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

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.

Early-life environmental exposure determinants of child behavior in Europe: A longitudinal, population-based study

“…Our results may indicate that the pregnancy period is most sensitive to the harmful effects of these exposures which is in line with the very rapid development of the nervous system during this time window but also the different ways individuals are exposed, for example in utero and/or passively to tobacco smoke ( Peterson et al, 2015 , Allen et al, 2017 ). In line with our results, childhood second-hand smoke (SHS) was not related to blood methylation in HELIX children (biomarkers of past exposure), indicating much weaker effects of recent SHS with respect to active maternal smoking in pregnancy ( Vives-Usano et al, 2020 ).…”

Multi-omics signatures of the human early life exposome

“…While blood DNA methylation and transcriptomics were measured genome-wide, the other omics followed a semi-targeted or targeted approach. Details of the plasma proteins and the urinary and serum metabolomic analyses can be found elsewhere (Lau et al, 2018; Vives-Usano et al, 2020).…”

“…Additionally, we observed that child exposure to second-hand smoke (cluster childhood#7) overlapped with existing literature, but to a lesser extent than maternal smoking (Figure 5C; Table S3) . Period specific effects have been investigated elsewhere in more detail (Vives-Usano et al, 2020). In order to understand which pathways were perturbed due to exposure to tobacco smoke, we performed functional enrichment analysis of genes annotated to molecular features associated with pregnancy or childhood exposure (Supplemental Experimental Procedures) .…”

Hypomethylation inFASTKD1detected in the association betweenin uterotobacco exposure and conduct problem in a New Zealand longitudinal study

“…However, the top nominally significant CpG sites were found in the genes FRMD4A, MYO1G, WIPF3 , and RTN1 . CpG sites in genes MYO1G and FRMD4A have been previously found to be differentially methylated in response to maternal smoking during pregnancy [40–42]. However, the CpG sites cg20745684 and cg01604380 within the genes WIPF3 and RTN1 respectively have not been implicated in any previous study.…”

“…Myosin 1G ( MYO1G ) and FERM Domain Containing 4A ( FRMD4A ) are more established biomarkers for in utero tobacco exposure [40–42]. However, these prior results come from the analysis of DNA methylation during childhood.…”