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Individuals are exposed to environmental pollutants with endocrine disrupting activity (endocrine disruptors, EDCs) and the early stages of life are particularly susceptible to these exposures. Previous studies have focused on identifying molecular signatures associated with EDCs, but none have used repeated sampling strategy and integrated multiple omics. We aimed to identify multi-omic signatures associated with childhood exposure to non-persistent EDCs. We used data from the HELIX Child Panel Study, which included 156 children aged 6 to 11. Children were followed for one week, in two time periods. Twenty-two non-persistent EDCs (10 phthalate, 7 phenol, and 5 organophosphate pesticide metabolites) were measured in two weekly pools of 15 urine samples each. Multi-omic profiles (methylome, serum and urinary metabolome, proteome) were measured in blood and in a pool urine samples. We developed visit-specific Gaussian Graphical Models based on pairwise partial correlations. The visit-specific networks were then merged to identify reproducible associations. Independent biological evidence was systematically sought to confirm some of these associations and assess their potential health implications. 950 reproducible associations were found among which 23 were direct associations between EDCs and omics. For 9 of them, we were able to find corroborating evidence from previous literature: DEP - serotonin, OXBE - cg27466129, OXBE - dimethylamine, triclosan - leptin, triclosan - serotonin, MBzP - Neu5AC, MEHP - cg20080548, oh-MiNP - kynurenine, oxo-MiNP − 5-oxoproline. We used these associations to explore possible mechanisms between EDCs and health outcomes, and found links to health outcomes for 3 analytes: serotonin and kynurenine in relation to neuro-behavioural development, and leptin in relation to obesity and insulin resistance. This multi-omics network analysis at two time points identified biologically relevant molecular signatures related to non-persistent EDC exposure in childhood, suggesting pathways related to neurological and metabolic outcomes. The research leading to these results was supported by the European Community’s Seventh Framework Programme [FP7/2007–2013] under grant agreement no. 308333 [the HELIX project], and by the European Union’s Horizon 2020 research and innovation programme under grant agreements no. 874583 [ATHLETE], and no. 733032 [HBM4EU]. We acknowledge the input of the entire HELIX consortium. We are grateful to all the participating families in the five cohorts (BiB, EDEN, INMA, MoBa, KANC, and RHEA cohorts) that took part in this study. We are equally grateful to all the fieldworkers for their dedication and efficiency in this study. LM is funded by a Juan de la Cierva-Incorporación fellowship (IJC2018-035394-I) awarded by the Spanish Ministerio de Economía, Industria y Competitividad. ISGlobal acknowledges 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.

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 (FP7/ 2007–2013, HELIX, ESCAPE, ENRIECO, Medall projects). 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 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). MC received funding from Instituto Carlos III (Ministry of Economy and Competitiveness) (CD12/00563 and MS16/00128). JU is supported by Spanish regional program PERIS (Ref.: SLT017/20/ 000119) Granted by Departament de Salut de la Generalitat de Catalunya. The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is 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)

Background: Urban environmental design is increasingly considered influential for health and wellbeing, but evidence is mostly based on adults and single exposure studies. We evaluated the association between a wide range of urban environment characteristics and health behaviours in childhood. Methods: We estimated exposure to 32 urban environment characteristics (related to the built environment, traffic, and natural spaces) for home and school addresses of 1,581 children aged 6-11 years from six European cohorts. We collected information on health behaviours including total amount of overall moderate-to-vigorous physical activity, physical activity outside school hours, active transport, sedentary behaviours and sleep duration, and developed patterns of behaviours with principal component analysis. We used an exposure-wide association study to screen all exposure-outcome associations, and the deletion-substitution-addition algorithm to build a final multi-exposure model. Results: In multi-exposure models, green spaces (Normalized Difference Vegetation Index, NDVI) were positively associated with active transport, and inversely associated with sedentary time (22.71 min/day less (95 %CI -39.90, -5.51) per interquartile range increase in NDVI). Residence in densely built areas was associated with more physical activity and less sedentary time, and densely populated areas with less physical activity outside school hours and more sedentary time. Presence of a major road was associated with lower sleep duration (-4.80 min/day (95 %CI -9.11, -0.48); compared with no major road). Results for the behavioural patterns were similar. Conclusions: This multicohort study suggests that areas with more vegetation, more building density, less population density and without major roads are associated with improved health behaviours in childhood. The research leading to these results has received funding from the European Community's Seventh Framework Programme [FP7/2007–2013] under grant agreement no 308333 – the HELIX project, from the European Union’s Horizon 2020 research and innovation programme [Grant Agreement No. 733206 LifeCycle], and from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 774548 – STOP project (http://www.stopchildobesity.eu/). The STOP Consortium is coordinated by Imperial College London and includes 24 organisations across Europe, the United States and New Zealand. The content of this publication reflects only the views of the authors, and the European Commission is not liable for any use that may be made of the information it contains.

Telomere length and mitochondrial DNA content are considered biomarkers of cellular aging, oxidative stress, and inflammation, but there is almost no information on their association with tobacco smoke exposure in fetal and early life. The aim of this study was to assess whether prenatal and childhood tobacco exposure were associated with leukocyte telomere length (LTL) and mitochondrial DNA (mtDNA) content in children. As part of a multi-centre European birth cohort study HELIX (Human Early-Life Exposome) (n = 1396) we assessed maternal smoking status during pregnancy through questionnaires, and through urinary cotinine levels that were then used to classify women as not exposed to smoking (50 mu g/L). When the children were around 8 years of age (range: 5.4-12.0 years), childhood SHS tobacco smoke exposure was assessed through an extensive questionnaire and through measurements of urinary cotinine (3.03 mu g/L detected). Leukocyte mtDNA content and LTL were measured in the children at 8 years employing real time polymerase chain reaction (qPCR). Effect estimates were calculated using multivariate linear regression models for prenatal and childhood exposures adjusted for potential confounders. Maternal cotinine levels indicative of SHS exposure during pregnancy were associated with a decrease of 3.90% in LTL in children (95% CI: -6.68, -0.91), compared with nonsmoking, whereas the association for maternal cotinine levels indicative of active smoking did not reach statistical significance (-3.24%; 95% CI: -6.59, 0.21). Childhood SHS tobacco exposure was not associated with LTL in children. Global SHS exposure during childhood was associated with an increase of 3.51% (95% CI: 0.78, 6.27) in mtDNA content. Our findings suggest that tobacco smoke exposure during pregnancy, even at SHS levels, may accelerate telomere shortening in children and thus induce biological aging from an early age. (C) 2019 Elsevier B.V. All rights reserved.

Background: Several environmental contaminants were reported to possibly influence fetal growth, generally from single exposure family studies, which are prone to publication bias. The exposome paradigm offers perspectives to avoid selective reporting of findings and to control for confounding by co-exposures. Objectives: We aimed to assess the association of the pregnancy chemical and external exposomes with fetal growth. Methods: Within HELIX project, 131 prenatal exposures were assessed using biomarkers and environmental models in 1,287 mother-child pairs from six European cohorts. We investigated their associations with fetal growth using a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering each exposure independently. We corrected for exposure misclassification, and tested for exposure-exposure and sex-exposure interactions. Findings: Lead blood level was the only exposure associated with fetal growth in the DSA model (97g weight decrease for each doubling in lead concentration). No exposure passed the multiple testing-corrected significance threshold of ExWAS; without multiple testing correction, this model was in favor of a negative association of fine particulate matter concentration with birth weight; and of a positive sex-specific association of parabens with birth weight in boys only. No two-way interaction between exposure variables was identified. Interpretation: This first large-scale exposome study of fetal growth simultaneously considered over 100 environmental exposures. Compared to single exposure studies, our approach allowed making all tests (usually reported in successive publications) explicit. Lead exposure is still a health concern in Europe and parabens health effects warrant further investigation. Funding Statement: FP7/2007-2013, HELIX project (no 308333). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the relevant ethical committees from each country and an informed consent form was assigned from all participants, or the parents of the children.