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In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children

Marta Vives-Usano 1, 2, 3, 4 Carles Hernandez-Ferrer 2, 1, 3 Léa Maitre 2, 1, 3 Carlos Ruiz-Arenas 2, 1, 3 Sandra Andrusaityte 5 Eva Borràs 4, 2 Ángel Carracedo 6, 7 Maribel Casas 2, 1, 3 Leda Chatzi 8 Muireann Coen 9, 10 Xavier Estivill 2, 3, 4, 11 Juan González 2, 1, 3 Regina Grazuleviciene 5 Kristine Gutzkow 12 Hector Keun 10 Chung-Ho Lau 10 Solène Cadiou 13 Johanna Lepeule 13 Dan Mason 14 Inés Quintela 15 Oliver Robinson 10 Eduard Sabidó 2, 4 Gillian Santorelli 14 Per Schwarze 12 Alexandros Siskos 10 Rémy Slama 13 Marina Vafeiadi 16 Eulàlia Martí 17, 3 Martine Vrijheid 1, 2, 3 Mariona Bustamante 1, 2, 3, * 
Abstract : Background The adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows. Methods We investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites. Results Maternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure. Conclusion In this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis.
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Submitted on : Monday, March 22, 2021 - 4:20:30 PM
Last modification on : Sunday, June 26, 2022 - 3:06:34 AM
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Marta Vives-Usano, Carles Hernandez-Ferrer, Léa Maitre, Carlos Ruiz-Arenas, Sandra Andrusaityte, et al.. In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children. BMC Medicine, BioMed Central, 2020, 18 (1), pp.243. ⟨10.1186/s12916-020-01686-8⟩. ⟨inserm-03176787⟩



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