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Background


The incidence of obesity (defined as abnormal or excessive fat accumulation that presents a risk to health) and its associated metabolic syndrome (i.e. metabolic abnormalities such as insulin resistance, type 2 diabetes, dyslipidaemia, and hypertension) has grown to epidemic proportions globally. Obesity is considered a disorder of imbalance with higher energy intake than energy expenditure, imposed on a background of genetic predisposition. However, there is still much uncertainty related to the causes and underlying physiological mechanisms of obesity. There is accumulating evidence that factors that influence long-term risk of obesity and related disorders begin very early in life. Both high and low birth weights have been linked to late development of obesity, as well as in utero nutrition, maternal weight, and gestational diabetes. A new paradigm has evolved in recent years, which stems from the idea that compromised fetal growth is strongly associated with a number of chronic conditions later in life (e.g., the “Barker hypothesis” or the “developmental origins of health and disease” (DOHaD) paradigm).

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Hypothesis


The OBELIX project will test the hypothesis that prenatal exposure to endocrine disrupting compounds (EDCs) in food is associated with the development of obesity and related disorders later in life. In animal models, in utero exposure to EDCs may lead to dose-related effects on obesity development, by altered epigenetic programming in target tissues involved in energy homeostasis and appetite regulation.

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Endocrine disrupting chemicals


The European Commission has defined an EDC or an “endocrine disruptor” as “an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations.” A growing body of literature suggests that exposure to chemicals during critical periods of development may result in obesity. Exposure to EDCs may disturb epigenetic, structural and functional adaptive responses responsible for developmental programming. In particular, an important mechanism for in utero and early developmental effects of EDCs is thought to be altered epigenetic control of gene expression, which alters developmental programming without changes in DNA sequences, and results in a tissue that may appear normal but is functionally compromised. OBELIX will study selected chemicals from six major groups of EDCs: dioxin-like compounds, non-dioxin like compounds, organochlorine pesticides, brominated flame retardants, phthalates and perfluorinated compounds. These chemical groups all have different mechanisms of endocrine action, and some evidence exists of their effects on obesity or related processes, either from epidemiological studies or from animal studies.

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Objectives of OBELIX


OBELIX will address 6 main objectives, which are divided over 4 work packages (WP):

1) To assess prenatal exposure in humans to major classes of endocrine disrupting chemicals in food identified as potential inducers of obesity and related disorders later in life, using mother-child cohorts from various European regions with different food contaminant exposure patterns. (WP 1)

2) To relate markers for early life exposure to EDCs with effect biomarkers, novel biomarkers and health outcome data which are related to risk for obesity and related disorders later in life. (WP 1)

3) To perform hazard characterization of in utero exposure to representatives of major classes of EDCs in food with respect to the development of obesity later in life, using dose-response analysis in a rodent (mouse) model. (WP2)

4) To determine mechanisms of action of obesogenic EDCs using analysis of effect biomarkers, gene expression and epigenetic analysis. Mouse models, in vitro models and analysis in peripheral mononuclear cells of biological samples from the cohorts, will be used as complementary tools. (WP 2)

5) To perform risk assessment of prenatal exposure to obesogenic EDCs in food, by integrating maternal exposure through food, contaminant exposure and health effect data in children, and hazard characterization and mechanistic information in animal and in in vitro studies. (WP 3)

6) To coordinate the project and disseminate the results. (WP4)

The Obelix Project