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In order to evaluate a proof-of-concept for the identification of mixture health effects, a selected set of case studies on human health endpoints of concern was conducted in the context of HBM4EU. This report describes each of the case studies, as well as a consistent assessment framework that was used for each of the case studies. The case studies show that chemicals from different regulatory domains work together to produce considerable exceedances of combined acceptable exposures.&nbsp

International audience; AbstractIntroduction: 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.

Background Several environmental contaminants were shown to possibly influence fetal growth, generally from single exposure family studies, which are prone to publication bias and confounding by co-exposures. The exposome paradigm offers perspectives to avoid selective reporting of findings and to control for confounding by co-exposures. We aimed to characterize associations of fetal growth with the pregnancy chemical and external exposomes. Methods Within the Human Early-Life Exposome project, 131 prenatal exposures were assessed using biomarkers and environmental models in 1287 mother–child pairs from six European cohorts. We investigated their associations with fetal growth using a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering each exposure independently. We corrected for exposure measurement error and tested for exposure–exposure and sex–exposure interactions. Results The DSA model identified lead blood level, which was associated with a 97 g birth weight decrease for each doubling in lead concentration. No exposure passed the multiple testing-corrected significance threshold of ExWAS; without multiple testing correction, this model was in favour of negative associations of lead, fine particulate matter concentration and absorbance with birth weight, and of a positive sex-specific association of parabens with birth weight in boys. No two-way interaction between exposure variables was identified. Conclusions This first large-scale exposome study of fetal growth simultaneously considered >100 environmental exposures. Compared with single exposure studies, our approach allowed making all tests (usually reported in successive publications) explicit. Lead exposure is still a health concern in Europe and parabens health effects warrant further investigation.

Background: The exposome is defined as encompassing all environmental exposures one undergoes from conception onwards. Challenges of the application of this concept to environmental-health association studies include a possibly high false-positive rate. Objectives: We aimed to reduce the dimension of the exposome using information from DNA methylation as a way to more efficiently characterize the relation between exposome and child body mass index (BMI). Methods: Among 1,173 mother-child pairs from HELIX cohort, 216 exposures ("whole exposome") were characterized. BMI and DNA methylation from immune cells of peripheral blood were assessed in children at age 6-10 years. A priori reduction of the methylome to preselect BMI-relevant CpGs was performed using biological pathways. We then implemented a tailored Meet-in-the-Middle approach to identify from these CpGs candidate mediators in the exposome-BMI association, using univariate linear regression models corrected for multiple testing: this allowed to point out exposures most likely to be associated with BMI ("reduced exposome"). Associations of this reduced exposome with BMI were finally tested. The approach was compared to an agnostic exposome-wide association study (ExWAS) ignoring the methylome. Results: Among the 2284 preselected CpGs (0.6% of the assessed CpGs), 62 were associated with BMI. Four factors (3 postnatal and 1 prenatal) of the exposome were associated with at least one of these CpGs, among which postnatal blood level of copper and PFOS were directly associated with BMI, with respectively positive and negative estimated effects. The agnostic ExWAS identified 18 additional postnatal exposures, including many persistent pollutants, generally unexpectedly associated with decreased BMI. Discussion: Our approach incorporating a priori information identified fewer significant associations than an agnostic approach. We hypothesize that this smaller number corresponds to a higher specificity (and possibly lower sensitivity), compared to the agnostic approach. Indeed, the latter cannot distinguish causal relations from reverse causation, e.g. for persistent compounds stored in fat, whose circulating level is influenced by BMI. The study has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 308,333 – the HELIX project for data collection and analyses. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant n°0.1 UO1 NS 047537–01 and grant no.2 UO1 NS 047537-06A1). We also received support from Région Auvergne-Rhône-Alpes for collaborations with Catalunya. Dr. Chatzi was supported by NIH P30ES007048, R21ES029681, R01ES029944, R01ES030364, R21ES028903, and by Environmental Protection Agency RD-83544101.

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 31472 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. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333-the HELIX project. Dr Maribel Casas and Dr Jordi Julvez received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (MS16/00128, MS14/00108). INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, the Conselleria de Sanitat, Generalitat Valenciana, Department of Health of the Basque Government; the Provincial Government of Gipuzkoa, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), and NIH/NINDS (grant no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1). The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011-2014; 'Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-2015). The work was also supported by MICINN (MTM2015-68140-R) and Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII. CW received funding from the Fondation de France.

Background Bacterial meningitis is a major public health problem in the African ‘Meningitis Belt', where recurrent unpredictable epidemics occur. Despite the introduction in 2010 of the conjugate A vaccine, the reactive strategy remains important for responding to epidemics caused by other bacteria and in areas not yet vaccinated. Review of weekly numbers of suspected cases in Niger, Mali and Burkina Faso identified spatial disparities in the annual patterns of meningitis, which suggested a more local way of defining epidemics and initiating a timely vaccination campaign. Method We defined an epidemic district-year as an excess of cases compared to the incidence previously experienced in the given district. Groups of similar districts in terms of seasonal patterns were identified by cluster analysis. We investigated a cluster-specific criterion of early epidemic onset to anticipate epidemic district-years. Results These were encouraging, as epidemic district-years were fairly efficiently captured, with an average time gained of 2.5 weeks over the current strategy. Conclusion This early-onset criterion could help ensure timely implementation of vaccination campaigns without the need to modify the implemented surveillance system. The next step is to extend this study to other countries of the Meningitis Belt, and to explain the differences in seasonal patterns in the different clusters

BACKGROUND: There 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. METHODS: Simulations 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. RESULTS: GLINTERNET 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. CONCLUSIONS: GLINTERNET and DSA provided better performance in detecting two-way interactions, compared to other existing methods.

Supplementary results (tables and figures). (PDF 1220 kb)

Objectives: Neisseria meningitidis is the major cause of seasonal meningitis epidemics in the African meningitis belt. In the changing context of a reduction in incidence of serogroup A and an increase in incidence of serogroups W and C and of Streptococcus pneumoniae, a better understanding of the determinants driving the disease transmission dynamics remains crucial to improving bacterial meningitis control. Methods: The literature was searched to provide a multi-disciplinary overview of the determinants of meningitis transmission dynamics in the African meningitis belt. Results: Seasonal hyperendemicity is likely predominantly caused by increased invasion rates, sporadic localized epidemics by increased transmission rates, and larger pluri-annual epidemic waves by changing population immunity. Carriage likely involves competition for colonization and cross-immunity. The duration of immunity likely depends on the acquisition type. Major risk factors include dust and low humidity, and presumably human contact rates and co-infections; social studies highlighted environmental and dietary factors, with supernatural explanations. Conclusions: Efforts should focus on implementing multi-country, longitudinal seroprevalence and epidemiological studies, validating immune markers of protection, and improving surveillance, including more systematic molecular characterizations of the bacteria. Integrating climate and social factors into disease control strategies represents a high priority for optimizing the public health response and anticipating the geographic evolution of the African meningitis belt.

The objectives of this study are to evaluate the effects of maternal exposure to diluted diesel exhaust at levels observedin large European urban aeres and placental growth using a rabbit model.

Particle size distribution during exposure. (PPTX 52Â kb)

Head measurements during gestation and post-mortem. During gestation, head length was measrued by ultrasound. Post-motem, head measurements were performed using a digital caliper. (PPTX 775Â kb)

Fetoplacental biometry at 28 dpc for the second generation. Female rabbits inhaled 1mg/m3 of NPs, 2 hours/day, 5 days/week, from 3 dpc to 27dpc. Dams were allowed to give birth generation F1. Adult F1 female (7.5 months of age) were mated and euthanized pregnant at 28 dpc. Fetoplacental units of generation F2 were collected in control (C) and exposed (E) groups. Effect of grand-dam (F0) pregnancy exposure to engine diesel exhaust on second-generation fetuses was estimated using linear model with random effect of dam (F1) adjusted for number of fetuses by dam, fetus position in the horn and fetus sex. All data are expressed as median [Q1;Q3]. (*p < 0.05). (PPTX 76Â kb)

Morphological analysis of labyrinthine area at 28 dpc from first generation. All data are expressed as median [Q1;Q3]. (PPTX 63Â kb)