Early Life Exposome Research Articles

Multiple environmental exposures in early-life and allergy-related outcomes in childhood

IntroductionEarly 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 MethodsAnalyses 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). ResultsIn 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. DiscussionThis 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.

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

BackgroundThe 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.MethodsWe 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.ResultsMaternal 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.ConclusionIn 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.

Early-Life Environmental Exposures and Childhood Obesity: An Exposome-Wide Approach.

Background:Chemical and nonchemical environmental exposures are increasingly suspected to influence the development of obesity, especially during early life, but studies mostly consider single exposure groups.Objectives:Our study aimed to systematically assess the association between a wide array of early-life environmental exposures and childhood obesity, using an exposome-wide approach.Methods:The HELIX (Human Early Life Exposome) study measured child body mass index (BMI), waist circumference, skinfold thickness, and body fat mass in 1,301 children from six European birth cohorts age 6–11 y. We estimated 77 prenatal exposures and 96 childhood exposures (cross-sectionally), including indoor and outdoor air pollutants, built environment, green spaces, tobacco smoking, and biomarkers of chemical pollutants (persistent organic pollutants, metals, phthalates, phenols, and pesticides). We used an exposure-wide association study (ExWAS) to screen all exposure–outcome associations independently and used the deletion-substitution-addition (DSA) variable selection algorithm to build a final multiexposure model.Results:The prevalence of overweight and obesity combined was 28.8%. Maternal smoking was the only prenatal exposure variable associated with higher child BMI (z-score increase of 0.28, 95% confidence interval: 0.09, 0.48, for active vs. no smoking). For childhood exposures, the multiexposure model identified particulate and nitrogen dioxide air pollution inside the home, urine cotinine levels indicative of secondhand smoke exposure, and residence in more densely populated areas and in areas with fewer facilities to be associated with increased child BMI. Child blood levels of copper and cesium were associated with higher BMI, and levels of organochlorine pollutants, cobalt, and molybdenum were associated with lower BMI. Similar results were found for the other adiposity outcomes.Discussion:This first comprehensive and systematic analysis of many suspected environmental obesogens strengthens evidence for an association of smoking, air pollution exposure, and characteristics of the built environment with childhood obesity risk. Cross-sectional biomarker results may suffer from reverse causality bias, whereby obesity status influenced the biomarker concentration. https://doi.org/10.1289/EHP5975

Deconstructing the Association of Early Life Exposome With Teen Suicidal Ideation: Evidence for Stress Inoculation Effect

Deconstructing the Association of Early Life Exposome With Teen Suicidal Ideation: Evidence for Stress Inoculation Effect

Metabolomics and adductomics of newborn bloodspots to retrospectively assess the early-life exposome.

Exposomics studies can measure health-relevant chemical exposures during a lifetime and estimate the 'internal' environment. However, sampling limitations make these features difficult to capture directly during the critical neonatal time period. We review the use of newborn dried bloodspots (DBS) archived from newborn screening programs for exposomic analysis in epidemiological children's health studies. Emerging 'omics technologies such as adductomics and metabolomics have been adapted for DBS analysis, and these technologies can now provide valuable etiological information on the complex interplay between exposures, biological response, and population phenotypes. Adductomics and metabolomics of DBS can provide robust measurements for retrospective epidemiological investigations. With extensive bioarchiving programs in the United States and other countries, DBS are poised to substantially aid epidemiological studies, particularly for rare and low-frequency childhood diseases and disorders.

Association of Fish Consumption and Mercury Exposure During Pregnancy With Metabolic Health and Inflammatory Biomarkers in Children

The balance of mercury risk and nutritional benefit from fish intake during pregnancy for the metabolic health of offspring to date is unknown. 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. 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. 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. 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. 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. 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.

Association between the pregnancy exposome and fetal growth.

Several environmental contaminants were shown to possibly influence fetal growth, generally from single exposure family studies, which are prone to publication bias and confounding by co-exposures. The exposome paradigm offers perspectives to avoid selective reporting of findings and to control for confounding by co-exposures. We aimed to characterize associations of fetal growth with the pregnancy chemical and external exposomes. Within the Human Early-Life Exposome project, 131 prenatal exposures were assessed using biomarkers and environmental models in 1287 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 measurement error and tested for exposure-exposure and sex-exposure interactions. The DSA model identified lead blood level, which was associated with a 97 g birth 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 favour of negative associations of lead, fine particulate matter concentration and absorbance with birth weight, and of a positive sex-specific association of parabens with birth weight in boys. No two-way interaction between exposure variables was identified. This first large-scale exposome study of fetal growth simultaneously considered >100 environmental exposures. Compared with 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.

P.275 Early life exposome pressure on later life immune fitness: a layman's perspective

The management of chronic cardiovascular diseases has evolved greatly in the last decades. Over the last thirty years, the management of acute coronary syndrome has improved, leading to an important lowering of the mortality in the acute phase of the event. Consequently, the optimal management of the secondary prevention of acute coronary syndrome has greatly evolved. Moreover, the increased number of pharmacological alternatives for patients affected by chronic heart failure and by non-valvular atrial fibrillation reserves a number of challenges for their correct management. Moreover, these diseases are without any reasonable doubt the largest contributor to global mortality in the present and will continue to be it in the future.The aim of this study was to provide the most updated information of the real-life drug use and their effectiveness. This review was performed to assess the potential knowledge gaps in the treatments of these diseases and to indicate potential perspective of pharmaco-epidemiological research in this area.

Early life tobacco exposure and children’s telomere length: The HELIX project

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 (<10 µg/L), exposed to secondhand smoke (SHS) (10–50 µg/L) and active smokers (>50 µg/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 µg/L non-detected, >3.03 µg/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 non-smoking, 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.

Early life exposome and allergy-related outcomes in children in the HELIX cohort

Early life exposome and allergy-related outcomes in children in the HELIX cohort

Normalizing Untargeted Periconceptional Urinary Metabolomics Data: A Comparison of Approaches.

Metabolomics studies of the early-life exposome often use maternal urine specimens to investigate critical developmental windows, including the periconceptional period and early pregnancy. During these windows changes in kidney function can impact urine concentration. This makes accounting for differential urinary dilution across samples challenging. Because there is no consensus on the ideal normalization approach for urinary metabolomics data, this study’s objective was to determine the optimal post-analytical normalization approach for untargeted metabolomics analysis from a periconceptional cohort of 45 women. Urine samples consisted of 90 paired pre- and post-implantation samples. After untargeted mass spectrometry-based metabolomics analysis, we systematically compared the performance of three common approaches to adjust for urinary dilution—creatinine adjustment, specific gravity adjustment, and probabilistic quotient normalization (PQN)—using unsupervised principal components analysis, relative standard deviation (RSD) of pooled quality control samples, and orthogonal partial least-squares discriminant analysis (OPLS-DA). Results showed that creatinine adjustment is not a reliable approach to normalize urinary periconceptional metabolomics data. Either specific gravity or PQN are more reliable methods to adjust for urinary concentration, with tighter quality control sample clustering, lower RSD, and better OPLS-DA performance compared to creatinine adjustment. These findings have implications for metabolomics analyses on urine samples taken around the time of conception and in contexts where kidney function may be altered.

探寻城市暴露的社会经济模式

Vol. 127, No. 3 论文导读Open Access探寻城市暴露的社会经济模式 Jori Lewis Jori Lewis Search for more papers by this author Published:15 July 2019CID: 034004https://doi.org/10.1289/EHP4807-zhView Article in:EnglishAboutSectionsPDF ToolsDownload CitationsTrack CitationsCopy LTI LinkHTMLPDF ShareShare onFacebookTwitterLinked InRedditEmail 与其他环境相比，城市的室外环境具有独特的条件。例如，它通常声音更大、空气污染水平更高、绿地更少。1 而且，城市暴露和相关风险在城市内部和城市之间并不是均匀分布，它们可能由家庭的社会或经济地位决定。最近发表在《环境与健康展望》(Environmental Health Perspectives)的一项研究评估了社会经济地位对城市暴露组的影响，包含了 6 个欧洲国家的孕妇在城市环境中经历的暴露总量。2“暴露组（exposome）”一词是由研究员 Christopher Wild 于 2005 年提出的，他将其定义为从胎儿期开始整个生命过程中的环境暴露，包括生活方式因素。3 暴露组概念相对较新，并提出了几种对它评估的方法。该概念旨在激励在流行病学研究中进行更全面的暴露评估，并投资开发新的暴露评估工具和方法。其中包括“组学”方法。4一篇新的论文阐述了在不同国家和城市环境暴露中，其风险因素和预测因子是如何变化的。例如，在美国地区的报告中较低的社会经济地位和较高的空气污染之间的关系一致，而与之相反的是，在欧洲的一些地方富裕群体中暴露率更高。Image: © LeoPatrizi/iStockphoto.该研究的第一作者、伦敦帝国理工学院（Imperial College London）MRC-PHE 环境与健康中心（Centre for Environment and Health）的研究员 Oliver Robinson 认为，这篇文章展示了一个新的城市环境流行病学框架。他说：“我们不再逐个察看[暴露]，而是同时察看多个暴露。” 这使得研究人员能够研究多次暴露的影响，并提高我们对疾病病因的理解。Robinson 说，这些室外因素中有许多是高度相关的，例如，空气污染水平与绿地的可用性和交通密度等因素有关。所以把它们放在一起考虑是很重要的。本文来源于人类早期生活暴露（Human Early Life Exposome，HELIX）项目，这是一项为期5年的合作，该项目汇集了欧洲9个城市的6项基于人群的出生队列研究，以研究暴露与儿童健康、福祉和早期发育之间的关系。5 它使用地理信息系统方法，通过获取家庭和学校的坐标，挖掘可用的市政数据，并使用建模来构建人们经历的暴露概况。他们追踪了近3万名孕妇的28项指标。布法罗大学公共卫生与健康专业学院（University at Buffalo School of Public Health and Health Professions）全球卫生倡议办公室主任 Lina Mu 表示，有了这么多的数据，本文可以帮助研究人员提高对多重环境暴露集体效应的视角。“我们开始讨论暴露组，但实际上要描述整个暴露的特征并不容易，” Mu 说，她没有参与这项研究。“本文提供了一个暴露组和健康结局分析的范例。”分析表明不同城市和社区的暴露程度不同，但很难找到一致的模式。Robinson 说：“这是环境特定的情况，每个国家的模式各不相同。”作者期望找到支持三重危险假说的结果，即贫困社区的人们更容易暴露于环境危害中、更容易生病，从而导致与环境因素有关的健康差异。在许多城市，研究结果确实支持这一假设。但在其他地方，如挪威的奥斯陆，情况恰恰相反，原因尚不清楚。希腊塞萨洛尼基亚里士多德大学（Aristotle University of Thessaloniki）化学工程副教授、多国暴露组项目—基于大规模人口调查的健康和环境协会（Health and Environment-wide Associations Based on Large Population Surveys，HEALS）的协调员 Denis Sarigiannis 表示：“还有更多的环境特定的情况需要考虑。”他说，对每个城市的不同社会和经济背景进行更深入、更多学科的研究可能会有所帮助，并能更好地解释为什么一些城市会遵循三重危险模式，而另一些城市则不会。“如果你在数据分析中没有把环境特定的因素考虑进去，那么你最终会得出相互矛盾的结论，” Sarigiannis 说。这一结论与英国布拉德福德市 (Bradford) 的三重危险相一致，该城市的数据显示，社会经济地位较低的孕妇更容易受到空气污染和噪音的影响，更不容易进入绿地空间。该研究的合著者、布拉德福德出生队列（Born in Bradford，BiB）的负责人 Rosie McEachan 说，BiB 的研究者们正在运用他们所学到的知识来改善受暴露相关不平等影响最大的社区。McEachan 说：“因为我们能够真正表明城市环境与健康和福祉之间的明确联系，这使我们能够与地方当局合作，试着去努力吸引投资，改变城市内部的状况。” BiB 团队正在研究改造公交车的举措，并在需要的地方设计更多的绿地。她说，这一切都是为了改善下一代生活面临的问题。Jori Lewis，居住在塞内加尔的达喀尔，撰写关于环境、农业和国际发展的文章。她目前正在编写一本关于西非花生早期历史的书。

Early-Life Environmental Exposures and Blood Pressure in Children

BackgroundGrowing evidence exists about the fetal and environmental origins of hypertension, but mainly limited to single-exposure studies. The exposome has been proposed as a more holistic approach by studying many exposures simultaneously. ObjectivesThis study aims to evaluate the association between a wide range of prenatal and postnatal exposures and blood pressure (BP) in children. MethodsSystolic and diastolic BP were measured among 1,277 children from the European HELIX (Human Early-Life Exposome) cohort aged 6 to 11 years. Prenatal (n = 89) and postnatal (n = 128) exposures include air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals, and lifestyles. Two methods adjusted for confounders were applied: an exposome-wide association study considering the exposures independently, and the deletion-substitution-addition algorithm considering all the exposures simultaneously. ResultsDecreases in systolic BP were observed with facility density (β change for an interquartile-range increase in exposure: −1.7 mm Hg [95% confidence interval (CI): −2.5 to −0.8 mm Hg]), maternal concentrations of polychlorinated biphenyl 118 (−1.4 mm Hg [95% CI: −2.6 to −0.2 mm Hg]) and child concentrations of dichlorodiphenyldichloroethylene (DDE: −1.6 mm Hg [95% CI: −2.4 to −0.7 mm Hg]), hexachlorobenzene (−1.5 mm Hg [95% CI: −2.4 to −0.6 mm Hg]), and mono−benzyl phthalate (−0.7 mm Hg [95% CI: −1.3 to −0.1 mm Hg]), whereas increases in systolic BP were observed with outdoor temperature during pregnancy (1.6 mm Hg [95% CI: 0.2 to 2.9 mm Hg]), high fish intake during pregnancy (2.0 mm Hg [95% CI: 0.4 to 3.5 mm Hg]), maternal cotinine concentrations (1.2 mm Hg [95% CI: -0.3 to 2.8 mm Hg]), and child perfluorooctanoate concentrations (0.9 mm Hg [95% CI: 0.1 to 1.6 mm Hg]). Decreases in diastolic BP were observed with outdoor temperature at examination (−1.4 mm Hg [95% CI: −2.3 to −0.5 mm Hg]) and child DDE concentrations (−1.1 mm Hg [95% CI: −1.9 to −0.3 mm Hg]), whereas increases in diastolic BP were observed with maternal bisphenol-A concentrations (0.7 mm Hg [95% CI: 0.1 to 1.4 mm Hg]), high fish intake during pregnancy (1.2 mm Hg [95% CI: −0.2 to 2.7 mm Hg]), and child copper concentrations (0.9 mm Hg [95% CI: 0.3 to 1.6 mm Hg]). ConclusionsThis study suggests that early-life exposure to several chemicals, as well as built environment and meteorological factors, may affect BP in children.

Prenatal and Childhood Traffic-Related Air Pollution Exposure and Telomere Length in European Children: The HELIX Project.

Background:Telomere length is a molecular marker of biological aging.Objective:Here we investigated whether early-life exposure to residential air pollution was associated with leukocyte telomere length (LTL) at 8 y of age.Methods:In a multicenter European birth cohort study, HELIX (Human Early Life Exposome) (), we estimated prenatal and 1-y childhood exposure to nitrogen dioxide (), particulate matter with aerodynamic diameter (), and proximity to major roads. Average relative LTL was measured using quantitative real-time polymerase chain reaction (qPCR). Effect estimates of the association between LTL and prenatal, 1-y childhood air pollution, and proximity to major roads were calculated using multiple linear mixed models with a random cohort effect and adjusted for relevant covariates.Results:LTL was inversely associated with prenatal and 1-y childhood and exposures levels. Each standard deviation (SD) increase in prenatal was associated with a (95% CI: , ) change in LTL. Prenatal was nonsignificantly associated with LTL ( per SD increase; 95% CI: , 0.6). For each SD increment in 1-y childhood and exposure, LTL shortened by (95% CI: , ) and (95% CI: , 0.1), respectively. Each doubling in residential distance to nearest major road during childhood was associated with a 1.6% (95% CI: 0.02, 3.1) lengthening in LTL.Conclusion:Lower exposures to air pollution during pregnancy and childhood were associated with longer telomeres in European children at 8 y of age. These results suggest that reductions in traffic-related air pollution may promote molecular longevity, as exemplified by telomere length, from early life onward. https://doi.org/10.1289/EHP4148

Early-life exposome and lung function in children in Europe: an analysis of data from the longitudinal, population-based HELIX cohort

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. 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. 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. 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. European Community's Seventh Framework Programme (HELIX project).

Epigenetic and Neurological Impairments Associated with Early Life Exposure to Persistent Organic Pollutants.

The incidence of neurodevelopmental and neurodegenerative diseases worldwide has dramatically increased over the last decades. Although the aetiology remains uncertain, evidence is now growing that exposure to persistent organic pollutants during sensitive neurodevelopmental periods such as early life may be a strong risk factor, predisposing the individual to disease development later in life. Epidemiological studies have associated environmentally persistent organic pollutant exposure to brain disorders including neuropathies, cognitive, motor, and sensory impairments; neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD); and neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). In many ways, this expands the classical “Developmental Origins of Health and Disease” paradigm to include exposure to pollutants. This model has been refined over the years to give the current “three-hit” model that considers the individual's genetic factors as a first “hit.” It has an immediate interaction with the early-life exposome (including persistent organic pollutants) that can be considered to be a second “hit.” Together, these first two “hits” produce a quiescent or latent phenotype, most probably encoded in the epigenome, which has become susceptible to a third environmental “hit” in later life. It is only after the third “hit” that the increased risk of disease symptoms is crystallised. However, if the individual is exposed to a different environment in later life, they would be expected to remain healthy. In this review, we examine the effect of exposure to persistent organic pollutants and particulate matters in early life and the relationship to subsequent neurodevelopmental and neurodegenerative disorders. The roles of those environmental factors which may affect epigenetic DNA methylation and therefore influence normal neurodevelopment are then evaluated.

Exposure to phthalate metabolites, phenols and organophosphate pesticide metabolites and blood pressure during pregnancy.

Hypertensive disorders during pregnancy are one of the leading causes of maternal and offspring mortality and morbidity. Exposure to environmental chemicals is suspected to increase blood pressure (BP) but few studies have investigated the impact of non-persistent chemicals, in particular among pregnant women. Women included in the study were 152 volunteer participants in the Human Early-Life Exposome (HELIX) project. They provided 3 urine samples daily over one week in two pregnancy trimesters (at around 18 and 32 weeks of gestation) to assess their exposure to phthalates (10 metabolites), phenols (7 compounds) and organophosphate pesticides (4 metabolites). BP was measured at the end of the two collection weeks. Associations between biomarkers of exposure and BP were investigated using generalized estimating equations (GEE) and linear regression, and adjusted for potential confounders. A significant decrease in systolic and/or diastolic BP was observed with exposure to some phthalate metabolites, BPA, and parabens (e.g. β GEE models for systolic BP = -0.91 mmHg (95%CI: -1.65; -0.17) per doubling of BPA concentrations). These associations were more frequently observed in the second trimester of pregnancy and remained statistically significant after correction for multiple testing for BPA only. No associations were observed with organophosphate pesticides. This study investigates the effect of exposure to non-persistent chemicals assessed using multiple biospecimens per subject on BP during pregnancy and suggests that higher exposure to some phthalates and phenols but not pesticides is associated with lower BP during pregnancy.

The early-life exposome: Description and patterns in six European countries

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.

Determinants of the urinary and serum metabolome in children from six European populations

BackgroundEnvironment and diet in early life can affect development and health throughout the life course. Metabolic phenotyping of urine and serum represents a complementary systems-wide approach to elucidate environment–health interactions. However, large-scale metabolome studies in children combining analyses of these biological fluids are lacking. Here, we sought to characterise the major determinants of the child metabolome and to define metabolite associations with age, sex, BMI and dietary habits in European children, by exploiting a unique biobank established as part of the Human Early-Life Exposome project (http://www.projecthelix.eu).MethodsMetabolic phenotypes of matched urine and serum samples from 1192 children (aged 6–11) recruited from birth cohorts in six European countries were measured using high-throughput 1H nuclear magnetic resonance (NMR) spectroscopy and a targeted LC-MS/MS metabolomic assay (Biocrates AbsoluteIDQ p180 kit).ResultsWe identified both urinary and serum creatinine to be positively associated with age. Metabolic associations to BMI z-score included a novel association with urinary 4-deoxyerythronic acid in addition to valine, serum carnitine, short-chain acylcarnitines (C3, C5), glutamate, BCAAs, lysophosphatidylcholines (lysoPC a C14:0, lysoPC a C16:1, lysoPC a C18:1, lysoPC a C18:2) and sphingolipids (SM C16:0, SM C16:1, SM C18:1). Dietary-metabolite associations included urinary creatine and serum phosphatidylcholines (4) with meat intake, serum phosphatidylcholines (12) with fish, urinary hippurate with vegetables, and urinary proline betaine and hippurate with fruit intake. Population-specific variance (age, sex, BMI, ethnicity, dietary and country of origin) was better captured in the serum than in the urine profile; these factors explained a median of 9.0% variance amongst serum metabolites versus a median of 5.1% amongst urinary metabolites. Metabolic pathway correlations were identified, and concentrations of corresponding metabolites were significantly correlated (r > 0.18) between urine and serum.ConclusionsWe have established a pan-European reference metabolome for urine and serum of healthy children and gathered critical resources not previously available for future investigations into the influence of the metabolome on child health. The six European cohort populations studied share common metabolic associations with age, sex, BMI z-score and main dietary habits. Furthermore, we have identified a novel metabolic association between threonine catabolism and BMI of children.

In-utero and childhood chemical exposome in six European mother-child cohorts

BackgroundHarmonized data describing simultaneous exposure to a large number of environmental contaminants in-utero and during childhood is currently very limited. ObjectivesTo characterize concentrations of a large number of environmental contaminants in pregnant women from Europe and their children, based on chemical analysis of biological samples from mother-child pairs. MethodsWe relied on the Early-Life Exposome project, HELIX, a collaborative project across six established population-based birth cohort studies in Europe. In 1301 subjects, biomarkers of exposure to 45 contaminants (i.e. organochlorine compounds, polybrominated diphenyl ethers, per- and polyfluoroalkyl substances, toxic and essential elements, phthalate metabolites, environmental phenols, organophosphate pesticide metabolites and cotinine) were measured in biological samples from children (6–12 years) and their mothers during pregnancy, using highly sensitive biomonitoring methods. ResultsMost of the exposure biomarkers had high detection frequencies in mothers (35 out of 45 biomarkers with >90% detected) and children (33 out of 45 biomarkers with >90% detected). Concentrations were significantly different between cohorts for all compounds, and were generally higher in maternal compared to children samples. For most of the persistent compounds the correlations between maternal and child concentrations were moderate to high (Spearman Rho > 0.35), while for most non-persistent compounds correlations were considerably lower (Spearman Rho < 0.15). For mercury, PFOS and PFOA a considerable proportion of the samples of both mothers and their children exceeded the HBM I value established by The Human Biomonitoring Commission of the German Federal Environment Agency. DiscussionAlthough not based on a representative sample, our study suggests that children across Europe are exposed to a wide range of environmental contaminants in fetal life and childhood including many with potential adverse effects. For values exceeding the HBM I value identification of specific sources of exposure and reducing exposure in an adequate way is recommended. Considerable variability in this “chemical exposome” was seen between cohorts, showing that place of residence is a strong determinant of one's personal exposome. This extensive dataset comprising >100,000 concentrations of environmental contaminants in mother-child pairs forms a unique possibility for conducting epidemiological studies using an exposome approach.