The early-life exposome and epigenetic age acceleration in children

The early-life exposome influences future health and accelerated biological aging has been proposed as one of the underlying biological mechanisms. We investigated the association between more than 100 exposures assessed during pregnancy and in childhood (including indoor and outdoor air pollutants, built environment, green environments, tobacco smoking, lifestyle exposures, and biomarkers of chemical pollutants), and epigenetic age acceleration in 1,173 children aged 7 years old from the Human Early-Life Exposome project. Age acceleration was calculated based on Horvath’s Skin and Blood clock using child blood DNA methylation measured by Infinium HumanMethylation450 BeadChips. We performed an exposure-wide association study between prenatal and childhood exposome and age acceleration. Maternal tobacco smoking during pregnancy was nominally associated with increased age acceleration. For childhood exposures, indoor particulate matter absorbance (PMabs) and parental smoking were nominally associated with an increase in age acceleration. Exposure to the organic pesticide dimethyl dithiophosphate and the persistent pollutant polychlorinated biphenyl-138 (inversely associated with child body mass index) were protective for age acceleration. None of the associations remained significant after multiple-testing correction. Pregnancy and childhood exposure to tobacco smoke and childhood exposure to indoor PMabs may accelerate epigenetic aging from an early ageThe study received funding from the European Community’s Seventh Framework Programme (FP7/2007-206) (grant agreement no 308333) (HELIX project), the H2020-EU.3.1.2. - Preventing Disease Programme (grant agreement no 874583) (ATHLETE project), and from the European Union’s Horizon 2020 research and innovation programme (grant Agreement number: 733206) (Early Life stressors and Lifecycle Health (LIFECYCLE)). BiB received funding from the Welcome Trust (WT101597MA), from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA was supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15). We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. OR was funded by a UKRI Future Leaders Fellowship (MR/S03532X/1). MV-U and CR-A were supported by a FI fellowship from the Catalan Government (FI-DGR 2015 and #016FI_B 00272). MC received funding from Instituto Carlos III (Ministry of Economy and Competitiveness) (CD12/00563 and MS16/00128)S

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

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

Sérialisation et gestion du risque de falsification dans le circuit de distribution du médicament dans l'Union Européenne: De la réglementation européenne à la réalité opérationnelle : le cas de l'AGEPS en France

Pour lutter contre l'introduction de médicaments falsifiés dans la chaîne de distribution légale, l'Union Européenne a produit une réglementation ambitieuse qui impose de sérialiser et de vérifier chaque boîte de médicaments. A l'Agence Générale des Equipements et Produits de Santé (AGEPS), des évolutions importantes seront nécessaires pour s'y conformer. La réflexion pour y élaborer une stratégie pour la mise en oeuvre amène aussi à s'interroger sur l'apport réel de la réglementation

The Exposome Approach to Decipher the Role of Multiple Environmental and Lifestyle Determinants in Asthma

International audienceAsthma is a widespread respiratory disease caused by complex contribution from genetic, environmental and behavioral factors. For several decades, its sensitivity to environmental factors has been investigated in single exposure (or single family of exposures) studies, which might be a narrow approach to tackle the etiology of such a complex multifactorial disease. The emergence of the exposome concept, introduced by C. Wild (2005), offers an alternative to address exposure-health associations. After presenting an overview of the exposome concept, we discuss different statistical approaches used to study the exposome-health associations and review recent studies linking multiple families of exposures to asthma-related outcomes. The few studies published so far on the association between the exposome and asthma-related outcomes showed differences in terms of study design, population, exposome definition and statistical methods used, making their results difficult to compare. Regarding statistical methods, most studies applied successively univariate (Exposome-Wide Association Study (ExWAS)) and multivariate (adjusted for co-exposures) (e.g., Deletion-Substitution-Addition (DSA) algorithm) regression-based models. This latest approach makes it possible to assess associations between a large set of exposures and asthma outcomes. However, it cannot address complex interactions (i.e., of order ≥3) or mixture effects. Other approaches like cluster-based analyses, that lead to the identification of specific profiles of exposure at risk for the studied health-outcome, or mediation analyses, that allow the integration of information from intermediate biological layers, could offer a new avenue in the understanding of the environment-asthma association. European projects focusing on the exposome research have recently been launched and should provide new results to help fill the gap that currently exists in our understanding of the effect of environment on respiratory health

Quelle interministérialité pour le Conseil National de l'Alimentation ?: Vers une gestion plus efficace et ciblée de l’interministérialité pour améliorer l’impact et la reconnaissance du CNA

Cette analyse s'inscrit dans un contexte de prise de poste récente de la secrétaire interministérielle du CNA et du démarrage d'une nouvelle mandature (2016-2019). Ce projet doit permettre au commanditaire de mieux appréhender les enjeux de la dimension interministérielle du CNA et de son fonctionnement. Nous proposons des préconisations et des outils pour améliorer la coordination interministérielle dans un futur proche

Performance of approaches relying on multidimensional intermediary data to decipher causal relationships between the exposome and health: A simulation study under various causal structures

International audienceAbstractChallenges in the assessment of the health effects of the exposome, defined as encompassing all environmental exposures from the prenatal period onwards, include a possibly high rate of false positive signals. It might be overcome using data dimension reduction techniques. Data from the biological layers lying between the exposome and its possible health consequences, such as the methylome, may help reducing exposome dimension. We aimed to quantify the performances of approaches relying on the incorporation of an intermediary biological layer to relate the exposome and health, and compare them with agnostic approaches ignoring the intermediary layer. We performed a Monte-Carlo simulation, in which we generated realistic exposome and intermediary layer data by sampling with replacement real data from the Helix exposome project. We generated a Gaussian outcome assuming linear relationships between the three data layers, in 2381 scenarios under five different causal structures, including mediation and reverse causality. We tested 3 agnostic methods considering only the exposome and the health outcome: ExWAS (for Exposome-Wide Association study), DSA, LASSO; and 3 methods relying on an intermediary layer: two implementations of our new oriented Meet-in-the-Middle (oMITM) design, using ExWAS and DSA, and a mediation analysis using ExWAS. Methods’ performances were assessed through their sensitivity and FDP (False-Discovery Proportion). The oMITM-based methods generally had lower FDP than the other approaches, possibly at a cost in terms of sensitivity; FDP was in particular lower under a structure of reverse causality and in some mediation scenarios. The oMITM–DSA implementation showed better performances than oMITM–ExWAS, especially in terms of FDP. Among the agnostic approaches, DSA showed the highest performance. Integrating information from intermediary biological layers can help lowering FDP in studies of the exposome health effects; in particular, oMITM seems less sensitive to reverse causality than agnostic exposome-health association studies

Challenges Raised by Mediation Analysis in a High-Dimension Setting

International audienceBackground:Mediation analysis is used in epidemiology to identify pathways through which exposures influence health. The advent of high-throughput (omics) technologies gives opportunities to perform mediation analysis with a high-dimension pool of covariates.Objective:We aimed to highlight some biostatistical issues of this expanding field of high-dimension mediation.Discussion:The mediation techniques used for a single mediator cannot be generalized in a straightforward manner to high-dimension mediation. Causal knowledge on the relation between covariates is required for mediation analysis, and it is expected to be more limited as dimension and system complexity increase. The methods developed in high dimension can be distinguished according to whether mediators are considered separately or as a whole. Methods considering each potential mediator separately do not allow efficient identification of the indirect effects when mutual influences exist among the mediators, which is expected for many biological (e.g., epigenetic) parameters. In this context, methods considering all potential mediators simultaneously, based, for example, on data reduction techniques, are more adapted to the causal inference framework. Their cost is a possible lack of ability to single out the causal mediators. Moreover, the ability of the mediators to predict the outcome can be overestimated, in particular because many machine-learning algorithms are optimized to increase predictive ability rather than their aptitude to make causal inference. Given the lack of overarching validated framework and the generally complex causal structure of high-dimension data, analysis of high-dimension mediation currently requires great caution and effort to incorporate a priori biological knowledge. https://doi-org.proxy.insermbiblio.inist.fr/10.1289/EHP624

Urinary metabolite quantitative trait loci in children and their interaction with dietary factors

Human metabolism is influenced by genetic and environmental factors. Previous studies have identified over 23 loci associated with more than 26 urine metabolites levels in adults, which are known as urinary metabolite quantitative trait loci (metabQTLs). The aim of the present study is the identification for the first time of urinary metabQTLs in children and their interaction with dietary patterns. Association between genome-wide genotyping data and 44 urine metabolite levels measured by proton nuclear magnetic resonance spectroscopy was tested in 996 children from the Human Early Life Exposome project. Twelve statistically significant urine metabQTLs were identified, involving 11 unique loci and 10 different metabolites. Comparison with previous findings in adults revealed that six metabQTLs were already known, and one had been described in serum and three were involved the same locus as other reported metabQTLs but had different urinary metabolites. The remaining two metabQTLs represent novel urine metabolite-locus associations, which are reported for the first time in this study [single nucleotide polymorphism (SNP) rs12575496 for taurine, and the missense SNP rs2274870 for 3-hydroxyisobutyrate]. Moreover, it was found that urinary taurine levels were affected by the combined action of genetic variation and dietary patterns of meat intake as well as by the interaction of this SNP with beverage intake dietary patterns. Overall, we identified 12 urinary metabQTLs in children, including two novel associations. While a substantial part of the identified loci affected urinary metabolite levels both in children and in adults, the metabQTL for taurine seemed to be specific to children and interacted with dietary patterns.This work was supported by the European Community’s Seventh Framework Programme (FP7/2007-206) [grant agreement no 308333 (HELIX project)]; and the H2020-EU.3.1.2. - Preventing Disease Programme [grant agreement no 874583 (ATHLETE project)]. The genotyping was supported by Instituto de Salud Carlos III [PI17/01225]; and co-funded by European Union (ERDF, “A way to make Europe”) and the Centro Nacional de Genotipado-CEGEN [PRB2-ISCIII]. BiB received core infrastructure funding from the Wellcome Trust [WT101597MA]; and a joint grant from the UK Medical Research Council and Economic and Social Science Research Council [MR/N024397/1]. INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology [6-04-2014_31V-66]. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea project was financially supported by European projects [EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX], and the Greek Ministry of Health [Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15]. We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023” Program [CEX2018-000806-S], and support from the Generalitat de Catalunya through the CERCA Program