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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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- Citations: 15
Nieuwenhuijsen MJ, Agier L, Basagaña X, et al., 2019, Influence of the urban exposome on birth weight, Environmental Health Perspectives, Vol: 127, ISSN: 0091-6765
Background:The exposome is defined as the totality of environmental exposures from conception onwards. It calls for providing a holistic view of environmental exposures and their effects on human health by evaluating multiple environmental exposures simultaneously during critical periods of life.Objective:We evaluated the association of the urban exposome with birth weight.Methods:We estimated exposure to the urban exposome, including the built environment, air pollution, road traffic noise, meteorology, natural space, and road traffic (corresponding to 24 environmental indicators and 60 exposures) for nearly 32,000 pregnant women from six European birth cohorts. To evaluate associations with either continuous birth weight or term low birth weight (TLBW) risk, we primarily relied on the Deletion-Substitution-Addition (DSA) algorithm, which is an extension of the stepwise variable selection method. Second, we used an exposure-by-exposure exposome-wide association studies (ExWAS) method accounting for multiple hypotheses testing to report associations not adjusted for coexposures.Results:The most consistent statistically significant associations were observed between increasing green space exposure estimated as Normalized Difference Vegetation Index (NDVI) and increased birth weight and decreased TLBW risk. Furthermore, we observed statistically significant associations among presence of public bus line, land use Shannon's Evenness Index, and traffic density and birth weight in our DSA analysis.Conclusion:This investigation is the first large urban exposome study of birth weight that tests many environmental urban exposures. It confirmed previously reported associations for NDVI and generated new hypotheses for a number of built-environment exposures. https://doi.org/10.1289/EHP3971
Fiorito G, McCrory C, Robinson O, et al., 2019, Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis, Aging, Vol: 11, Pages: 2045-2070, ISSN: 1945-4589
Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) hasbeen proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life. We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries. The four biological aging biomarkers were associated with education and different sets of risk factors independently,and themagnitude of the effectsdiffereddepending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception ofsmoking, which hada significantly stronger effect. Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.
Reimann B, Janssen BG, Alfano R, et al., 2019, The cord blood insulin and mitochondrial DNA content related methylome, Frontiers in Genetics, Vol: 10, ISSN: 1664-8021
Mitochondrial dysfunction seems to play a key role in the etiology of insulin resistance. At birth, a link has already been established between mitochondrial DNA (mtDNA) content and insulin levels in cord blood. In this study, we explore shared epigenetic mechanisms of the association between mtDNA content and insulin levels, supporting the developmental origins of this link. First, the association between cord blood insulin and mtDNA content in 882 newborns of the ENVIRONAGE birth cohort was assessed. Cord blood mtDNA content was established via qPCR, while cord blood levels of insulin were determined using electrochemiluminescence immunoassays. Then the cord blood DNA methylome and transcriptome were determined in 179 newborns, using the human 450K methylation Illumina and Agilent Whole Human Genome 8 × 60 K microarrays, respectively. Subsequently, we performed an epigenome-wide association study (EWAS) adjusted for different maternal and neonatal variables. Afterward, we focused on the 20 strongest associations based on p-values to assign transcriptomic correlates and allocate corresponding pathways employing the R packages ReactomePA and RDAVIDWebService. On the regional level, we examined differential methylation using the DMRcate and Bumphunter packages in R. Cord blood mtDNA content and insulin were significantly correlated (r = 0.074, p = 0.028), still showing a trend after additional adjustment for maternal and neonatal variables (p = 0.062). We found an overlap of 33 pathways which were in common between the association with cord blood mtDNA content and insulin levels, including pathways of neurodevelopment, histone modification, cytochromes P450 (CYP)-metabolism, and biological aging. We further identified a DMR annotated to Repulsive Guidance Molecule BMP Co-Receptor A (RGMA) linked to cord blood insulin as well as mtDNA content. Metabolic variation in early life represented by neonatal insulin levels and mtDNA content might reflect or accommodate
Rojas-Rueda D, Vrijheid M, Robinson O, et al., 2019, Environmental burden of childhood disease in Europe, International Journal of Environmental Research and Public Health, Vol: 16, ISSN: 1660-4601
Background: Environmental factors determine children’s health. Quantifying the health impacts related to environmental hazards for children is essential to prioritize interventions to improve health in Europe. Objective: This study aimed to assess the burden of childhood disease due to environmental risks across the European Union. Methods: We conducted an environmental burden of childhood disease assessment in the 28 countries of the EU (EU28) for seven environmental risk factors (particulate matter less than 10 micrometer of diameter (PM10) and less than 2.5 micrometer of diameter (PM2.5), ozone, secondhand smoke, dampness, lead, and formaldehyde). The primary outcome was disability-adjusted life years (DALYs), assessed from exposure data provided by the World Health Organization, Global Burden of Disease project, scientific literature, and epidemiological risk estimates. Results: The seven studied environmental risk factors for children in the EU28 were responsible for around 211,000 DALYs annually. Particulate matter (PM10 and PM2.5) was the main environmental risk factor, producing 59% of total DALYs (125,000 DALYs), followed by secondhand smoke with 20% of all DALYs (42,500 DALYs), ozone 11% (24,000 DALYs), dampness 6% (13,000 DALYs), lead 3% (6200 DALYs), and formaldehyde 0.2% (423 DALYs). Conclusions: Environmental exposures included in this study were estimated to produce 211,000 DALYs each year in children in the EU28, representing 2.6% of all DALYs in children. Among the included environmental risk factors, air pollution (particulate matter and ozone) was estimated to produce the highest burden of disease in children in Europe, half of which was due to the effects of PM10 on infant mortality. Effective policies to reduce environmental pollutants across Europe are needed.
Tamayo-Uria I, Maitre L, Thomsen C, et al., 2019, The early-life exposome: description and patterns in six European countries, Environment International, Vol: 123, Pages: 189-200, ISSN: 0160-4120
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 stud
Agier L, Basagaña X, Maitre L, et al., 2019, Early life exposome and lung function in children in Europe: An analysis of data from the longitudinal, population-based HELIX cohort, Lancet Planetary Health, Vol: 3, Pages: e81-e92, ISSN: 2542-5196
BackgroundSeveral 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.MethodsIn 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.FindingsIn 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
Haug LS, Sakhi AK, Cequier E, et al., 2018, In-utero and childhood chemical exposome in six European mother-child cohorts, Environment International, Vol: 121, Pages: 751-763, ISSN: 0160-4120
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 advers
Casas M, Basagana X, Sakhi AK, et al., 2018, Variability of urinary concentrations of non-persistent chemicals in pregnant women and school-aged children, Environment International, Vol: 121, Pages: 561-573, ISSN: 0160-4120
BackgroundExposome studies are challenged by exposure misclassification for non-persistent chemicals, whose temporal variability contributes to bias in dose-response functions.ObjectivesWe evaluated the variability of urinary concentrations of 24 non-persistent chemicals: 10 phthalate metabolites, 7 phenols, 6 organophosphate (OP) pesticide metabolites, and cotinine, between weeks from different pregnancy trimesters in pregnant women, and between days and between seasons in children.Methods154 pregnant women and 152 children from six European countries were enrolled in 2014–2015. Pregnant women provided three urine samples over a day (morning, midday, and night), for one week in the 2nd and 3rd pregnancy trimesters. Children provided two urines a day (morning and night), over two one-week periods, six months apart. We pooled all samples for a given subject that were collected within a week. In children, we also made four daily pools (combining morning and night voids) during the last four days of the first follow-up week. Pools were analyzed for all 24 metabolites of interest. We calculated intraclass-correlation coefficients (ICC) and estimated the number of pools needed to obtain an ICC above 0.80.ResultsAll phthalate metabolites and phenols were detected in >90% of pools whereas certain OP pesticide metabolites and cotinine were detected in <43% of pools. We observed fair (ICC = 0.40–0.59) to good (0.60–0.74) between-day reliability of the pools of two samples in children for all chemicals. Reliability was poor (<0.40) to fair between trimesters in pregnant women and between seasons in children. For most chemicals, three daily pools of two urines each (for weekly exposure windows) and four weekly pools of 15–20 urines each would be necessary to obtain an ICC above 0.80.ConclusionsThis quantification of the variability of biomarker measurements of many non-persistent chemicals during several time windows shows that for many of thes
Maitre L, Robinson O, Martinez D, et al., 2018, Urine metabolic signatures of multiple environmental pollutants in pregnant women - an exposome approach, Environmental Science and Technology, Vol: 52, Pages: 13469-13480, ISSN: 0013-936X
Exposure to environmental pollutants, particularly during pregnancy, can have adverse consequences on child development but little is known about the effects of pollutant mixtures on endogenous metabolism in pregnant women. We aimed to identify urinary metabolic signatures associated with low level exposure to multiple environmental pollutants in pregnant women from the INMA (INfancia y Medio Ambiente) birth cohort (Spain, N = 750). 35 chemical exposures were quantified in first trimester blood samples (organochlorine pesticides, PCBs, PFAS), in cord blood (mercury), and twice in urine at 12 and 32 weeks of pregnancy (metals, phthalates, bisphenol A). 1H nuclear magnetic resonance (NMR) metabolic profiles of urine were acquired in the same samples as pollutants. We explored associations between exposures and metabolism through an exposome-metabolome wide association scan and multivariate O2PLS modeling. Novel and reproducible associations were found across two periods of pregnancy for three nonpersistent pollutants and across two subcohorts for four of the persistent pollutants. We found novel metabolic signatures associated with arsenic exposure: TMAO and dimethylamine possibly related to gut microbial methylamine metabolism and homarine related to fish intake. Tobacco smoke exposure was related to coffee metabolism and PCBs with 3-hydroxyvaleric acid, usually released under ketoacidosis. These findings will have implications for further understanding of maternal-fetal health, and health across the life-course.
Lau CH, Siskos AP, Maitre L, et al., 2018, Determinants of the urinary and serum metabolome in children from six European populations, BMC Medicine, Vol: 16, ISSN: 1741-7015
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
Dagnino S, Macherone A, 2018, Unraveling the exposome: A practical view, ISBN: 9783319893204
This volume presents a comprehensive overview of the science and application of the Exposome through seventeen chapters from leaders in the field. At just over ten years since the term was coined by Christopher Wild in 2005, this is the first, field-defining volume to offer a holistic picture of the important and growing field of Exposomics. The term "Exposome" describes the sum of all exposures (not only chemical) that an individual can receive over a lifetime from both exogenous sources (environmental contaminants, food, lifestyle, drugs, air, etc.) and endogenous sources (metabolism, oxidative stress, lipid peroxidation, chemicals synthesized by the microbiome, etc.). The first section of this book contains chapters that discuss how the Exposome is defined and how the concept fits into the fields of public health and epidemiology. The second section provides an overview of techniques and methods to measure the human Exposome. The third section contains methods and applications for measuring the Exposome through external exposures. Section four provides an overview on statistical and computational techniques- including big data analysis - for characterizing the Exposome. Section five presents a global collection of case studies.
Laine JE, Robinson O, 2018, Framing Fetal and Early Life Exposome within Epidemiology, Unraveling the Exposome: A Practical View, Editors: Dagnino, Macherone, Publisher: Springer
Robinson O, Hyam MC, Karaman I, et al., 2018, Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort
<jats:title>Abstract</jats:title><jats:p>Markers of biological ageing have potential utility in primary care and public health. We developed an elastic net regression 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 (almost 100,000 features assayed), within a large sample (N=2,239) from the UK occupational Airwave cohort. We investigated the determinants of accelerated ageing, including genetic, lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (r=0.85 in independent test set). Increased metabolomic age acceleration (mAA) was associated (p<0.0025) with overweight/obesity and depression and nominally associated (p<0.05) with high alcohol use and low income. DNA methylation age acceleration (N=1,102) was nominally associated (p<0.05) with high alcohol use, anxiety and post-traumatic stress disorder, but not correlated with mAA. Biological age acceleration may present an important mechanism linking psycho-social stress to age-related disease.</jats:p>
Siroux V, Agier L, Basagana X, et al., 2018, Early life exposome and lung function in children from the HELIX cohort, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 2
Maitre L, de Bont J, Casas M, et al., 2018, Human Early Life Exposome (HELIX) study: a European population-based exposome cohort, BMJ Open, Vol: 8, ISSN: 2044-6055
Purpose Essential to exposome research is the collection of data on many environmental exposures from different domains in the same subjects. The aim of the Human Early Life Exposome (HELIX) study was to measure and describe multiple environmental exposures during early life (pregnancy and childhood) in a prospective cohort and associate these exposures with molecular omics signatures and child health outcomes. Here, we describe recruitment, measurements available and baseline data of the HELIX study populations.Participants The HELIX study represents a collaborative project across six established and ongoing longitudinal population-based birth cohort studies in six European countries (France, Greece, Lithuania, Norway, Spain and the UK). HELIX used a multilevel study design with the entire study population totalling 31 472 mother-child pairs, recruited during pregnancy, in the six existing cohorts (first level); a subcohort of 1301 mother-child pairs where biomarkers, omics signatures and child health outcomes were measured at age 6–11 years (second level) and repeat-sampling panel studies with around 150 children and 150 pregnant women aimed at collecting personal exposure data (third level).Findings to date Cohort data include urban environment, hazardous substances and lifestyle-related exposures for women during pregnancy and their offspring from birth until 6–11 years. Common, standardised protocols were used to collect biological samples, measure exposure biomarkers and omics signatures and assess child health across the six cohorts. Baseline data of the cohort show substantial variation in health outcomes and determinants between the six countries, for example, in family affluence levels, tobacco smoking, physical activity, dietary habits and prevalence of childhood obesity, asthma, allergies and attention deficit hyperactivity disorder.Future plans HELIX study results will inform on the early life exposome and its association with molecul
Robinson OJK, Tamayo I, de Castro M, et al., 2018, The urban exposome during pregnancy and its socioeconomic determinants, Environmental Health Perspectives, Vol: 126, Pages: 077005-1-077005-15, ISSN: 0091-6765
Background: The urban exposome is the set of environmental factors that are experienced in the outdoor urban environment and that may influence child development.Objective: The authors’ goal was to describe the urban exposome among European pregnant women and understand its socioeconomic determinants.Methods: Using geographic information systems, remote sensing and spatio-temporal modeling we estimated exposure during pregnancy to 28 environmental indicators in almost 30,000 women from six population-based birth cohorts, in nine urban areas from across Europe. Exposures included meteorological factors, air pollutants, traffic noise, traffic indicators, natural space, the built environment, public transport, facilities, and walkability. Socioeconomic position (SEP), assessed at both the area and individual level, was related to the exposome through an exposome-wide association study and principal component (PC) analysis.Results: Mean±standard deviation (SD) NO2 levels ranged from 13.6±5.1 μg/m3 (in Heraklion, Crete) to 43.2±11 μg/m3 (in Sabadell, Spain), mean±SD walkability score ranged from 0.22±0.04 (Kaunas, Lithuania) to 0.32±0.07 (Valencia, Spain) and mean±SD Normalized Difference Vegetation Index ranged from 0.21±0.05 in Heraklion to 0.51±0.1 in Oslo, Norway. Four PCs explained more than half of variation in the urban exposome. There was considerable heterogeneity in social patterning of the urban exposome across cities. For example, high-SEP (based on family education) women lived in greener, less noisy, and less polluted areas in Bradford, UK (0.39 higher PC1 score, 95% confidence interval (CI): 0.31, 0.47), but the reverse was observed in Oslo (−0.57 PC1 score, 95% CI: −0.73, −0.41). For most cities, effects were stronger when SEP was assessed at the area level: In Bradford, women living in high SEP areas had a 1.34 higher average PC1 score (
Demetriou CA, Degli Esposti D, Fedinick KP, et al., 2018, Filling the gap between chemical carcinogenesis and the hallmarks of cancer: A temporal perspective, EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Vol: 48, ISSN: 0014-2972
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- Citations: 11
Plusquin M, Chadeau-Hyam M, Ghantous A, et al., 2018, DNA Methylome Marks of Exposure to Particulate Matter at Three Time Points in Early Life, ENVIRONMENTAL SCIENCE & TECHNOLOGY, Vol: 52, Pages: 5427-5437, ISSN: 0013-936X
Castagne R, Gares V, Karimi M, et al., 2018, Allostatic load and subsequent all-cause mortality: which biological markers drive the relationship? Findings from a UK birth cohort, European Journal of Epidemiology, Vol: 33, Pages: 441-458, ISSN: 0393-2990
The concept of allostatic load (AL) refers to the idea of a global physiological ‘wear and tear’ resulting from the adaptationto the environment through the stress response systems over the life span. The link between socioeconomic position (SEP)and mortality has now been established, and there is evidence that AL may capture the link between SEP and mortality. Inorder to quantitatively assess the role of AL on mortality, we use data from the 1958 British birth cohort including elevenyear mortality in 8,113 adults. Specifically, we interrogate the hypothesis of a cumulative biological risk (allostatic load)reflecting 4 physiological systems potentially predicting future risk of death (N = 132). AL was defined using 14biomarkers assayed in blood from a biosample collected at 44 years of age. Cox proportional hazard regression analysisrevealed that higher allostatic load at 44 years old was a significant predictor of mortality 11 years later [HR = 3.56 (2.3 to5.53)]. We found that this relationship was not solely related to early-life SEP, adverse childhood experiences and youngadulthood health status, behaviours and SEP [HR = 2.57 (1.59 to 4.15)]. Regarding the ability of each physiologicalsystem and biomarkers to predict future death, our results suggest that the cumulative measure was advantageous comparedto evaluating each physiological system sub-score and biomarker separately. Our findings add some evidence of a biologicalembodiment in response to stress which ultimately affects mortality.
Robinson O, Keski-Rahkonen P, Chatzi L, et al., 2018, Cord blood metabolic signatures of birthweight: a population based study, Journal of Proteome Research, Vol: 3, Pages: 1235-1247, ISSN: 1535-3893
Birthweight is an important indicator of maternal and fetal health, and a predictor of health in later life. However, the determinants of variance in birthweight are still poorly understood. We aimed to identify the biological pathways, which may be perturbed by environmental exposures, that are important in determining birthweight. We applied untargeted mass-spectrometry based metabolomics to 481 cord blood samples collected at delivery in four birth cohorts from across Europe: ENVIRONAGE (Belgium), INMA (Spain), Piccolipiu (Italy) and Rhea (Greece). We performed a metabolome-wide association scan for birthweight on over 4000 metabolic features, controlling the false discovery rate at 5%. Annotation of compounds was conducted through reference to authentic standards. We identified 68 metabolites significantly associated with birthweight, including vitamin A, progesterone, docosahexaenoic acid, indolelactic acid, and multiple acylcarnitines and phosphatidylcholines. We observed enrichment (p < 0.05) of the tryptophan metabolism, prostaglandin formation, C21-steroid hormone signalling, carnitine shuttle and glycerophospholipid metabolism pathways. Vitamin A was associated with both maternal smoking and birthweight, suggesting a mediation pathway. Our findings shed new light on the pathways central to fetal growth and will have implications for antenatal and perinatal care and potentially for health in later life.
Fiorito G, Polidoro S, Dugue P-A, et al., 2017, Social adversity and epigenetic aging: a multi-cohort study on socioeconomic differences in peripheral blood DNA methylation, Scientific Reports, Vol: 7, ISSN: 2045-2322
Low socioeconomic status (SES) is associated with earlier onset of age-related chronic conditions and reduced life-expectancy, but the underlying biomolecular mechanisms remain unclear. Evidence of DNA-methylation differences by SES suggests a possible association of SES with epigenetic age acceleration (AA). We investigated the association of SES with AA in more than 5,000 individuals belonging to three independent prospective cohorts from Italy, Australia, and Ireland. Low SES was associated with greater AA (β = 0.99 years; 95% CI 0.39,1.59; p = 0.002; comparing extreme categories). The results were consistent across different SES indicators. The associations were only partially modulated by the unhealthy lifestyle habits of individuals with lower SES. Individuals who experienced life-course SES improvement had intermediate AA compared to extreme SES categories, suggesting reversibility of the effect and supporting the relative importance of the early childhood social environment. Socioeconomic adversity is associated with accelerated epigenetic aging, implicating biomolecular mechanisms that may link SES to age-related diseases and longevity.
Vineis P, Avendano-Pabon M, Barros H, et al., 2017, The biology of inequalities in health: the LIFEPATH project, Longitudinal and Life Course Studies, Vol: 8, Pages: 417-449, ISSN: 1757-9597
Socioeconomic differences in health have been consistently observed worldwide. Physical health deteriorates more rapidly with age among men and women with lower socioeconomic status (SES) than among those with higher SES. The biological processes underlying these differences are best understood by adopting a life-course approach. In this paper we introduce the pan-European LIFEPATH project which uses the revised Strachan-Sheikh (2004) model to describe ageing across the life-course. This model presents ageing as a phenomenon with two broad stages across life: build-up and decline. The ‘build-up’ stage, from conception and early intra-uterine life to late adolescence or early twenties, is characterised by rapid successions of developmentally and socially sensitive periods. The second stage, starting in early adulthood, is a period of 'decline' from maximum attained health to loss of function, overt disease and death.LIFEPATH adopts a study design that integrates social science and public health approaches with biology (including molecular epidemiology), using well-characterised population cohorts and omics measurements (particularly epigenomics). The specific objectives of the project are: (a) to show that healthy ageing is an achievable goal for society; (b) to improve the understanding of the mechanisms through which healthy ageing pathways diverge by SES, by investigating life-course biological pathways using omic technologies; (c) to examine the consequences of the current economic recession on health and the biology of ageing (and the consequent increase in social inequalities); (d) to provide updated, relevant and innovative evidence for healthy ageing policies (particularly “health in all policies”) using both observational studies and an experimental approach based on a reanalysis of data from a "conditional cash transfer" randomised experiment in New York and new data collected as part of an earned income tax credit randomis
Barrera-Gomez J, Agier L, Portengen L, et al., 2017, A systematic comparison of statistical methods to detect interactions in exposome-health associations, ENVIRONMENTAL HEALTH, Vol: 16, ISSN: 1476-069X
BackgroundThere is growing interest in examining the simultaneous effects of multiple exposures and, more generally, the effects of mixtures of exposures, as part of the exposome concept (being defined as the totality of human environmental exposures from conception onwards). Uncovering such combined effects is challenging owing to the large number of exposures, several of them being highly correlated. We performed a simulation study in an exposome context to compare the performance of several statistical methods that have been proposed to detect statistical interactions.MethodsSimulations were based on an exposome including 237 exposures with a realistic correlation structure. We considered several statistical regression-based methods, including two-step Environment-Wide Association Study (EWAS2), the Deletion/Substitution/Addition (DSA) algorithm, the Least Absolute Shrinkage and Selection Operator (LASSO), Group-Lasso INTERaction-NET (GLINTERNET), a three-step method based on regression trees and finally Boosted Regression Trees (BRT). We assessed the performance of each method in terms of model size, predictive ability, sensitivity and false discovery rate.ResultsGLINTERNET and DSA had better overall performance than the other methods, with GLINTERNET having better properties in terms of selecting the true predictors (sensitivity) and of predictive ability, while DSA had a lower number of false positives. In terms of ability to capture interaction terms, GLINTERNET and DSA had again the best performances, with the same trade-off between sensitivity and false discovery proportion. When GLINTERNET and DSA failed to select an exposure truly associated with the outcome, they tended to select a highly correlated one. When interactions were not present in the data, using variable selection methods that allowed for interactions had only slight costs in performance compared to methods that only searched for main effects.ConclusionsGLINTERNET and DSA provided better perf
Pañella P, Casas M, Donaire-Gonzalez D, et al., 2017, Ultrafine particles and black carbon personal exposures in asthmatic and non-asthmatic children at school age., Indoor Air, Vol: 27, Pages: 891-899, ISSN: 0905-6947
Traffic-related air pollution (TRAP) exposure during childhood is associated with asthma; however, the contribution of the different TRAP pollutants in each microenvironment (home, school, transportation, others) in asthmatic and non-asthmatic children is unknown. Daily (24-h) personal black carbon (BC), ultrafine particle (UFP), and alveolar lung-deposited surface area (LDSA) individual exposure measurements were obtained from 100 children (29 past and 21 current asthmatics, 50 non-asthmatics) aged 9±0.7 years from the INMA-Sabadell cohort (Catalonia, Spain). Time spent in each microenvironment was derived by the geolocation provided by the smartphone and a new spatiotemporal map-matching algorithm. Asthmatics and non-asthmatics spent the same amount of time at home (60% and 61%, respectively), at school (20% and 23%), on transportation (8% and 7%), and in other microenvironments (7% and 5%). The highest concentrations of all TRAPs were attributed to transportation. No differences in TRAP concentrations were found overall or by type of microenvironment between asthmatics and non-asthmatics, nor when considering past and current asthmatics, separately. In conclusion, asthmatic and non-asthmatic children had a similar time-activity pattern and similar average exposures to BC, UFP, and LDSA concentrations. This suggests that interventions should be tailored to general population, rather than to subgroups defined by disease.
Maitre L, Lau C-HE, Vizcaino E, et al., 2017, Assessment of metabolic phenotypic variability in children's urine using H-1 NMR spectroscopy, Scientific Reports, Vol: 7, ISSN: 2045-2322
The application of metabolic phenotyping in clinical and epidemiological studies is limited by a poor understanding of inter-individual, intra-individual and temporal variability in metabolic phenotypes. Using 1H NMR spectroscopy we characterised short-term variability in urinary metabolites measured from 20 children aged 8–9 years old. Daily spot morning, night-time and pooled (50:50 morning and night-time) urine samples across six days (18 samples per child) were analysed, and 44 metabolites quantified. Intraclass correlation coefficients (ICC) and mixed effect models were applied to assess the reproducibility and biological variance of metabolic phenotypes. Excellent analytical reproducibility and precision was demonstrated for the 1H NMR spectroscopic platform (median CV 7.2%). Pooled samples captured the best inter-individual variability with an ICC of 0.40 (median). Trimethylamine, N-acetyl neuraminic acid, 3-hydroxyisobutyrate, 3-hydroxybutyrate/3-aminoisobutyrate, tyrosine, valine and 3-hydroxyisovalerate exhibited the highest stability with over 50% of variance specific to the child. The pooled sample was shown to capture the most inter-individual variance in the metabolic phenotype, which is of importance for molecular epidemiology study design. A substantial proportion of the variation in the urinary metabolome of children is specific to the individual, underlining the potential of such data to inform clinical and exposome studies conducted early in life.
Stringhini S, Carmeli C, Jokela M, et al., 2017, Socioeconomic status and the 25 x 25 risk factors as determinants of premature mortality: a multicohort study and meta-analysis of 1.7 million men and women, The Lancet, Vol: 389, Pages: 1229-1237, ISSN: 0140-6736
Background:In 2011, WHO member states signed up to the 25 × 25 initiative, a plan to cut mortality due to non-communicable diseases by 25% by 2025. However, socioeconomic factors influencing non-communicable diseases have not been included in the plan. In this study, we aimed to compare the contribution of socioeconomic status to mortality and years-of-life-lost with that of the 25 × 25 conventional risk factors.Methods:We did a multicohort study and meta-analysis with individual-level data from 48 independent prospective cohort studies with information about socioeconomic status, indexed by occupational position, 25 × 25 risk factors (high alcohol intake, physical inactivity, current smoking, hypertension, diabetes, and obesity), and mortality, for a total population of 1 751 479 (54% women) from seven high-income WHO member countries. We estimated the association of socioeconomic status and the 25 × 25 risk factors with all-cause mortality and cause-specific mortality by calculating minimally adjusted and mutually adjusted hazard ratios [HR] and 95% CIs. We also estimated the population attributable fraction and the years of life lost due to suboptimal risk factors.Findings:During 26·6 million person-years at risk (mean follow-up 13·3 years [SD 6·4 years]), 310 277 participants died. HR for the 25 × 25 risk factors and mortality varied between 1·04 (95% CI 0·98–1·11) for obesity in men and 2 ·17 (2·06–2·29) for current smoking in men. Participants with low socioeconomic status had greater mortality compared with those with high socioeconomic status (HR 1·42, 95% CI 1·38–1·45 for men; 1·34, 1·28–1·39 for women); this association remained significant in mutually adjusted models that included the 25 × 25 factors (HR 1·26, 1·21–1·32, men and women combined). The population attrib
Vineis P, Chadeau-Hyam M, Gmuender H, et al., 2016, The exposome in practice: Design of the EXPOsOMICS project, International Journal of Hygiene and Environmental Health, Vol: 220, Pages: 142-151, ISSN: 1618-131X
EXPOsOMICS is a European Union funded project that aims to develop a novel approach to the assessment of exposure to high priority environmental pollutants, by characterizing the external and the internal components of the exposome. It focuses on air and water contaminants during critical periods of life. To this end, the project centres on 1) exposure assessment at the personal and population levels within existing European short and long-term population studies, exploiting available tools and methods which have been developed for personal exposure monitoring (PEM); and 2) multiple "omic" technologies for the analysis of biological samples (internal markers of external exposures). The search for the relationships between external exposures and global profiles of molecular features in the same individuals constitutes a novel advancement towards the development of "next generation exposure assessment" for environmental chemicals and their mixtures. The linkage with disease risks opens the way to what are defined here as 'exposome-wide association studies' (EWAS).
Robinson O, Toledano MB, Sands C, et al., 2016, Global metabolic changes induced by plant-derived pyrrolizidine alkaloids following a human poisoning outbreak and in a mouse model, Toxicology Research, Vol: 5, Pages: 1594-1603, ISSN: 2045-4538
Several hundred cases of Hirmi Valley Liver Disease (HVLD), an often fatal liver injury, occurred from 2001 to 2011 in a cluster of rural villages in Tigray, Ethiopia. HVLD is principally caused by contamination of the food supply with plant derived pyrrolizidine alkaloids (PAs), with high exposure to the pesticide DDT among villagers increasing their susceptibility. In an untargeted global approach we aimed to identify metabolic changes induced by PA exposure through 1H NMR spectroscopic based metabolic profiling. We analysed spectra acquired from urine collected from HVLD cases and controls and a murine model of PA exposure and PA/DDT co-exposure, using multivariate partial least squares discriminant analysis. In the human models we identified changes in urinary concentrations of tyrosine, pyruvate, bile acids, N-acetylglycoproteins, N-methylnicotinamide and formate, hippurate, p-cresol sulphate, p-hydroxybenzoate and 3-(3-hydroxyphenyl) propionic acid. Tyrosine and p-cresol sulphate were associated with both exposure and disease. Similar changes to tyrosine, one-carbon intermediates and microbial associated metabolites were observed in the mouse model, with tyrosine correlated with the extent of liver damage. These results provide mechanistic insight and implicate the gut microflora in the human response to challenge with toxins. Pathways identified here may be useful in translational research and as “exposome” signals.
Lopez-Vicente M, Forns J, Esnaola M, et al., 2016, Physical Activity and Cognitive Trajectories in Schoolchildren, Pediatr Exerc Sci, Vol: 28, Pages: 431-438, ISSN: 0899-8493
PURPOSE: The evidence regarding the role of physical activity (PA) habits on cognitive development in children is still scarce. Our study aimed to assess the association between PA habits and cognitive growth patterns, including working memory (WM) and inattentiveness in a large sample of primary schoolchildren. METHOD: This study included 2,897 children between 7 and 10 years old. WM was measured using the n-back task (2- and 3-back) and inattentiveness was measured using the attentional network task (ANT) on four occasions during one year. Parents completed a questionnaire with data about the extracurricular exercise of their child, commuting to school and other sociodemographic information at the first visit. RESULTS: Exercising twice per week or more was associated with better 2-back, 3-back and inattentiveness scores at baseline, as compared with the once per week or less category. Active commuting for more than 50 min was associated with better 3-back scores at baseline, as compared with passive commuting. No consistent associations were found between PA and cognitive growth. CONCLUSION: Overall, although children with high levels of PA performed better in cognitive tasks at baseline, PA levels had no clear effects on cognitive growth trajectories.
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