Objectives:
General objectives are to:
- Provide relevant data/samples for testing the hypothesis of exposure-effect relationships of endocrine disruptors to metabolic disorders, overweight, obesity and diabetes.
- Quantify the link between exposures to endocrine disruptors and obesity and diabetes taking overweight as an intermediate phenotype.
Specific objectives are to:
- Identify major gaps in knowledge in the relationships between endocrine disruptors and overweight, obesity and diabetes by analysing existing data available in HEALS that focuses on internal and external exposures and their effects on metabolic disorders such as overweight, obesity and diabetes;
- Assess internal exposure, investigate hypotheses on mechanisms of action using the Stream 2 methodological framework on –omics and epigenetics and assess biomarkers of exposure, effect and susceptibility throughavailable data;
- Assess external exposure in link with Stream 3 and its associations with overweight, obesity and diabetes after taking into account potential confounders and interactions (lifestyle, physical activity, social class, smoking, air pollution) through the analysis of data from existing cohorts and studies;
- Assess the spatio-temporal relationships between internal and external environmental exposures and health data through the analysis of data from existing cohorts and studies geocoded when possible;
- Apply the HEALS methodology to validate a model strategy for the establishment of causal links between exposures and overweight, obesity and diabetes to be applied to available data (general population, singletons, twins’ studies, matched singletons).
Description of work and role of partners:
The overall aim of this WP is to provide relevant data to unravel the relationship between body burden from endocrine disrupting chemicals and the onset of overweight, obesity and diabetes in childhood. Secondly, this WP aims at validating and helping to refine the development of the HEALS methodological framework and platform. Data allowing the exposome assessment will be made available, namely: biological samples (e.g. umbilical cord blood, urine) useful for -omics analyses; information about lifestyle and health from questionnaires and follow-up studies, individual and environmental geocoded data for the assessment and management of temporally-spatially resolved data and models. In this work, results from the EU-funded OBELIX project will be taken into account.
The “OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life” has provided useful data on whether prenatal exposure to endocrine disrupting compounds in food plays a role in the development of obesity and related disorders later in life through a multidisciplinary approach that combined epidemiology, neonatology, endocrinology, toxicology, analytical chemistry and risk that will be of integrated in the HEALS approach. The links with OBELIX will be established through collaborations, exchanges, publications and other initiatives including common initiatives like a workshop.
Populations
Effects from exposures to endocrine disruptors on metabolism will be studied on studies/cohort for which data of interest are available. Mother-child cohorts where both exposure (fetal and/or neonatal) and weight outcomes have been measured will be preferentially considered. Methods perfected in the previous WPs and Streams (relevant human biomonitoring, -omics; multi-media and systems biology modelling, etc.) will be used to define mechanistic associations between these environmental stressors and adverse effects on metabolism. Such population studies/cohorts will include individuals of different age groups and mother-child pairs in several European countries (DEMOCOPHES, n=1,000), Slovenia (PHIME and DEMOCOPHES, n=600), France (EDEN, n=1,200), Spain (INMA and CHIS2000, n=1,820), Croatia (PHIME, n=285) and Poland (RePRO_PL, n=1,700), exposed to phthalates, Bisphenol A and/or monitored for hormone activity in blood by the Calux assay, and Portugal (EPITeen, n=2160) for a total of almost 8,500 individuals. In addition, twin registries and cohorts in Europe and Australia will also contribute to these WPs for a total of almost 150,000 individuals with information on BMI and diabetes.
The work will be divided into 4 tasks:
Task 16.1 State of art review on exposome in relation to overweight, obesity and diabetes (UPMC, UPD, JSI, LMU, CSIC, FMUP, NCSRD, KCL)
Endocrine disruptors comprise a range of chemicals and medicines. The most commonly measured chemicals are phthalates and Bisphenol A as available in the DEMOCOPHES, French, Spanish and Slovenian samples. The effect biomarker of hormone activity (among others, Calux measured by TNO) reflects exposures to estrogenic and antiandrogenic exposures (e.g. dioxin) and biomonitoring data is available in the HBM samples as previously mentioned. Available anonymised data will be sought as secondary use from the original studies, taking into account the ethical aspects of privacy and data protection and data sharing according to informed consent, local ethical approval and the governance structures of each relevant HEALS partner involved in this WP. Accurate geo-referencing of the place of residence will be carried out for all relevant study persons to complete the already existing geo-referenced data. If possible, other places of activities (such as mother’s workplace) will be collected and geocoded.
Task 16.2 Selection and analysis of samples for definition of internal exposome (UPD, FMUP, JSI, UPMC, NCSRD, CSIC)
With the support of Stream 2 partners, available biological samples will be selected for -omics and biomarker analyses where possible. Eventual planning of new sample collection in WP17 will also be considered as needed to complete the available dataset or as inclusion in planned not yet started studies. From the results obtained with the metabolomic study, UPD will analyze at the mRNA level (and when possible at the protein level) the expression of genes involved in the modifications of metabolites on relevant cellular models (for example the human adipocyte-like cell line hMADS or a liver-derived cell line such as hepaRG, HepG2, HuH7) following exposure to the pollutants found in the same biological samples for confirmation of the mechanistic hypotheses constructed using the metabolome and adductome data. According to the available budget, this step will concern samples of up to 1,000 individuals.
Task 16.3 External exposure assessment (UPMC, LMU, CSIC, NCSRD, OIKON)
In close connection with Stream 3 partners, the availability of spatio-time-related and cumulative environmental exposures (air, soil, water, food) to endocrine disruptors will be checked. Effects resulting from such exposure currently have attracted significant attention and the international actions in monitoring and evaluating environmental sources and exposures will be followed through the HEALS platform (Stream 4). External exposure assessment will be conducted for all the individuals for whom personal address is available, which means at least 5000 individuals from major birth cohorts and twins registries.
Task 16.4 Application of the HEALS methodology to population studies (UPMC, KCL, NIPH, SDU, FMUP, UPD, OIKON, JSI)
The exposome components (internal and external exposures) reflecting environmental and domestic exposure sources will be used for construction of determinants of exposure to endocrine disruptors in the general population and for the establishment of the links between exposome and overweight, obesity and diabetes. The HEALS methodology will be refined in Task 16.4 through its application on the population samples and data collected by the participating cohorts described under Populations above. The refined methodological protocols will be used in WP17 to study environment-wide associations with the specific health perturbations (obesity and type II diabetes).
