Publications
100 results found
de Prado-Bert P, Ruiz-Arenas C, Vives-Usano M, et al., 2021, The early-life exposome and epigenetic age acceleration in children, Environment International, Vol: 155, ISSN: 0160-4120
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.
Stratakis N, Siskos AP, Papadopoulou E, et al., 2021, Urinary metabolic biomarkers of diet quality in European children are associated with metabolic health
<jats:title>Abstract</jats:title><jats:p>Urinary metabolic profiling is a promising powerful tool to reflect dietary intake and can help understand metabolic alterations in response to diet quality. Here, we used<jats:sup>1</jats:sup>H-NMR spectroscopy in a multi-country study in European children (1147 children from 6 different cohorts) and identified a common panel of 4 urinary metabolites (hippurate,<jats:italic>N</jats:italic>-methylnicotinic acid, urea and sucrose) that was predictive of Mediterranean diet adherence (KIDMED) and ultra-processed food (UPF) consumption and also had higher capacity in discriminating children’s diet quality than that of established sociodemographic determinants. Further, we showed that the identified metabolite panel also reflected the associations of these diet quality indicators with C-peptide, a stable and accurate marker of insulin resistance and future risk of metabolic disease. This methodology enables objective assessment of dietary patterns in European child populations, complementary to traditional questionary methods, and can be used in future studies to evaluate diet quality. Moreover, this knowledge can provide mechanistic evidence of common biological pathways that characterize healthy and unhealthy dietary patterns, and diet-related molecular alterations that could associate to metabolic disease.</jats:p>
Julvez J, Robinson O, 2021, Early life multiple exposures and child cognitive function: a multi-centric birth cohort study in six European countries, Environmental Pollution, Vol: 284, Pages: 1-11, ISSN: 0269-7491
Epidemiological studies mostly focus on single environmental exposures. This study aims to systematically assess associations between a wide range of prenatal and childhood environmental exposures and cognition. The study sample included data of 1298 mother-child pairs, children were 6–11 years-old, from six European birth cohorts. We measured 87 exposures during pregnancy and 122 cross-sectionally during childhood, including air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals and life styles. The measured cognitive domains were fluid intelligence (Raven's Coloured Progressive Matrices test, CPM), attention (Attention Network Test, ANT) and working memory (N-Back task). We used two statistical approaches to assess associations between exposure and child cognition: the exposome-wide association study (ExWAS) considering each exposure independently, and the deletion-substitution-addition algorithm (DSA) considering all exposures simultaneously to build a final multiexposure model. Based on this multiexposure model that included the exposure variables selected by ExWAS and DSA models, child organic food intake was associated with higher fluid intelligence (CPM) scores (beta = 1.18; 95% CI = 0.50, 1.87) and higher working memory (N-Back) scores (0.23; 0.05, 0.41), and child fast food intake (−1.25; −2.10, −0.40), house crowding (−0.39; −0.62, −0.16), and child environmental tobacco smoke (ETS) (−0.89; −1.42, −0.35), were all associated with lower CPM scores. Indoor PM2.5 exposure was associated with lower N-Back scores (−0.09; −0.16, −0.02). Additional associations in the unexpected direction were found: Higher prenatal mercury levels, maternal alcohol consumption and child higher perfluorooctane sulfonic acid (PFOS) levels were associated with better cognitive performance; and higher green exposure during pregnancy with lower cognitive performance. This fi
Stratakis N, Golden-Mason L, Margetaki K, et al., 2021, In utero exposure to mercury is associated with increased susceptibility to liver injury and inflammation in childhood, Hepatology, Vol: 74, Pages: 1546-1559, ISSN: 0270-9139
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of liver disease in children. Mercury (Hg), a ubiquitous toxic metal, has been proposed as an environmental factor contributing to toxicant‐associated fatty liver disease. We investigated the effect of prenatal exposure to Hg on childhood liver injury by combining epidemiological results from a multicenter mother‐child cohort with complementary in vitro experiments on monocyte cells that are known to play a key role in liver immune homeostasis and NAFLD. We used data from 872 mothers and their children (median age, 8.1 years; interquartile range [IQR], 6.5‐8.7) from the European Human Early‐Life Exposome (HELIX) cohort. We measured Hg concentration in maternal blood during pregnancy (median, 2.0 μg/L; IQR, 1.1‐3.6). We also assessed serum levels of alanine aminotransferase (ALT), a common screening tool for pediatric NAFLD, and plasma concentrations of inflammation‐related cytokines in children. We found that prenatal Hg exposure was associated with a phenotype in children that was characterized by elevated ALT (≥22.1 U/L for females and ≥25.8 U/L for males) and increased concentrations of circulating interleukin (IL)‐1β, IL‐6, IL‐8, and tumor necrosis factor α (TNF‐α). Consistently, inflammatory monocytes exposed in vitro to a physiologically relevant dose of Hg demonstrated significant up‐regulation of genes encoding these four cytokines and increased concentrations of IL‐8 and TNF‐α in the supernatants.Conclusion:These findings suggest that developmental exposure to Hg can contribute to inflammation and increased NAFLD risk in early life.
Wielscher M, Mandaviya P, Kuehnel B, et al., 2021, DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases
<jats:title>Abstract</jats:title> <jats:p>We performed a trans-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We found 1,511 independent differentially methylated loci associated with CRP. These CpG sites showed correlation structures across chromosomes, and were primarily situated in euchromatin, depleted in CpG islands and enriched in transcription factor binding sites and genomic enhancer regions. Mendelian randomisation analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis revealed obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we found that a fully activated CpG signature, meaning that if all novel discovered CpGs would either be fully methylated or unmethylated depending on their CRP associated direction of effect, the risk of myocardial infarction would be increased by 20.3%, risk of T2D by 11.3% and the risk of COPD by 5.6%.</jats:p>
Maitre L, Julvez J, López-Vicente M, et al., 2021, Early-life environmental exposure determinants of child behavior in Europe: a longitudinal, population-based study, Environment International, Vol: 153, ISSN: 0160-4120
BackgroundEnvironmental 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 findingsWe 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.ConclusionsOur systematic exposome approach identified several environmental contaminants and healthy lifestyle habits that may influence behavioral problems in children. Modifying
Handakas E, Keski-Rahkonen P, Chatzi L, et al., 2021, Cord blood metabolic signatures predictive of childhood overweight and rapid growth, International Journal of Obesity, Vol: 45, Pages: 2252-2260, ISSN: 0307-0565
INTRODUCTION:Metabolomics may identify biological pathways predisposing children to risk of overweight and obesity. In this study, we have investigated the cord blood metabolic signatures of rapid growth in infancy and overweight in early childhood in four European birth cohorts.METHODS:Untargeted liquid chromatography-mass spectrometry metabolomic profiles were measured in cord blood from 399 newborns from four European cohorts (ENVIRONAGE, Rhea, INMA and Piccolipiu). Rapid growth in the first year of life and overweight in childhood were defined with reference to WHO growth charts. Metabolome-wide association scans for rapid growth and overweight on over 4500 metabolic features were performed using multiple adjusted logistic mixed effect models and controlling the false discovery rate (FDR) at 5%. Additionally, we performed a look-up analysis of 43 pre-annotated metabolites, previously associated with birthweight or rapid growth. RESULTS:In the MWAS analysis, we identified three and eight metabolites associated with rapid growth and overweight respectively, after FDR correction. Higher levels of cholestenone, a cholesterol derivative produced by microbial catabolism, was predictive of rapid growth (p=1.6x10-3). Lower levels of the branched chain amino acid (BCAA) valine (p=8.6x10-6) was predictive of overweight in childhood. The area under the receiver operator curve for multivariate prediction models including these metabolites and traditional risk factors was 0.77 for rapid growth and 0.82 for overweight, compared to 0.69 and 0.69 respectively for models using traditional risk factors alone. Among the 43 pre-annotated metabolites, seven and five metabolites were nominally associated (P<0.05) with rapid growth and overweight respectively. The BCAA leucine, remained associated (1.6x 0-3) with overweight after FDR correction.CONCLUSION:The metabolites identified here may assist in the identification of children at risk of developing obesity and improve understa
McCartney DL, Min JL, Richmond RC, et al., 2021, Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging, Genome Biology, Vol: 22, ISSN: 1474-7596
Background:Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.Results:Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.Conclusion:This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
Robinson O, Lau C, 2021, DNA methylation age as a biomarker for cancer, International Journal of Cancer, Vol: 148, Pages: 2652-2663, ISSN: 0020-7136
Cancer is well established as an age‐associated disease, and there is substantial overlap in the molecular, cellular and physiological changes observed with both ageing and the progression of cancer. Age‐specific declines in resilience mechanisms such as DNA repair or epigenetic maintenance may contribute to the development of cancer. These declines may be assessed through biomarkers that measure biological age and through the related concept of “age acceleration”. Epigenetic clocks, assessed through DNA methylation levels, are among the most widely used biological age markers in cancer studies. In this review, we discuss the use of DNA methylation ageing measures to predict population cancer incidence, mortality and survival. Blood‐based DNA methylation age estimators appear to be promising measures of increased cancer risk and mortality, although their reported effects are generally weak, thus its clinical relevance remains to be validated in large case‐cohort and longitudinal studies. Future development of epigenetic and other biological age biomarkers will likely further elucidate the links between ageing and cancer.
Robinson O, Carter AR, Aola-Korpela M, et al., 2021, Metabolic profiles of socioeconomic position: a multi-cohort analysis, International Journal of Epidemiology, Vol: 50, Pages: 768-782, ISSN: 0300-5771
BackgroundLow socioeconomic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear. MethodsWe examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles, in approximately 30,000 adults and 4,000 children across ten UK and Finnish cohort studies. ResultsIn risk factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents), and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared to non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids.ConclusionsOur work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavorable metabolic profile, consistent across ages and cohorts. The metabolites we found associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities.
Maitre L, Bustamante M, Hernández-Ferrer C, et al., 2021, Multi-omics signatures of the human early life exposome
<jats:title>Summary</jats:title><jats:p>Environmental exposures during early life play a critical role in life-course health, yet the molecular phenotypes underlying environmental effects on health are poorly understood. In the Human Early Life Exposome (HELIX) project, a multi-centre cohort of 1,301 mother-child pairs, we associated individual exposomes consisting of >100 chemical, physical and lifestyle exposures assessed in pregnancy and childhood, with multi-omics profiles (methylome, transcriptome, metabolome and proteins) in childhood. We identified 1,170 associations, 249 in pregnancy and 921 in childhood, which revealed potential biological responses and sources of exposure. The methylome best captures the persistent influence of pregnancy exposures, including maternal smoking; while childhood exposures were associated with features from all omics layers, revealing novel signatures for indoor air quality, essential trace elements, endocrine disruptors and weather conditions. This study provides a unique resource (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://helixomics.isglobal.org/">https://helixomics.isglobal.org/</jats:ext-link>) to guide future investigation on the biological effects of the early life exposome.</jats:p>
Warembourg C, Nieuwenhuijsen M, Ballester F, et al., 2021, Urban environment during early-life and blood pressure in young children, Environment International, Vol: 146, ISSN: 0160-4120
BackgroundThe 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).MethodsSystolic 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.ResultsIn 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]).ConclusionThis 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.
Robinson O, Lau C, 2020, Measuring biological age using metabolomics, Aging, Vol: 12, Pages: 22352-22353, ISSN: 1945-4589
Laine JE, Bodinier B, Robinson O, et al., 2020, Prenatal exposure to multiple air pollutants, mediating molecular mechanisms, and shifts in birthweight., Environmental Science and Technology (Washington), Vol: 54, Pages: 14502-14513, ISSN: 0013-936X
Mechanisms underlying adverse birth and later in life health effects from exposure to air pollution during the prenatal period have not been not fully elucidated, especially in the context of mixtures. We assessed the effects of prenatal exposure to mixtures of air pollutants of particulate matter (PM), PM2.5, PM10, nitrogen oxides, NO2, NO x , ultrafine particles (UFP), and oxidative potential (OP) of PM2.5 on infant birthweight in four European birth cohorts and the mechanistic underpinnings through cross-omics of metabolites and inflammatory proteins. The association between mixtures of air pollutants and birthweight z-scores (standardized for gestational age) was assessed for three different mixture models, using Bayesian machine kernel regression (BKMR). We determined the direct effect for PM2.5, PM10, NO2, and mediation by cross-omic signatures (identified using sparse partial least-squares regression) using causal mediation BKMR models. There was a negative association with birthweight z-scores and exposure to mixtures of air pollutants, where up to -0.21 or approximately a 96 g decrease in birthweight, comparing the 75th percentile to the median level of exposure to the air pollutant mixture could occur. Shifts in birthweight z-scores from prenatal exposure to PM2.5, PM10, and NO2 were mediated by molecular mechanisms, represented by cross-omics scores. Interleukin-17 and epidermal growth factor were identified as important inflammatory responses underlyingair pollution-associated shifts in birthweight. Our results signify that by identifying mechanisms through which mixtures of air pollutants operate, the causality of air pollution-associated shifts in birthweight is better supported, substantiating the need for reducing exposure in vulnerable populations.
Granum B, Oftedal B, Agier L, et al., 2020, Multiple environmental exposures in early-life and allergy-related outcomes in childhood, Environment International, Vol: 144, Pages: 1-9, ISSN: 0160-4120
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
Robinson O, 2020, Prenatal exposure to perfluoroalkyl substances associated with increased susceptibility to liver Injury in children, Hepatology, Vol: 72, Pages: 1758-1770, ISSN: 0270-9139
Background and AimsPer‐ and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been shown to have hepatotoxic effects in animal models. However, human evidence is scarce. We evaluated how prenatal exposure to PFAS associates with established serum biomarkers of liver injury and alterations in serum metabolome in children.Approach and ResultsWe used data from 1,105 mothers and their children (median age, 8.2 years; interquartile range, 6.6‐9.1) from the European Human Early‐Life Exposome cohort (consisting of six existing population‐based birth cohorts in France, Greece, Lithuania, Norway, Spain, and the United Kingdom). We measured concentrations of perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate, perfluorohexane sulfonate, and perfluoroundecanoate in maternal blood. We assessed concentrations of alanine aminotransferase, aspartate aminotransferase, and gamma‐glutamyltransferase in child serum. Using Bayesian kernel machine regression, we found that higher exposure to PFAS during pregnancy was associated with higher liver enzyme levels in children. We also measured child serum metabolomics through a targeted assay and found significant perturbations in amino acid and glycerophospholipid metabolism associated with prenatal PFAS. A latent variable analysis identified a profile of children at high risk of liver injury (odds ratio, 1.56; 95% confidence interval, 1.21‐1.92) that was characterized by high prenatal exposure to PFAS and increased serum levels of branched‐chain amino acids (valine, leucine, and isoleucine), aromatic amino acids (tryptophan and phenylalanine), and glycerophospholipids (phosphatidylcholine [PC] aa C36:1 and Lyso‐PC a C18:1).ConclusionsDevelopmental exposure to PFAS can contribute to pediatric liver injury.
Vineis P, Chadeau M, Dagnino S, et al., 2020, What's new in the Exposome?, Environment International, Vol: 143, Pages: 1-13, ISSN: 0160-4120
The exposome concept refers to the totality of exposures from a variety of external and internal sources including chemical agents, biological agents, or radiation, from conception onward, over a complete lifetime. It encompasses also “psychosocial components” including the impact of social relations and socio-economic position on health. In this review we provide examples of recent contributions from exposome research, where we believe their application will be of the greatest value for moving forward. So far, environmental epidemiology has mainly focused on hard outcomes, such as mortality, disease exacerbation and hospitalizations. However, there are many subtle outcomes that can be related to environmental exposures, and investigations can be facilitated by an improved understanding of internal biomarkers of exposure and response, through the application of omic technologies. Second, though we have a wealth of studies on environmental pollutants, the assessment of causality is often difficult because of confounding, reverse causation and other uncertainties. Biomarkers and omic technologies may allow better causal attribution, for example using instrumental variables in triangulation, as we discuss here. Even more complex is the understanding of how social relationships (in particular socio-economic differences) influence health and imprint on the fundamental biology of the individual. The identification of molecular changes that are intermediate between social determinants and disease status is a way to fill the gap. Another field in which biomarkers and omics are relevant is the study of mixtures. Epidemiology often deals with complex mixtures (e.g. ambient air pollution, food, smoking) without fully disentangling the compositional complexity of the mixture, or with rudimentary approaches to reflect the overall effect of multiple exposures or components.From the point of view of disease mechanisms, most models hypothesize that several stages need t
Demetriou CA, Esposti DD, Fedinick KP, et al., 2020, The exposome and meet-in-the-middle as tools in addressing open questions in air pollution research, Publisher: OXFORD UNIV PRESS, Pages: V559-V559, ISSN: 1101-1262
Chadeau M, Alfano R, Ghantous A, et al., 2020, A multi-omic analysis of birthweight in newborn cord blood reveals new underlying mechanisms related to cholesterol metabolism, Metabolism: clinical and experimental, Vol: 110, Pages: 1-12, ISSN: 0026-0495
BackgroundBirthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited.MethodsTo investigate the systems biology of birthweight, we cross-sectionally integrated the methylome, the transcriptome, the metabolome and a set of inflammatory proteins measured in cord blood samples, collected from four birth-cohorts (n = 489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all other omic features via bipartite Pearson correlations.ResultsThis dataset revealed that the set of metabolome and methylome signatures of birthweight have seven signals in common, including three metabolites [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22). CCL22, a macrophage-derived chemokine has not been previously identified in relation to birthweight. Since the results of the omics integration indicated the central role of cholesterol metabolism, we explored the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n = 1097), finding that higher birthweight was associated with increased high-density lipoprotein cholesterol and that high-density lipoprotein cholesterol was lower in small versus large for gestational age newborns.ConclusionsOur data suggests that an integration of different omic-layers in addition to single omics studies is a useful approach to generate new hypotheses regarding biological mechanisms. CCL22 and cholesterol metabolism in cord blood play a mechanistic role in birthweight.
Robinson O, 2020, In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children, BMC Medicine, Vol: 18, Pages: 1-19, ISSN: 1741-7015
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
Vrijheid M, Fossati S, Maitre L, et al., 2020, Early-life environmental exposures and childhood obesity: An exposome-wide approach, Environmental Health Perspectives, Vol: 128, ISSN: 0091-6765
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 suspecte
Robinson O, Chadeau Hyam M, Karaman I, et al., 2020, Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort, Aging Cell, Vol: 19, Pages: 1-13, ISSN: 1474-9718
Markers of biological aging have potential utility in primary care and public health. We developed a model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry in urine and serum, within a large sample (N = 2,239) from the UK Airwave cohort. We validated a subset of model predictors in a Finnish cohort including repeat measurements from 2,144 individuals. We investigated the determinants of accelerated aging, including lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (mean r = .86 across independent test sets). Increased metabolomic age acceleration (mAA) was associated after false discovery rate (FDR) correction with overweight/obesity, diabetes, heavy alcohol use and depression. DNA methylation age acceleration measures were uncorrelated with mAA. Increased DNA methylation phenotypic age acceleration (N = 1,110) was associated after FDR correction with heavy alcohol use, hypertension and low income. In conclusion, metabolomics is a promising approach for the assessment of biological age and appears complementary to established epigenetic clocks.
Vineis P, Avendano-Pabon M, Barros H, et al., 2020, Special report: the biology of inequalities in health: the lifepath consortium, Frontiers in Public Health, Vol: 8, Pages: 1-37, ISSN: 2296-2565
Funded by the European Commission Horizon 2020 programme, the Lifepath research consortium aimed to investigate the effects of socioeconomic inequalities on the biology of healthy aging. The main research questions included the impact of inequalities on health, the role of behavioral and other risk factors, the underlying biological mechanisms, the efficacy of selected policies, and the general implications of our findings for theories and policies. The project adopted a life-course and comparative approach, considering lifetime effects from childhood and adulthood, and pooled data on up to 1.7 million participants of longitudinal cohort studies from Europe, USA, and Australia. These data showed that socioeconomic circumstances predicted mortality and functional decline as strongly as established risk factors currently targeted by global prevention programmes. Analyses also looked at socioeconomically patterned biological markers, allostatic load, and DNA methylation using richly phenotyped cohorts, unraveling their association with aging processes across the life-course. Lifepath studies suggest that socioeconomic circumstances are embedded in our biology from the outset—i.e., disadvantage influences biological systems from molecules to organs. Our findings have important implications for policy, suggesting that (a) intervening on unfavorable socioeconomic conditions is complementary and as important as targeting well-known risk factors, such as tobacco and alcohol consumption, low fruit and vegetable intake, obesity and a sedentary lifestyle, and that (b) effects of preventive interventions in early life integrate interventions in adulthood. The report has an executive summary that refers to the different sections of the main paper.
Agier L, Basagaña X, Hernandez-Ferrer C, et al., 2020, Association between the pregnancy exposome and fetal growth, International Journal of Epidemiology, Vol: 49, Pages: 572-586, ISSN: 0300-5771
BackgroundSeveral 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.MethodsWithin 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.ResultsThe 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.ConclusionsThis 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.
Robinson O, Vineis P, 2019, EXPOsOMICS: Novel approach to the assessment of exposure to high priority environmental pollutants, 55th Congress of the European-Societies-of-Toxicology (EUROTOX) - Toxicology - Science Providing Solutions, Publisher: ELSEVIER IRELAND LTD, Pages: S18-S18, ISSN: 0378-4274
Robinson O, Vineis P, 2019, The exposome in practice, 55th Congress of the European-Societies-of-Toxicology (EUROTOX) - Toxicology - Science Providing Solutions, Publisher: ELSEVIER IRELAND LTD, Pages: S40-S40, ISSN: 0378-4274
Warembourg C, Maitre L, Tamayo-Uria I, et al., 2019, Early-life environmental exposures and blood pressure in children, Journal of the American College of Cardiology, Vol: 74, Pages: 1317-1328, ISSN: 0735-1097
Background: Growing 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. Objectives: This study aims to evaluate the association between a wide range of prenatal and postnatal exposures and blood pressure (BP) in children. Methods: Systolic 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. Results: Decreases 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 examinati
CLEMENTE BATALHA PARDAL D, Robinson O, 2019, Prenatal and childhood traffic-related air pollution exposure and telomere length in European children: The HELIX project, Environmental Health Perspectives, Vol: 127, Pages: 087001-1-087001-8, ISSN: 0091-6765
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) (n=1,396), we estimated prenatal and 1-y childhood exposure to nitrogen dioxide (NO2), particulate matter with aerodynamic diameter ≤2.5μm (PM2.5), 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 NO2 and PM2.5 exposures levels. Each standard deviation (SD) increase in prenatal NO2 was associated with a −1.5% (95% CI: −2.8, −0.2) change in LTL. Prenatal PM2.5 was nonsignificantly associated with LTL (−0.7% per SD increase; 95% CI: −2.0, 0.6). For each SD increment in 1-y childhood NO2 and PM2.5 exposure, LTL shortened by −1.6% (95% CI: −2.9, −0.4) and −1.4% (95% CI: −2.9, 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.
Donaire-Gonzalez D, Curto A, Valentin A, et al., 2019, Personal assessment of the external exposome during pregnancy and childhood in Europe, ENVIRONMENTAL RESEARCH, Vol: 174, Pages: 95-104, ISSN: 0013-9351
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McCrory C, Leahy S, Ribeiro AI, et al., 2019, Maternal educational inequalities in measured body mass index trajectories in three European countries, PAEDIATRIC AND PERINATAL EPIDEMIOLOGY, Vol: 33, Pages: 226-237, ISSN: 0269-5022
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