Vives Usano, Marta, 1990-Hernández-Ferrer, CarlesMaitre, LéaRuiz Arenas, Carlos, 1990-Borràs, EvaCasas Sanahuja, MaribelEstivill, Xavier, 1955-González, Juan RamónSabidó Aguadé, Eduard, 1981-Vrijheid, MartineBustamante Pineda, Mariona2020-10-272020-10-272020Vives-Usano M, Hernandez-Ferrer C, Maitre L, Ruiz-Arenas C, Andrusaityte S, Borràs E et al. In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children. BMC Med. 2020; 18(1):243. DOI: 10.1186/s12916-020-01686-81741-7015http://hdl.handle.net/10230/45579Background: 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.application/pdfeng© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data mainfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1186/s12916-020-01686-8ChildrenDNA methylationMetabolomicsMolecular phenotypesOmicsPregnancySecondhand smokeTobacco smokingTranscriptionmiRNAinfo:eu-repo/semantics/openAccess