• Marta Vives-Usano, Carles Hernandez-Ferrer, Léa Maitre, Carlos Ruiz-Arenas, Sandra Andrusaityte, Eva Borràs, Ángel Carracedo, Maribel Casas, Leda Chatzi, Muireann Coen, Xavier Estivill, Juan R González, Regina Grazuleviciene, Kristine B Gutzkow, Hector C Keun, Chung-Ho E Lau, Solène Cadiou, Johanna Lepeule, Dan Mason, Inés Quintela, Oliver Robinson, Eduard Sabidó, Gillian Santorelli, Per E Schwarze, Alexandros P Siskos, Rémy Slama, Marina Vafeiadi, Eulàlia Martí, Martine Vrijheid, and Mariona Bustamante.
• Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
• Bmc Med. 2020 Aug 19; 18 (1): 243243.

BackgroundThe 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.MethodsWe 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.ResultsMaternal 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.ConclusionIn 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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