspectives”); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.

History

Date received : 26 February 2016

Date revision received : 13 June 2016

Date accepted : 22 June 2016

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