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Data Protection Declaration
Imprint
Analysis of the funtional interaction of the circadian rythm with the endocrine system for the establishment of sensitive in vitro test systems.
Project
Project code: BfR-TOX-08-1322-636
Contract period: 01.04.2015
- 31.12.2018
Purpose of research: Experimental development
The importance of substances that interfere the endocrine system leading to health effects , so called endocrine disruptors, have been a matter of controversial discussions in recent years that are still ongoing. A ban of substances that are classified as endocrine disruptor has already been implemented in the regulation of chemicals, pesticides as well as biocides, although a final assessment process for identifying and classifying of endocrine disruptors is still pending. Here, in vitro test systems could be a useful tool to provide mechanistic insights that facilitate this process and might also help to minimize the use of animal experiments in the analysis of this endpoint. The aim of the project described here is to evaluate the importance of the interaction of the estrogen receptor alpha (Er-alpha) with the circadian system for the establishment of sensitive and predictive test methods in the field of endocrine disruptors. For this purpose, entrained cells will be treated with Er-alpha-agonists and –antagonists at various points in time to test for an influence on the sensitivity of the test system. If successful, this might allow the detection of endocrine activities at biologically and toxicologically relevant concentrations. Furthermore, new molecular endpoints are to be identified, whereby the components of the circadian system themselves could be of interest. These analyses are therefore aiming at the development of sensitive and predictive molecular test systems for the identification of potential endocrine disruptors.
In this funding peroid we were abel to establish the necessary experimental tools to analyse the circadian rhythm of cells in culture, including the entrainment procedure itself, the expression analysis of genes involved in the circadian regulatory network, as well as the generation of stable transgenic cell lines that allow the direct detection of the various circadian phasis in living cells. However, despite previous pubished observations, the selected cell line hTert-HME1 proved to be not suitable for the analysis of functional interactions between the cicadian rhythm and estrogen signalling. To this end, this is the only cell line that has been described to be estrogen responsive and displaying an reproducible and stable circadian rhythm. Thus, future work has to show, if other cells lines can be identified or generated that fullfill these criteria. For now, it seems more appropriate to focus on other toxicological relevant aspects that have been shown to be modulated by the circadian rhythm, e.g. the regulation of metabolic enzymes of the CYP family.
Section overview
Subjects
- Animal health
- Toxicology
Framework programme
Funding programme
Excutive institution
BfR - Department 9: Experimental Toxicology and ZEBET (BfR - TOX)
