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Joint Research Activities
The research activities have been structured around eight interactive work packages: WP12-13 Novel detection methods, WP14 Functional screening, WP15 Nutrigenomics, WP16 Cross-species comparison, WP17 Mechanisms of disease development, WP18 Metabolism, and WP19 Chemicals as contaminants in food. WP12 - Analytic MethodsThe main objective of WP12 is to develop analytical test systems which allow the detection and quantification of chemical contaminants in food samples. The enormous number of food-derived chemicals makes it impracticable to study all. CASCADE researchers have therefore chosen four model compounds: genistein, bisphenol A, vinclozolin, and TCDD. These four compounds are known to interfere with the endocrine system of the human body. In order to trace low concentrations of those compounds in food items, advanced analytical methods are required. WP12 researchers deve
WP leader: Emilio Benfenati WP13 - In silico ScreeningThe priority of WP13 is to develop computer based tools that allow to identify new chemical compounds with possible endocrine disrupting properties. Hereby, researchers make use of known nuclear receptor structures in order to find chemicals which could possible interact with them. One method used for receptor interaction studies is QSAR which stands for Quantitative Structure-Activity Relationships. This method is based on the assumption that chemicals with similar chemical properties have similar biological activities. Once new endocrine disrupting candidates have been identified, the strength of the interactions between those candidates and the nuclear receptors are measured by applying RIfS -Reflectometric Interference Spectroscopy. WP13 will finally provide a list of potential endocrine disrupters to be studied in WP14-17.
WP leader: Günther Gauglitz WP14 - Functional ScreeningThe aim of WP14 is to generate cell and animal model systems suitable for a toxicological analysis of endocrine disrupting chemicals. The main interest in generating cell model systems is to be able to screen a large number of chemicals for their potential to interfere with nuclear receptors. These cells contain gene constructs that contain regulatory elements (e.g. hormone-responsive elements) that are linked to reporter genes such as luciferase or green flourescent dye. These reporter cells response with high sensitivity to chemicals, which means that even low-dose of chemicals can be studied. After exposure to endocrine disrupting chemicals, changes in gene expression and signal transduction can be detected. Animal model systems are used to study tissue specific and physiological responses. Here the uptake and distribution of endocrine disrupting chemicals are examined, and the effects on the animal metabolism are monitored. For example, reporter mice for estrogen and androgen receptors are used for study long-term effects of diets contaminated by endocrine disrupting chemicals. In addition to the mouse reporter systems, WP14 researchers generate amphibian model systems, such as tadpoles. The amphibians are used for large scale screening of hormone-interfering compounds and for the study of their effects on the amphibian metabolism, angiogenic, immune and neurogenic systems.
WP leader: Adriana Maggi WP15 - NutrigenomicsThe goal of WP15 is to identify genes whose activation is indicative of exposure to endocrine disrupting chemicals. WP15 researchers test three model organisms: fish, mouse and mammals. All three organisms are exposed to the four CASCADE model compounds (genistein, bisphenol A, vinclozolin, and TCDD) as well as to the list of putative endocrine disrupting chemicals retrieved from WP12-13, and target gene expression profiles are obtained. The final outcome is to deliver a repertoire of genes (biomarkers) that are specifically regulated in response to endocrine disrupting chemicals. In collaboration with WP17, these genes are then compared to the list of genes indicative for pathophysiological conditions of an organism. If possible, predictions on the effect of a chemical on different human disease situations will be attempted. The identified biomarkers will provide indicators to measure the effects of contaminated food intake. The results of WP15 will subsequently feed into the activities of the risk assessment work group (WP10 and 11).
WP leader: Martin Göttlicher
WP16 - Cross-Species Comparison
In addition, the sensitivity and specificity of different CASCADE reporter systems (WP14) are compared. The goal is to provide validated detection systems that allow to test whether any given chemical compound has pathophysiological effects.
WP leader: Vincent Laudet
WP17 - Mechanism of Disease DevelopmentThe main objective of WP17 is to understand the role of nuclear receptors in the development of diseases caused by food-derived contaminants. Nuclear receptors play a critical role in the organism development and maintains of health. The exposure to food-derived contaminants that interfere with them may result in aberrant nuclear receptor functions. Dysfunctions of nuclear receptors have been related to diseases, such as breast, prostate and colon cancer, atherosclerosis, type 2 diabetes and osteoporosis. In order to study nuclear receptor related diseases, reporter animals are exposed to different diets and the mechanisms of disease development are analyzed. Latest results have revealed that endocrine disruptive compounds have to be considered as multi-facetted chemical modulators of complex networks of physiological processes. WP17 researchers have started to look beyond this networks and aim to explore the complexity of regulatory mechanism such as receptor-co-activator interactions and crosstalks between two or more signalling pathways.
WP leader: Olli Jänne WP18 - MetabolismThe main purpose of the WP18 is to provide information on the metabolic change induced by chemicals in living systems. Previous study of the metabolic pathways of CASCADE model compounds revealed a set of metabolites produced in response to the exposure to those compounds. Our researchers continue now to study the biological effects of those metabolites on living organisms. Since chemical compounds undertake different pathways to reach their target, the metabolites duration and location need to be monitored. Hereby it is necessary to apply very sensitive methods as the turnover of many metabolites is very fast with half-lives of less than a second. In order to evaluate the endocrine disrupting activity of the metabolites the reporter cell systems described in WP14 are used. Furthermore, in silico screening methods from WP13 will help to identify those metabolites that are likely to bind to a selected nuclear receptor.
WP leader: Cathrine Leclercq WP19 - Chemicals as Contaminants in FoodWP19 is a joint project based on the expertise of all CASCADE researchers. The main objectives are to identify the most relevant endocrine disrupters present in food and to develop suitable methods to test food contaminated by them.
The final outcome is to deliver a new food testing platform based on the fact that nuclear receptors can act as sensors for environmental stimuli. So far, two food items have been selected – bread and babyfood. For each of them an expert group has been formed and the following subprojects have been designed:
Whole grain wheat bread In this project multiple CASCADE methods will be used to assess the possible endocrine disruptive activities of chemicals in wheat bread. The obtained data will be implemented in subsequent health risk assessment studies (WP10-11).
WP leader: Sari Mäkelä
Babyfood The main objective of the Babyfood project is to analyse the nutritional quality of commercial infant food and to provide information on the impact of potential endocrine disrupting contaminants. The results will be used to develop recommendations for risks on children’s health.
WP leader: K.W. Schramm
Photos by Anders Kallersand
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