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BACKGROUND: Precision Health aims to revolutionize disease prevention by leveraging information across multiple omic datasets (multi-omics). However, existing methods generally do not consider personalized environmental risk factors (e.g., environmental pollutants). OBJECTIVE: To develop and apply a precision health framework which combines multiomic integration (including early, intermediate, and late integration, representing sequential stages at which omics layers are combined for modeling) with mediation approaches (including high-dimensional mediation to identify biomarkers, mediation with latent factors to identify pathways, and integrated/quasi-mediation to identify high-risk subpopulations) to identify novel biomarkers of prenatal mercury induced metabolic dysfunction-associated fatty liver disease (MAFLD), elucidate molecular pathways linking prenatal mercury with MAFLD in children, and identify high-risk children based on integrated exposure and multiomics data. METHODS: This prospective cohort study used data from 420 mother-child pairs from the Human Early Life Exposome (HELIX) project. Mercury concentrations were determined in maternal or cord blood from pregnancy. Cytokeratin 18 (CK-18; a MAFLD biomarker) and five omics layers (DNA Methylation, gene transcription, microRNA, proteins, and metabolites) were measured in blood in childhood (age 6-10 years). RESULTS: Each standard deviation increase in prenatal mercury was associated with a 0.11 [95% confidence interval: 0.02-0.21] standard deviation increase in CK-18. High dimensional mediation analysis identified 10 biomarkers linking prenatal mercury and CK-18, including six CpG sites and four transcripts. Mediation with latent factors identified molecular pathways linking mercury and MAFLD, including altered cytokine signaling and hepatic stellate cell activation. Integrated/quasi-mediation identified high risk subgroups of children based on unique combinations of exposure levels, omics profiles (driven by epigenetic markers), and MAFLD. CONCLUSIONS: Prenatal mercury exposure is associated with elevated liver enzymes in childhood, likely through alterations in DNA methylation and gene expression. Our analytic framework can be applied across many different fields and serve as a resource to help guide future precision health investigations.
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In utero and children's exposure to per- and polyfluoroalkyl substances (PFAS) is a major concern in health risk assessment as early life exposures are suspected to induce adverse health effects. Our work aims to estimate children's exposure (from birth to 12 years old) to PFOA and PFOS, using a Physiologically-Based Pharmacokinetic (PBPK) modelling approach. A model for PFAS was updated to simulate the internal PFAS exposures during the in utero life and childhood, and including individual characteristics and exposure scenarios (e.g., duration of breastfeeding, weight at birth, etc.). Our approach was applied to the HELIX cohort, involving 1,239 mother-child pairs with measured PFOA and PFOS plasma concentrations at two sampling times: maternal and child plasma concentrations (6 to 12 y.o). Our model predicted an increase in plasma concentrations during fetal development and childhood until 2 y.o when the maximum concentrations were reached. Higher plasma concentrations of PFOA than PFOS were predicted until 2 y.o, and then PFOS concentrations gradually became higher than PFOA concentrations. From 2 to 8 y.o, mean concentrations decreased from 3.1 to 1.88 µg/L or ng/mL (PFOA) and from 4.77 to 3.56 µg/L (PFOS). The concentration-time profiles vary with the age and were mostly influenced by in utero exposure (on the first 4 months after birth), breastfeeding (from 5 months to 2 (PFOA) or 5 (PFOS) y.o of the children), and food intake (after 3 (PFOA) or 6 (PFOS) y.o of the children). Similar measured biomarker levels can correspond to large differences in the simulated internal exposures, highlighting the importance to investigate the children's exposure over the early life to improve exposure classification. Our approach demonstrates the possibility to simulate individual internal exposures using PBPK models when measured biomarkers are scarce, helping risk assessors in gaining insight into internal exposure during critical windows, such as early life.
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Ácidos Alcanossulfônicos , Aleitamento Materno , Caprilatos , Poluentes Ambientais , Fluorocarbonos , Exposição Materna , Humanos , Fluorocarbonos/sangue , Ácidos Alcanossulfônicos/sangue , Feminino , Caprilatos/sangue , Gravidez , Criança , Pré-Escolar , Lactente , Poluentes Ambientais/sangue , Exposição Materna/estatística & dados numéricos , Recém-Nascido , Masculino , Exposição Ambiental/análise , Dieta , Efeitos Tardios da Exposição Pré-Natal , AdultoRESUMO
Chemical exposures often occur in mixtures and exposures during pregnancy may lead to adverse effects on the fetal brain, potentially reducing lower cognitive abilities and fine motor function of the child. We investigated the association of mothers exposure to a mixture of chemicals during pregnancy (i.e., organochlorine compounds, per- and polyfluoroalkyl substances, phenols, phthalates, organophosphate pesticides) with cognitive abilties and fine motor function in their children. We studied 1097 mother-child pairs from five European cohorts participating in the Human Early Life Exposome study (HELIX). Measurement of 26 biomarkers of exposure to chemicals was performed on urine or blood samples of pregnant women (mean age 31 years). Cognitive abilities and fine motor function were assessed in their children (mean age 8 years) with a battery of computerized tests administered in person (Ravens Coloured Progressive Matrices, Attention Network Test, N-back Test, Trail Making Test, Finger Tapping Test). We estimated the joint effect of prenatal exposure to chemicals on cognitive abilities and fine motor function using the quantile-based g-computation method, adjusting for sociodemographic characteristics. A quartile increase in all the chemicals in the overall mixture was associated with worse fine motor function, specifically lower scores in the Finger Tapping Test [-8.5 points, 95 % confidence interval (CI) -13.6 to -3.4; -14.5 points, 95 % CI -22.4 to -6.6, and -18.0 points, 95 % CI -28.6 to -7.4) for the second, third and fourth quartile of the overal mixture, respectively, when compared to the first quartile]. Organochlorine compounds, phthalates, and per- and polyfluoroalkyl substances contributed most to this association. We did not find a relationship with cognitive abilities. We conclude that exposure to chemical mixtures during pregnancy may influence neurodevelopment, impacting fine motor function of the offspring.
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Poluentes Ambientais , Fluorocarbonos , Hidrocarbonetos Clorados , Ácidos Ftálicos , Efeitos Tardios da Exposição Pré-Natal , Humanos , Feminino , Gravidez , Adulto , Criança , Exposição Materna/efeitos adversos , Cognição , Poluentes Ambientais/toxicidadeRESUMO
Developing children are particularly vulnerable to the effects of exposure to per- and polyfluoroalkyl substances (PFAS), a group of endocrine disrupting chemicals. We hypothesized that early life exposure to PFASs is associated with poor metabolic health in children. We studied the association between prenatal and postnatal PFASs mixture exposure and cardiometabolic health in children, and the role of inflammatory proteins. In 1,101 mothers-child pairs from the Human Early Life Exposome project, we measured the concentrations of PFAS in blood collected in pregnancy and at 8 years (range = 6-12 years). We applied Bayesian Kernel Machine regression (BKMR) to estimate the associations between exposure to PFAS mixture and the cardiometabolic factors as age and sex- specific z-scores of waist circumference (WC), systolic and diastolic blood pressures (BP), and concentrations of triglycerides (TG), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterol. We measured thirty six inflammatory biomarkers in child plasma and examined the underlying role of inflammatory status for the exposure-outcome association by integrating the three panels into a network. Exposure to the PFAS mixture was positively associated with HDL-C and systolic BP, and negatively associated with WC, LDL-C and TG. When we examined the independent effects of the individual chemicals in the mixture, prenatal PFHxS was negatively associated with HDL-C and prenatal PFNA was positively associated with WC and these were opposing directions from the overall mixture. Further, the network consisted of five distinct communities connected with positive and negative correlations. The selected inflammatory biomarkers were positively, while the postnatal PFAS were negatively related with the included cardiometabolic factors, and only prenatal PFOA was positively related with the pro-inflammatory cytokine IL-1beta and WC. Our study supports that prenatal, rather than postnatal, PFAS exposure might contribute to an unfavorable lipidemic profile and adiposity in childhood.
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Ácidos Alcanossulfônicos , Doenças Cardiovasculares , Poluentes Ambientais , Fluorocarbonos , Teorema de Bayes , Poluentes Ambientais/toxicidade , Feminino , Fluorocarbonos/toxicidade , Humanos , Inflamação/induzido quimicamente , GravidezRESUMO
BACKGROUND: Environmental exposures in early life influence the development of behavioral outcomes in children, but research has not considered multiple exposures. We therefore aimed to investigate the impact of a broad spectrum of pre- and postnatal environmental exposures on child behavior. METHODS AND FINDINGS: We used data from the HELIX (Human Early Life Exposome) project, which was based on six longitudinal population-based birth cohorts in Europe. At 6-11 years, children underwent a follow-up to characterize their exposures and assess behavioral problems. We measured 88 prenatal and 123 childhood environmental factors, including outdoor, indoor, chemical, lifestyle and social exposures. Parent-reported behavioral problems included (1) internalizing, (2) externalizing scores, using the child behavior checklist (CBCL), and (3) the Conner's Attention Deficit Hyperactivity Disorder (ADHD) index, all outcomes being discrete raw counts. We applied LASSO penalized negative binomial regression models to identify which exposures were associated with the outcomes, while adjusting for co-exposures. In the 1287 children (mean age 8.0 years), 7.3% had a neuropsychiatric medical diagnosis according to parent's reports. During pregnancy, smoking and car traffic showing the strongest associations (e.g. smoking with ADHD index, aMR:1.31 [1.09; 1.59]) among the 13 exposures selected by LASSO, for at least one of the outcomes. During childhood, longer sleep duration, healthy diet and higher family social capital were associated with reduced scores whereas higher exposure to lead, copper, indoor air pollution, unhealthy diet were associated with increased scores. Unexpected decreases in behavioral scores were found with polychlorinated biphenyls (PCBs) and organophosphate (OP) pesticides. CONCLUSIONS: Our systematic exposome approach identified several environmental contaminants and healthy lifestyle habits that may influence behavioral problems in children. Modifying environmental exposures early in life may limit lifetime mental health risk.
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Poluentes Ambientais , Bifenilos Policlorados , Efeitos Tardios da Exposição Pré-Natal , Criança , Comportamento Infantil , Exposição Ambiental/análise , Poluentes Ambientais/análise , Europa (Continente) , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologiaRESUMO
INTRODUCTION: Early onset and high prevalence of allergic diseases result in high individual and socio-economic burdens. Several studies provide evidence for possible effects of environmental factors on allergic diseases, but these are mainly single-exposure studies. The exposome provides a novel holistic approach by simultaneously studying a large set of exposures. The aim of the study was to evaluate the association between a broad range of prenatal and childhood environmental exposures and allergy-related outcomes in children. MATERIAL AND METHODS: Analyses of associations between 90 prenatal and 107 childhood exposures and allergy-related outcomes (last 12 months: rhinitis and itchy rash; ever: doctor-diagnosed eczema and food allergy) in 6-11 years old children (n = 1270) from the European Human Early-Life Exposome cohort were performed. Initially, we used an exposome-wide association study (ExWAS) considering the exposures independently, followed by a deletion-substitution-addition selection (DSA) algorithm considering all exposures simultaneously. All the exposure variables selected in the DSA were included in a final multi-exposure model using binomial general linear model (GLM). RESULTS: In ExWAS, no exposures were associated with the outcomes after correction for multiple comparison. In multi-exposure models for prenatal exposures, lower distance of residence to nearest road and higher di-iso-nonyl phthalate level were associated with increased risk of rhinitis, and particulate matter absorbance (PMabs) was associated with a decreased risk. Furthermore, traffic density on nearest road was associated with increased risk of itchy rash and diethyl phthalate with a reduced risk. DSA selected no associations of childhood exposures, or between prenatal exposures and eczema or food allergy. DISCUSSION: This first comprehensive and systematic analysis of many environmental exposures suggests that prenatal exposure to traffic-related variables, PMabs and phthalates are associated with rhinitis and itchy rash.
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Eczema , Hipersensibilidade Alimentar , Criança , Estudos de Coortes , Eczema/epidemiologia , Eczema/etiologia , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Gravidez , PrevalênciaRESUMO
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 molecular omics signatures and child health outcomes. Cohort data are accessible for future research involving researchers external to the project.
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Exposição Ambiental , Mães/estatística & dados numéricos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Biomarcadores/sangue , Biomarcadores/urina , Pressão Sanguínea , Composição Corporal , Pesos e Medidas Corporais , Pré-Escolar , Metilação de DNA , Exposição Ambiental/análise , Europa (Continente)/epidemiologia , Feminino , Hipersensibilidade Alimentar/epidemiologia , Interação Gene-Ambiente , Substâncias Perigosas , Humanos , Lactente , Recém-Nascido , Masculino , Metaboloma , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Estudos Prospectivos , Proteoma , Testes Psicológicos , Testes de Função Respiratória , Fumar/epidemiologia , Fatores Socioeconômicos , Transcriptoma , População Urbana , Adulto JovemRESUMO
Per- and polyfluoroalkyl substances (PFASs) are man-made chemicals that contain at least one perfluoroalkyl moiety, [Formula: see text]. To date, over 4,000 unique PFASs have been used in technical applications and consumer products, and some of them have been detected globally in human and wildlife biomonitoring studies. Because of their extraordinary persistence, human and environmental exposure to PFASs will be a long-term source of concern. Some PFASs such as perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) have been investigated extensively and thus regulated, but for many other PFASs, knowledge about their current uses and hazards is still very limited or missing entirely. To address this problem and prepare an action plan for the assessment and management of PFASs in the coming years, a group of more than 50 international scientists and regulators held a two-day workshop in November, 2017. The group identified both the respective needs of and common goals shared by the scientific and the policy communities, made recommendations for cooperative actions, and outlined how the science-policy interface regarding PFASs can be strengthened using new approaches for assessing and managing highly persistent chemicals such as PFASs. https://doi.org/10.1289/EHP4158.
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Exposição Ambiental/prevenção & controle , Poluentes Ambientais , Poluição Ambiental/prevenção & controle , Fluorocarbonos , Monitoramento Ambiental , HumanosRESUMO
BACKGROUND: Diet is a major source of human exposure to hazardous environmental chemicals, including many perfluoroalkyl acids (PFAAs). Several assessment methods of dietary exposure to PFAAs have been used previously, but there is a lack of comparisons between methods. AIM: To assess human exposure to PFAAs through diet by different methods and compare the results. METHODS: We studied the dietary exposure to PFAAs in 61 Norwegian adults (74% women, average age: 42 years) using three methods: i) by measuring daily PFAA intakes through a 1-day duplicate diet study (separately in solid and liquid foods), ii) by estimating intake after combining food contamination with food consumption data, as assessed by 2-day weighted food diaries and iii) by a Food Frequency Questionnaire (FFQ). We used existing food contamination data mainly from samples purchased in Norway and if not available, data from food purchased in other European countries were used. Duplicate diet samples (n=122) were analysed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to quantify 15 PFAAs (11 perfluoroalkyl carboxylates and 4 perfluoroalkyl sulfonates). Differences and correlations between measured and estimated intakes were assessed. RESULTS: The most abundant PFAAs in the duplicate diet samples were PFOA, PFOS and PFHxS and the median total intakes were 5.6ng/day, 11ng/day and 0.78ng/day, respectively. PFOS and PFOA concentrations were higher in solid than liquid samples. PFOS was the main contributor to the contamination in the solid samples (median concentration 14pg/g food), while it was PFOA in the liquid samples (median concentrations: 0.72pg/g food). High intakes of fats, oils, and eggs were statistically significantly related to high intakes of PFOS and PFOA from solid foods. High intake of milk and consumption of alcoholic beverages, as well as food in paper container were related to high PFOA intakes from liquid foods. PFOA intakes derived from food diary and FFQ were significantly higher than those derived from duplicate diet, but intakes of PFOS derived from food diary and FFQ were significantly lower than those derived from duplicate diet. We found a positive and statistically significant correlation between the PFOS intakes derived from duplicate diet with those using the food diary (rho=0.26, p-value=0.041), but not with the FFQ. Additionally, PFOA intakes derived by duplicate diet were significantly correlated with estimated intakes from liquid food derived from the food diary (rho=0.34, p=0.008) and estimated intakes from the FFQ (rho=0.25, p-value=0.055). CONCLUSIONS: We provide evidence that a food diary or a FFQ-based method can provide comparable intake estimates to PFOS and PFOA intakes derived from a duplicate diet study. These less burdensome methods are valuable and reliable tools to assess dietary exposure to PFASs in human studies.
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Bebidas/análise , Exposição Ambiental , Poluentes Ambientais/análise , Fluorocarbonos/análise , Contaminação de Alimentos/análise , Adulto , Cromatografia Líquida , Dieta/estatística & dados numéricos , Monitoramento Ambiental , Feminino , Humanos , Pessoa de Meia-Idade , Noruega , Avaliação Nutricional , Espectrometria de Massas em TandemRESUMO
Dioxin analysis in food and feed can be characterized as an analytical application where very high accuracy is required at very low levels of contamination. Gas chromatography (GC) in combination with 13C-label isotope dilution (ID) high resolution mass spectrometry (HRMS) is the reference congener-specific technique characterized by pronounced selectivity, precision and trueness at parts-per-trillion (ppt) and sub-parts-per-trillion (sub-ppt) levels. The quality of the analytical data produced routinely by a laboratory should be adequate for its intended purpose, i.e., one will seek a compromise between the cost and time needed and the consequences of incorrect decisions due to erroneous results. The requirements for reproducibility are usually dependent on the analyte concentrations and have been expressed in various empirical functions. While Horwitz or modified functions are widely useful for many purposes, it would be difficult to expect these functions to cover every analytical problem. This study reports on precision characteristics achieved by the GC-ID-HRMS reference method for polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (DL-PCBs) in food and feed in two interlaboratory method-performance studies among expert laboratories with long-standing experience in this field. Striking linear functions in log scale between reproducibility standard deviation and congener's level over a concentration range of 10(-8)-10(-14)g per g fresh weight are observed. The data fit very well to a Horwitz-type function of the form sR=0.153c0.904, where sR and c are dimensionless mass ratios expressed in pg g(-1) on fresh weight, regardless of the nature of the toxic congeners, food and feed matrices, or sample preparation methods. We demonstrate that the proposed function is suitable for use as a fitness-for-purpose criterion for proficiency assessment in interlaboratory comparisons on dioxins and related compounds in food.