Prenatal Smoking Exposures and Epigenome-wide Methylation in Newborn Blood

Thanh T Hoang^{1

2

3

4}, Marta Cosin-Tomas^{5

6

7}, Yunsung Lee⁸, Giulietta Monasso^{9

10}, Zongli Xu¹¹, Sebastian Shaobo Li¹², Xuehuo Zeng¹³, Anne P Starling^{14

15}, Brigitte Reimann¹⁶, Stefan Röder¹⁷, Lea Zillich¹⁸, Dereje D Jima^{19

20}, Chris H L Thio²¹, Giancarlo Pesce^{22

23}, Elin T G Kersten^{24

25}, Charles E Breeze²⁶, Adam B Burkholder²⁷, Mikyeong Lee¹, James M Ward²⁸, Bios Consortium, Rossella Alfano¹⁶, Michael Deuschle²⁹, Liesbeth Duijts^{30

31}, Akhgar Ghassabian^{32

33}, Laura-Concepció Gómez Herrera^{5

16

34}, Vincent Wv Jaddoe^{9

10}, Alison A Motsinger-Reif¹¹, Rolv T Lie^{8

35}, Tim S Nawrot^{36

37}, Christian M Page³⁸, Tabea S Send²⁹, Gemma Sharp³⁹, Dan J Stein^{40

41}, Fabian Streit^{18

29

42

43}, Jordi Sunyer^{5

6

7

44}, Allen J Wilcox⁴⁵, Heather J Zar⁴⁶, Gerard H Koppelman^{24

25}, Isabella Annesi-Maesano^{47

48}, Eva Corpeleijn²¹, Harold Snieder²¹, Cathrine Hoyo^{19

20

49

50}, Anke Hüls^{51

52

53}, Lea Sirignano¹⁸, Stephanie H Witt^{18

42

54}, Gunda Herberth¹⁷, Michelle Plusquin¹⁶, Dana Dabelea¹⁴, Edwina Yeung⁵⁵, Joseph L Wiemels¹², Rebecca C Richmond^{56

57}, Jack A Taylor⁴³, Janine F Felix^{9

10}, Siri E Håberg^{8

58}, Mariona Bustamante^{5

6

7}, Stephanie J London¹

Affiliations

¹ Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
² Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA.
³ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
⁴ Cancer and Hematology Center, Texas Children's Hospital, Houston, TX, USA.
⁵ ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.
⁶ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁷ Centro de investigación biomédica en red en epidemiología y salud pública (CIBERESP), Madrid, Spain.
⁸ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
⁹ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000, CA, Rotterdam, the Netherlands.
¹⁰ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000, CA, Rotterdam, the Netherlands.
¹¹ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
¹² Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
¹³ Glotech, Inc., Rockville, MD, USA.
¹⁴ Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁵ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
¹⁶ Centre for Environmental Sciences (CMK), Hasselt University, 3590 Diepenbeek, Belgium.
¹⁷ Department of Environmental Immunology, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany.
¹⁸ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁹ Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27695, USA.
²⁰ Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27607, USA.
²¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²² Epidemiology of Allergic and Respiratory Diseases (EPAR) Team, Faculté de Médecine Saint-Antoine, Institute Pierre Louis d'Epidemiologie et Sante Publique (IPLESP), Sorbonne Université and INSERM UMR-S 1136, Paris, France.
²³ Certara Italy, Milan, Italy.
²⁴ University Medical Center Groningen, University of Groningen, Beatrix Children's Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, Groningen, the Netherlands.
²⁵ University Medical Center Groningen, University of Groningen, Groningen Research Institute of Asthma and COPD (GRIAC), Groningen, the Netherlands.
²⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
²⁷ Office of Environmental Science Cyberinfrastructure, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
²⁸ Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
²⁹ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
³⁰ Department of Pediatrics, Division of Respiratory Medicine and Allergology a Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
³¹ Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
³² Department of Pediatrics, New York University Grossman School of Medicine, New York, NY 10016, USA.
³³ Department of Population Health, New York University Grossman School of Medicine, New York, NY 10016, USA.
³⁴ Universitat de Barcelona (UB), Barcelona, Spain.
³⁵ Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
³⁶ Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.
³⁷ Health and Environment Unit, Leuven University, Leuven, Belgium.
³⁸ Department of Physical Health and Ageing, Division of Public Health and Prevention, Norwegian Institute of Public Health, Oslo, Norway.
³⁹ School of Psychology, University of Exeter, Exeter EX4 4QG, UK.
⁴⁰ Department of Psychiatry, Neuroscience Institute, Faculty of Health Sciences, University of Cape Town, South Africa.
⁴¹ South African Medical Research Council (SAMRC) Unit on Risk and Resilience in Mental Disorders, Cape Town, South Africa.
⁴² German Center for Mental Health (DZPG), partner site Mannheim/Heidelberg/Ulm, Germany.
⁴³ Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁴⁴ IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
⁴⁵ Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
⁴⁶ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, and South African Medical Research Council (SAMRC) Unit on Child and Adolescent Health, Cape Town, South Africa.
⁴⁷ Institute Desbrest of Epidemiology and Public Health UMR1318, INSERM et Université de Montpellier, Montpellier, France.
⁴⁸ Department of Pulmonology, Allergy and Thoracic Oncology, University Hospital of Montpellier, Montpellier, France.
⁴⁹ Toxicology Program, North Carolina State University, Raleigh, NC, USA.
⁵⁰ Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
⁵¹ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁵² Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁵³ Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁵⁴ Center for Innovative Psychiatry and Psychotherapy Research (ZIPP), Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁵⁵ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA.
⁵⁶ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.
⁵⁷ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.
⁵⁸ DDepartment of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.

PMID: 40478623
DOI: 10.1289/EHP16303

Free article

Prenatal Smoking Exposures and Epigenome-wide Methylation in Newborn Blood

Thanh T Hoang et al. Environ Health Perspect. 2025.

Free article

. 2025 Jun 6.

doi: 10.1289/EHP16303. Online ahead of print.

Authors

Affiliations

¹ Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
² Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA.
³ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
⁴ Cancer and Hematology Center, Texas Children's Hospital, Houston, TX, USA.
⁵ ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.
⁶ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁷ Centro de investigación biomédica en red en epidemiología y salud pública (CIBERESP), Madrid, Spain.
⁸ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
⁹ The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000, CA, Rotterdam, the Netherlands.
¹⁰ Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000, CA, Rotterdam, the Netherlands.
¹¹ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
¹² Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
¹³ Glotech, Inc., Rockville, MD, USA.
¹⁴ Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁵ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
¹⁶ Centre for Environmental Sciences (CMK), Hasselt University, 3590 Diepenbeek, Belgium.
¹⁷ Department of Environmental Immunology, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany.
¹⁸ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁹ Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27695, USA.
²⁰ Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27607, USA.
²¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²² Epidemiology of Allergic and Respiratory Diseases (EPAR) Team, Faculté de Médecine Saint-Antoine, Institute Pierre Louis d'Epidemiologie et Sante Publique (IPLESP), Sorbonne Université and INSERM UMR-S 1136, Paris, France.
²³ Certara Italy, Milan, Italy.
²⁴ University Medical Center Groningen, University of Groningen, Beatrix Children's Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, Groningen, the Netherlands.
²⁵ University Medical Center Groningen, University of Groningen, Groningen Research Institute of Asthma and COPD (GRIAC), Groningen, the Netherlands.
²⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
²⁷ Office of Environmental Science Cyberinfrastructure, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
²⁸ Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
²⁹ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
³⁰ Department of Pediatrics, Division of Respiratory Medicine and Allergology a Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
³¹ Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
³² Department of Pediatrics, New York University Grossman School of Medicine, New York, NY 10016, USA.
³³ Department of Population Health, New York University Grossman School of Medicine, New York, NY 10016, USA.
³⁴ Universitat de Barcelona (UB), Barcelona, Spain.
³⁵ Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
³⁶ Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.
³⁷ Health and Environment Unit, Leuven University, Leuven, Belgium.
³⁸ Department of Physical Health and Ageing, Division of Public Health and Prevention, Norwegian Institute of Public Health, Oslo, Norway.
³⁹ School of Psychology, University of Exeter, Exeter EX4 4QG, UK.
⁴⁰ Department of Psychiatry, Neuroscience Institute, Faculty of Health Sciences, University of Cape Town, South Africa.
⁴¹ South African Medical Research Council (SAMRC) Unit on Risk and Resilience in Mental Disorders, Cape Town, South Africa.
⁴² German Center for Mental Health (DZPG), partner site Mannheim/Heidelberg/Ulm, Germany.
⁴³ Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁴⁴ IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
⁴⁵ Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
⁴⁶ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, and South African Medical Research Council (SAMRC) Unit on Child and Adolescent Health, Cape Town, South Africa.
⁴⁷ Institute Desbrest of Epidemiology and Public Health UMR1318, INSERM et Université de Montpellier, Montpellier, France.
⁴⁸ Department of Pulmonology, Allergy and Thoracic Oncology, University Hospital of Montpellier, Montpellier, France.
⁴⁹ Toxicology Program, North Carolina State University, Raleigh, NC, USA.
⁵⁰ Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
⁵¹ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁵² Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁵³ Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁵⁴ Center for Innovative Psychiatry and Psychotherapy Research (ZIPP), Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁵⁵ Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA.
⁵⁶ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.
⁵⁷ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.
⁵⁸ DDepartment of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.

PMID: 40478623
DOI: 10.1289/EHP16303

Abstract

Background: Maternal sustained smoking during pregnancy is associated with thousands of differentially methylated CpGs in newborns, but impacts of other prenatal tobacco smoking exposures remain unclear.

Objective: To identify differential DNA methylation in newborns from maternal sustained smoking and less studied prenatal smoking exposures (i.e., maternal exposure to secondhand smoke [SHS] exposure during pregnancy, maternal quitting before pregnancy, paternal smoking around conception, paternal quitting before pregnancy).

Methods: We conducted a large meta-analysis of prenatal tobacco smoking exposures and epigenome-wide newborn blood DNA methylation through the Pregnancy And Childhood Epigenetics Consortium (PACE). Across 19 cohorts, 11,175 parent-newborn pairs contributed information on at least one prenatal smoking exposure, mostly from questionnaires. Maternal blood or urine cotinine measurements, available in a few studies, provided objective data on maternal SHS and smoking during pregnancy. Primary analyses used Illumina450K methylation data; secondary analyses in 5 cohorts examined CpGs unique to the EPIC array.

Results: Maternal sustained smoking associated with differential DNA methylation (false discovery rate [FDR] <0.05) at 8,862 CpGs on the 450K (n=8,148) and did not differ by infant sex. We identified over 300 novel genes not previously identified in EWAS of smoking. No differential methylation was associated with maternal SHS, maternal former smoking, or paternal smoking around conception. However, cg24805739 (MED13L) was associated with paternal former smoking. Forty-one novel genes were identified using maternal cotinine measurements compared to questionnaire. In EPIC unique analyses (n=3,415), differential methylation was observed with maternal sustained smoking (211 CpGs), maternal SHS (5 CpGs), and paternal former smoking (4 CpGs). Smoking-associated CpGs in blood were strongly enriched for functional elements across multiple tissues.

Conclusions: Maternal sustained smoking has the largest impact on newborn DNA methylation, suggesting a strong influence of the intrauterine environment. We observed minimal impacts for less studied exposures including SHS, maternal former smoking and paternal smoking. https://doi.org/10.1289/EHP16303.

PubMed Disclaimer

LinkOut - more resources

Full Text Sources
- Atypon

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Prenatal Smoking Exposures and Epigenome-wide Methylation in Newborn Blood

Affiliations

Prenatal Smoking Exposures and Epigenome-wide Methylation in Newborn Blood

Authors

Affiliations

Abstract

LinkOut - more resources

Full Text Sources