Suchergebnisse

The exposome represents the totality of life course environmental exposures (including lifestyle and other non-genetic factors), from the prenatal period onwards. This holistic concept of exposure provides a new framework to advance the understanding of complex and multifactorial diseases. Prospective pregnancy and birth cohort studies provide a unique opportunity for exposome research as they are able to capture, from prenatal life onwards, both the external (including lifestyle, chemical, social and wider community-level exposures) and the internal (including inflammation, metabolism, epigenetics, and gut microbiota) domains of the exposome. In this paper, we describe the steps required for applying an exposome approach, describe the main strengths and limitations of different statistical approaches and discuss their challenges, with the aim to provide guidance for methodological choices in the analysis of exposome data in birth cohort studies. An exposome approach implies selecting, pre-processing, describing and analyzing a large set of exposures. Several statistical methods are currently available to assess exposome-health associations, which differ in terms of research question that can be answered, of balance between sensitivity and false discovery proportion, and between computational complexity and simplicity (parsimony). Assessing the association between many exposures and health still raises many exposure assessment issues and statistical challenges. The exposome favors a holistic approach of environmental influences on health, which is likely to allow a more complete understanding of disease etiology. ; This work was supported by the European Union's Horizon 2020 research and innovation programme under Grant Agreement 733206 (LifeCycle Project) and 874583 (ATHLETE Project).

Background: The exposome is defined as the totality of environmental exposures from conception onwards. It calls for providing a holistic view of environmental exposures and their effects on human health by evaluating multiple environmental exposures simultaneously during critical periods of life. Objective: We evaluated the association of the urban exposome with birth weight. Methods: We estimated exposure to the urban exposome, including the built environment, air pollution, road traffic noise, meteorology, natural space, and road traffic (corresponding to 24 environmental indicators and 60 exposures) for nearly 32,000 pregnant women from six European birth cohorts. To evaluate associations with either continuous birth weight or term low birth weight (TLBW) risk, we primarily relied on the Deletion-Substitution-Addition (DSA) algorithm, which is an extension of the stepwise variable selection method. Second, we used an exposure-by-exposure exposome-wide association studies (ExWAS) method accounting for multiple hypotheses testing to report associations not adjusted for coexposures. Results: The most consistent statistically significant associations were observed between increasing green space exposure estimated as Normalized Difference Vegetation Index (NDVI) and increased birth weight and decreased TLBW risk. Furthermore, we observed statistically significant associations among presence of public bus line, land use Shannon's Evenness Index, and traffic density and birth weight in our DSA analysis. Conclusion: This investigation is the first large urban exposome study of birth weight that tests many environmental urban exposures. It confirmed previously reported associations for NDVI and generated new hypotheses for a number of built-environment exposures. ; The study has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under Grant Agreement No. 308333—the HELIX project—for data collection and analyses. The HELIX program built on six existing cohorts that received previous funding, including the major cohorts listed here. INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, the Conselleria de Sanitat, Generalitat Valenciana, Department of Health of the Basque Government; the Provincial Government of Gipuzkoa, 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). MoBa (Norwegian Mother and Child Cohort Study) is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (Contract No. N01-ES-75558), and the U.S. National Institutes of Health (NIH) National Institute of Environmental Health Sciences (NIEHS; Contract No. N01-ES-75558), and National Institute of Neurological Disorders and Stroke (Grant No. 1 UO1 NS 047537-01 and Grant No. 2 UO1 NS 047537-06A1). 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, EUFP7-HEALTH-2012 Proposal No. 308333 HELIX, FP7 European Union Project No. 264357 MeDALL), 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). L.C. received additional funding from the Southern California Environmental Health Sciences Center (Grant No. P30ES007048) funded by NIEHS. We acknowledge the support of the program for international scientific collaborations of Région Rhône-Alpes-Auvergne.

Characterization of the "exposome", the set of all environmental factors that one is exposed to from conception onwards, has been advocated to better understand the role of environmental factors on chronic diseases. Here, we aimed to describe the early-life exposome. Specifically, we focused on the correlations between multiple environmental exposures, their patterns and their variability across European regions and across time (pregnancy and childhood periods). We relied on the Human Early-Life Exposome (HELIX) project, in which 87 environmental exposures during pregnancy and 122 during the childhood period (grouped in 19 exposure groups) were assessed in 1301 pregnant mothers and their children at 6-11 years in 6 European birth cohorts. Some correlations between exposures in the same exposure group reached high values above 0.8. The median correlation within exposure groups was >0.3 for many exposure groups, reaching 0.69 for water disinfection by products in pregnancy and 0.67 for the meteorological group in childhood. Median correlations between different exposure groups rarely reached 0.3. Some correlations were driven by cohort-level associations (e.g. air pollution and chemicals). Ten principal components explained 45% and 39% of the total variance in the pregnancy and childhood exposome, respectively, while 65 and 90 components were required to explain 95% of the exposome variability. Correlations between maternal (pregnancy) and childhood exposures were high (>0.6) for most exposures modeled at the residential address (e.g. air pollution), but were much lower and even close to zero for some chemical exposures. In conclusion, the early life exposome was high dimensional, meaning that it cannot easily be measured by or reduced to fewer components. Correlations between exposures from different exposure groups were much lower than within exposure groups, which have important implications for co-exposure confounding in multiple exposure studies. Also, we observed the early life exposome to be variable over time and to vary by cohort, so measurements at one time point or one place will not capture its complexities. ; This work was supported by the European Commission Seventh Framework Programme (FP7/2007–2013) [grant number: 308333–the HELIX project]. 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 and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537-01 and grant no.2 UO1 NS 047537-06A1). 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, EUFP7-HEALTH-2012 Proposal No 308333 HELIX, FP7 European Union project, No. 264357 MeDALL), 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).

Exposure to environmental pollutants, particularly during pregnancy, can have adverse consequences on child development but little is known about the effects of pollutant mixtures on endogenous metabolism in pregnant women. We aimed to identify urinary metabolic signatures associated with low level exposure to multiple environmental pollutants in pregnant women from the INMA (INfancia y Medio Ambiente) birth cohort (Spain, N = 750). 35 chemical exposures were quantified in first trimester blood samples (organochlorine pesticides, PCBs, PFAS), in cord blood (mercury), and twice in urine at 12 and 32 weeks of pregnancy (metals, phthalates, bisphenol A). 1H nuclear magnetic resonance (NMR) metabolic profiles of urine were acquired in the same samples as pollutants. We explored associations between exposures and metabolism through an exposome-metabolome wide association scan and multivariate O2PLS modeling. Novel and reproducible associations were found across two periods of pregnancy for three nonpersistent pollutants and across two subcohorts for four of the persistent pollutants. We found novel metabolic signatures associated with arsenic exposure: TMAO and dimethylamine possibly related to gut microbial methylamine metabolism and homarine related to fish intake. Tobacco smoke exposure was related to coffee metabolism and PCBs with 3-hydroxyvaleric acid, usually released under ketoacidosis. These findings will have implications for further understanding of maternal-fetal health, and health across the life-course. ; This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 308333–the HELIX project, the Medical Research Council Integrative Toxicology Training Partnership (ITTP) through a PhD studentship (recipient LM), an MRC-ITTP career development fellowship (recipient MC), an MRC early career fellowship (recipient OR), and the Medical Research Council–Public Health England (MRC-PHE) Centre for Environment and Health (MR/L01341X/1). The subcohort studies were funded by grants from Instituto de Salud Carlos III (Red INMA G03/176, FIS-PI06/0867, FIS-PS09/00090 and FIS-PI13/02187), Generalitat de Catalunya-CIRIT 1999SGR 00241, Department of Health of the Basque Government (2005111093, 2009111069, and 2013111089), and the Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001). Convenios anuales con los ayuntamientos de la zona del estudio (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). We thank Olivier Cloarec and Ekaterina (Katya) Nevedomskaya for developing the in-house script to perform O2PLS models.

Introduction: Early onset and high prevalence of allergic diseases result in high individual and socio-economic burdens. Several studies provide evidence for possible effects of environmental factors on allergic diseases, but these are mainly single-exposure studies. The exposome provides a novel holistic approach by simultaneously studying a large set of exposures. The aim of the study was to evaluate the association between a broad range of prenatal and childhood environmental exposures and allergy-related outcomes in children. Material and methods: Analyses of associations between 90 prenatal and 107 childhood exposures and allergy-related outcomes (last 12 months: rhinitis and itchy rash; ever: doctor-diagnosed eczema and food allergy) in 6-11 years old children (n = 1270) from the European Human Early-Life Exposome cohort were performed. Initially, we used an exposome-wide association study (ExWAS) considering the exposures independently, followed by a deletion-substitution-addition selection (DSA) algorithm considering all exposures simultaneously. All the exposure variables selected in the DSA were included in a final multi-exposure model using binomial general linear model (GLM). Results: In ExWAS, no exposures were associated with the outcomes after correction for multiple comparison. In multi-exposure models for prenatal exposures, lower distance of residence to nearest road and higher di-iso-nonyl phthalate level were associated with increased risk of rhinitis, and particulate matter absorbance (PMabs) was associated with a decreased risk. Furthermore, traffic density on nearest road was associated with increased risk of itchy rash and diethyl phthalate with a reduced risk. DSA selected no associations of childhood exposures, or between prenatal exposures and eczema or food allergy. Discussion: This first comprehensive and systematic analysis of many environmental exposures suggests that prenatal exposure to traffic-related variables, PMabs and phthalates are associated with rhinitis and itchy rash. ; This work was supported by the European Community's Seventh Framework Programme [grant agreement no 308333—the HELIX project]; Instituto de Salud Carlos III; CIBERESP; Conselleria de Sanitat; Generalitat Valenciana; Department of Health of the Basque Government; Provincial Government of Gipuzkoa; Generalitat de Catalunya-CIRIT; Lithuanian Agency for Science Innovation and Technology [grant number 6-04-2014_31V-66]; Norwegian Ministry of Health and Care Services; Norwegian Ministry of Education and Research; Greek Ministry of Health; Ministerio de Ciencia Innovacion y Universidades [grant number MTM2015-68140-R]; Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII; Fondation de France.

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 age. ; The 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).

IMPORTANCE: The balance of mercury risk and nutritional benefit from fish intake during pregnancy for the metabolic health of offspring to date is unknown. OBJECTIVE: To assess the associations of fish intake and mercury exposure during pregnancy with metabolic syndrome in children and alterations in biomarkers of inflammation in children. DESIGN, SETTING, AND PARTICIPANTS: This population-based prospective birth cohort study used data from studies performed in 5 European countries (France, Greece, Norway, Spain, and the UK) between April 1, 2003, and February 26, 2016, as part of the Human Early Life Exposome (HELIX) project. Mothers and their singleton offspring were followed up until the children were aged 6 to 12 years. Data were analyzed between March 1 and August 2, 2019. EXPOSURES: Maternal fish intake during pregnancy (measured in times per week) was assessed using validated food frequency questionnaires, and maternal mercury concentration (measured in micrograms per liter) was assessed using maternal whole blood and cord blood samples. MAIN OUTCOMES AND MEASURES: An aggregate metabolic syndrome score for children was calculated using the z scores of waist circumference, systolic and diastolic blood pressures, and levels of triglyceride, high-density lipoprotein cholesterol, and insulin. A higher metabolic syndrome score (score range, -4.9 to 7.5) indicated a poorer metabolic profile. Three protein panels were used to measure several cytokines and adipokines in the plasma of children. RESULTS: The study included 805 mothers and their singleton children. Among mothers, the mean (SD) age at cohort inclusion or delivery of their infant was 31.3 (4.6) years. A total of 400 women (49.7%) had a high educational level, and 432 women (53.7%) were multiparous. Among children, the mean (SD) age was 8.4 (1.5) years (age range, 6-12 years). A total of 453 children (56.3%) were boys, and 734 children (91.2%) were of white race/ethnicity. Fish intake consistent with health recommendations (1 to 3 times per week) during pregnancy was associated with a 1-U decrease in metabolic syndrome score in children (β = -0.96; 95% CI, -1.49 to -0.42) compared with low fish consumption (<1 time per week) after adjusting for maternal mercury levels and other covariates. No further benefit was observed with fish intake of more than 3 times per week. A higher maternal mercury concentration was independently associated with an increase in the metabolic syndrome score of their offspring (β per 2-fold increase in mercury concentration = 0.18; 95% CI, 0.01-0.34). Compared with low fish intake, moderate and high fish intake during pregnancy were associated with reduced levels of proinflammatory cytokines and adipokines in children. An integrated analysis identified a cluster of children with increased susceptibility to metabolic disease, which was characterized by low fish consumption during pregnancy, high maternal mercury levels, decreased levels of adiponectin in children, and increased levels of leptin, tumor necrosis factor α, and the cytokines interleukin 6 and interleukin 1β in children. CONCLUSIONS AND RELEVANCE: Results of this study suggest that moderate fish intake consistent with current health recommendations during pregnancy was associated with improvements in the metabolic health of children, while high maternal mercury exposure was associated with an unfavorable metabolic profile in children. ; This study was supported by grant 308333 from the European Community Seventh Framework Programme; grant 874583 from the European Union Horizon 2020 Research and Innovation Programme; grant SEV-2012-0208 from the Centro de Excelencia Severo Ochoa 2013-2017, Spanish Ministry of Science, Innovation and Universities; grant 2017SGR595 from the Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya; grant CB06/021/0041 from the Consorcio de Investigación Biomedica en Red de Epidemiologia y Salud Publica; grant 1999SGR00241 from the Comissió Interdepartamental de Recerca i Innovació Tecnologica, Generalitat de Catalunya; grant 31V-66 from the Lithuanian Agency for Science Innovation and Technology; grant PT17/0019 via the Plan Estatal de I+D+I 2013- 2016 project from the Instituto de Salud Carlos III and the European Regional Development Fund; grants R21 ES029681 and P30 ES007048-23 from the National Institute for Health Sciences (Dr Stratakis); grant P30 DK048522-24 from the National Institute of Diabetes and Digestive and Kidney Diseases (Dr Stratakis); grants P01CA196569, R01CA140561, and R01 ES016813 from the National Institute for Health Sciences (Dr Conti); grant MS16/00128 from the Ministry of Economy and Competitiveness at the Instituto de Salud Carlos III (Dr Casas); grants R21 ES029681, P30 ES007048-23, and P01 ES022845 from the National Institute for Health Sciences (Dr McConnell); grant RD-83544101 from the Environmental Protection Agency (Dr McConnell); and grants R01 ES029944, R21 ES029681, R21 ES028903, and P30 ES007048-23 from the National Institute for Health Sciences (Dr Chatzi)

Background: Several single-exposure studies have documented possible effects of environmental factors on lung function, but none has relied on an exposome approach. We aimed to evaluate the association between a broad range of prenatal and postnatal lifestyle and environmental exposures and lung function in children. Methods: In this analysis, we used data from 1033 mother–child pairs from the European Human Early-Life Exposome (HELIX) cohort (consisting of six existing longitudinal birth cohorts in France, Greece, Lithuania, Norway, Spain, and the UK of children born between 2003 and 2009) for whom a valid spirometry test was recorded for the child. 85 prenatal and 125 postnatal exposures relating to outdoor, indoor, chemical, and lifestyle factors were assessed, and lung function was measured by spirometry in children at age 6–12 years. Two agnostic linear regression methods, a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering exposures independently, were applied to test the association with forced expiratory volume in 1 s percent predicted values (FEV1%). We tested for two-way interaction between exposures and corrected for confounding by co-exposures. Findings: In the 1033 children (median age 8·1 years, IQR 6·5–9·0), mean FEV1% was 98·8% (SD 13·2). In the ExWAS, prenatal perfluorononanoate (p=0·034) and perfluorooctanoate (p=0·030) exposures were associated with lower FEV1%, and inverse distance to nearest road during pregnancy (p=0·030) was associated with higher FEV1%. Nine postnatal exposures were associated with lower FEV1%: copper (p=0·041), ethyl-paraben (p=0·029), five phthalate metabolites (mono-2-ethyl 5-carboxypentyl phthalate [p=0·016], mono-2-ethyl-5-hydroxyhexyl phthalate [p=0·023], mono-2-ethyl-5-oxohexyl phthalate [p=0·0085], mono-4-methyl-7-oxooctyl phthalate [p=0·040], and the sum of di-ethylhexyl phthalate metabolites [p=0·014]), house crowding (p=0·015), and facility density around schools (p=0·027). However, no exposure passed the significance threshold when corrected for multiple testing in ExWAS, and none was selected with the DSA algorithm, including when testing for exposure interactions. Interpretation: Our systematic exposome approach identified several environmental exposures, mainly chemicals, that might be associated with lung function. Reducing exposure to these ubiquitous chemicals could help to prevent the development of chronic respiratory disease. Funding: European Community's Seventh Framework Programme (HELIX project). ; The study has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement number 308333—the HELIX project—for data collection and analyses. The HELIX program built on six existing cohorts that received previous funding, including the major cohorts listed here. MoBa (Norwegian Mother and Child Cohort Study) is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, and the US National Institutes of Health (NIH) National Institute of Environmental Health Sciences (NIEHS; contract number N01-ES-75558), and National Institute of Neurological Disorders and Stroke (grant number 1 UO1 NS 047537–01 and grant number 2 UO1 NS 047537–06A1). The RHEA project was financially supported by European Union 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 number 226285 ENRIECO, EUFP7-HEALTH-2012 proposal number 308333 HELIX, FP7 European Union project, number 264357 MeDALL), and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, Heraklion district, Crete, Greece: 2011–14; "RHEA Plus": Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–15). LC received additional funding from the Southern California Environmental Health Sciences Center (grant number P30ES007048) funded by NIEHS.

Polymorphic genomic inversions are chromosomal variants with intrinsic variability that play important roles in evolution, environmental adaptation, and complex traits. We investigated the DNA methylation patterns of three common human inversions, at 8p23.1, 16p11.2, and 17q21.31 in 1,009 blood samples from children from the Human Early Life Exposome (HELIX) project and in 39 prenatal heart tissue samples. We found inversion-state specific methylation patterns within and nearby flanking each inversion region in both datasets. Additionally, numerous inversion-exposure interactions on methylation levels were identified from early-life exposome data comprising 64 exposures. For instance, children homozygous at inv-8p23.1 and higher meat intake were more susceptible to TDH hypermethylation (P = 3.8 × 10-22); being the inversion, exposure, and gene known risk factors for adult obesity. Inv-8p23.1 associated hypermethylation of GATA4 was also detected across numerous exposures. Our data suggests that the pleiotropic influence of inversions during development and lifetime could be substantially mediated by allele-specific methylation patterns which can be modulated by the exposome. ; The study has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement no 308333 (HELIX project), and the H2020-EU.3.1.2.—Preventing Disease Programme under grant agreement no 874583 (ATHLETE project). The HELIX genotyping was supported by the projects PI17/01225 and PI17/01935, funded by the Instituto de Salud Carlos III and cofunded 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 (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA-SAB data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de ...

Exposure to air pollution influences children's health, however, the biological mechanisms underlying these effects are not completely elucidated. We investigated the association between short- and medium-term outdoor air pollution exposure with protein profiles and their link with blood pressure in 1170 HELIX children aged 6-11 years. Different air pollutants (NO2, PM10, PM2.5, and PM2.5abs) were estimated based on residential and school addresses at three different windows of exposure (1-day, 1-week, and 1-year before clinical and molecular assessment). Thirty-six proteins, including adipokines, cytokines, or apolipoproteins, were measured in children's plasma using Luminex. Systolic and diastolic blood pressure (SBP and DBP) were measured following a standardized protocol. We performed an association study for each air pollutant at each location and time window and each outcome, adjusting for potential confounders. After correcting for multiple-testing, hepatocyte growth factor (HGF) and interleukin 8 (IL8) levels were positively associated with 1-week home exposure to some of the pollutants (NO2, PM10, or PM2.5). NO2 1-week home exposure was also related to higher SBP. The mediation study suggested that HGF could explain 19% of the short-term effect of NO2 on blood pressure, but other study designs are needed to prove the causal directionality between HGF and blood pressure. ; The 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). The study was supported by the European Union FP7 programmes ...

Background: The urban environment is characterised by many exposures that may influence hypertension development from early life onwards, but there is no systematic evaluation of their impact on child blood pressure (BP). Methods: Systolic and diastolic blood pressure were measured in 4,279 children aged 4-5 years from a multi-centre European cohort (France, Greece, Spain, and UK). Urban environment exposures were estimated during pregnancy and childhood, including air pollution, built environment, natural spaces, traffic, noise, meteorology, and socioeconomic deprivation index. Single- and multiple-exposure linear regression models and a cluster analysis were carried out. Results: In multiple exposure models, higher child BP, in particular diastolic BP, was observed in association with higher exposure to air pollution, noise and ambient temperature during pregnancy, and with higher exposure to air pollution and higher building density during childhood (e.g., mean change [95% confidence interval] for an interquartile range increase in prenatal NO2 = 0.7 mmHg[0.3;1.2]). Lower BP was observed in association with higher temperature and better street connectivity during childhood (e.g., temperature = -1.1[-1.6;-0.6]). Some of these associations were not robust in the sensitivity analyses. Mother-child pairs were grouped into six urban environment exposure clusters. Compared to the cluster representing the least harmful urban environment, the two clusters representing the most harmful environment (high in air pollution, traffic, noise, and low in green space) were both associated with higher diastolic BP (1.3[0.1;2.6] and 1.5[0.5;2.5]). Conclusion: This first large systematic study suggests that living in a harmful urban environment may impact BP regulation in children. These findings reinforce the importance of designing cities that promote healthy environments to reduce long-term risk of hypertension and other cardiovascular diseases. ; This work was supported by funding from the European Community's Seventh Framework Programme [FP7/2007–206 n°308333; the HELIX project], and by the European Union's Horizon 2020 research and innovation programme [H2020 n°733206; the LifeCycle project]. CW holds a Sara Borrell fellowship from the Instituto de Salud Carlos III [CD18/00132]. INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya- CIRIT (Spain). The Rhea project was financially supported by European projects, 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). The work was also supported by MICINN [MTM2015-68140-R] and Centro Nacional de Genotipado- CEGEN- PRB2- ISCIII (Spain). This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber (UK). Core support for Born in Bradford is also provided by the Wellcome Trust (WT101597MA, UK). The EDEN study was supported by Foundation for medical research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR cohorte santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A), and Human Nutrition National Research Programs, Paris-Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the European Union FP7 programmes (ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients (AFD)), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l'Education Nationale a complementary health insurance (MGEN), French national agency for food security, French-speaking association for the study of diabetes and metabolism (ALFEDIAM).

Background: Environmental exposures in early life influence the development of behavioral outcomes in children, but research has not considered multiple exposures. We therefore aimed to investigate the impact of a broad spectrum of pre- and postnatal environmental exposures on child behavior. Methods and findings: We used data from the HELIX (Human Early Life Exposome) project, which was based on six longitudinal population-based birth cohorts in Europe. At 6-11 years, children underwent a follow-up to characterize their exposures and assess behavioral problems. We measured 88 prenatal and 123 childhood environmental factors, including outdoor, indoor, chemical, lifestyle and social exposures. Parent-reported behavioral problems included (1) internalizing, (2) externalizing scores, using the child behavior checklist (CBCL), and (3) the Conner's Attention Deficit Hyperactivity Disorder (ADHD) index, all outcomes being discrete raw counts. We applied LASSO penalized negative binomial regression models to identify which exposures were associated with the outcomes, while adjusting for co-exposures. In the 1287 children (mean age 8.0 years), 7.3% had a neuropsychiatric medical diagnosis according to parent's reports. During pregnancy, smoking and car traffic showing the strongest associations (e.g. smoking with ADHD index, aMR:1.31 [1.09; 1.59]) among the 13 exposures selected by LASSO, for at least one of the outcomes. During childhood, longer sleep duration, healthy diet and higher family social capital were associated with reduced scores whereas higher exposure to lead, copper, indoor air pollution, unhealthy diet were associated with increased scores. Unexpected decreases in behavioral scores were found with polychlorinated biphenyls (PCBs) and organophosphate (OP) pesticides. Conclusions: Our systematic exposome approach identified several environmental contaminants and healthy lifestyle habits that may influence behavioral problems in children. Modifying environmental exposures early in life may limit lifetime mental health risk. ; The LIFE-CYCLE project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 733206.

Background: Multiple omics technologies are increasingly applied to detect early, subtle molecular responses to environmental stressors for future disease risk prevention. However, there is an urgent need for further evaluation of stability and variability of omics profiles in healthy individuals, especially during childhood. Methods: We aimed to estimate intra-, inter-individual and cohort variability of multi-omics profiles (blood DNA methylation, gene expression, miRNA, proteins and serum and urine metabolites) measured 6 months apart in 156 healthy children from five European countries. We further performed a multi-omics network analysis to establish clusters of co-varying omics features and assessed the contribution of key variables (including biological traits and sample collection parameters) to omics variability. Results: All omics displayed a large range of intra- and inter-individual variability depending on each omics feature, although all presented a highest median intra-individual variability. DNA methylation was the most stable profile (median 37.6% inter-individual variability) while gene expression was the least stable (6.6%). Among the least stable features, we identified 1% cross-omics co-variation between CpGs and metabolites (e.g. glucose and CpGs related to obesity and type 2 diabetes). Explanatory variables, including age and body mass index (BMI), explained up to 9% of serum metabolite variability. Conclusions: Methylation and targeted serum metabolomics are the most reliable omics to implement in single time-point measurements in large cross-sectional studies. In the case of metabolomics, sample collection and individual traits (e.g. BMI) are important parameters to control for improved comparability, at the study design or analysis stage. This study will be valuable for the design and interpretation of epidemiological studies that aim to link omics signatures to disease, environmental exposures, or both. ; The study has received funding from the European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 (HELIX project) and the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (ATHLETE project). Additionally, BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (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 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). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I+D+i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We acknowledge support from the Spanish Ministry of Science and Innovation and State Research Agency through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. 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) (MS16/00128). LM is funded by a Juan de la Cierva-Incorporación fellowship (IJC2018-035394-I) awarded by the Spanish Ministerio de Economía, Industria y Competitividad.

Telomere length is considered a biomarker of biological aging. Shorter telomeres and obesity have both been associated with age-related diseases. To evaluate the association between various indices of obesity with leukocyte telomere length (LTL) in childhood, data from 1,396 mother-child pairs of the multi-centre European birth cohort study HELIX were used. Maternal pre-pregnancy body mass index (BMI) and 4 adiposity markers in children at age 8 (6-11) years were assessed: BMI, fat mass, waist circumference, and skinfold thickness. Relative LTL was obtained. Associations of LTL with each adiposity marker were calculated using linear mixed models with a random cohort effect. For each 1 kg/m² increment in maternal pre-pregnancy BMI, the child's LTL was 0.23% shorter (95%CI: 0.01,0.46%). Each unit increase in child BMI z-score was associated with 1.21% (95%CI: 0.30,2.11%) shorter LTL. Inverse associations were observed between waist circumference and LTL (-0.96% per z-score unit; 95%CI: -2.06,0.16%), and skinfold thickness and LTL (-0.10% per z-score unit; 95%CI: -0.23,0.02%). In conclusion, this large multicentric study suggests that higher child adiposity indicators are associated with short telomeres in children, and that associations are stronger for child BMI than for maternal pre-pregnancy BMI. ; This work was supported by the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement no 308333 – the HELIX project. INMA data collection was supported by grant C/ from the Instituto de Salud Carlos III. This project has received funding from the European Union's Horizon 2020 research and innovation program under Grant Agreement No 774548. Tim S. Nawrot was funded by the EU Program "Ideas" (ERC-2012-StG 310898). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. We are grateful to all the participating families in the six countries who took part in this study.

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 age ; The 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) ...