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Data Protection Declaration
Imprint
Modelling of the toxome of cultivated human hepatocytes (LivSys)
Project
Project code: BfR-LMS-08-1334-219
Contract period: 01.12.2013
- 30.06.2016
Purpose of research: Applied research
Upon exposure to toxic compounds hepatocytes activate ‘stress response pathways’. The principal research objectives are (1) to model the stress pathways in 3D cultures of human hepatocytes and (2) to test and validate their applicability for identification of hepatotoxic compounds. It has been well established that upon exposure to toxic com-pounds hepatocytes react with activation of ‘stress response pathways’ in order to re-establish the cellular equilibrium. Using ‘omics’ data it is possible to analyse if and to which extent ‘stress response pathways’ are activated. Moreover, the pattern and intensity of activated stress pathways allows conclusions about the involved mechanisms. The current project will be based on our already established data base of hepatotoxic compounds tested in human hepatocytes by Affymetrix gene arrays. Using a sets of ‘training’ and ‘follow-up’ compounds we will model which stress pathways are activated and can be used as ‘alerts’ for toxicological risk evaluation.
In the LivSys pilot phase, the central result of IfADo was the identification of a set of seven marker genes (7 gene signature), which were shown to be deregulated in human primary hepatocytes in the presence of hepatotoxic compounds. A prevalidation study was conducted at BfR that verified the predictivity of these marker genes. The results showed a good correlation with the results that were generated at IfADo demonstrating a good robustness of the in vitro test system. This is the basis for the success of future work that is planned regarding the follow-up project LivSys-Transfer. Moreover, the characterization of the molecular effects of eight perfluorinated substances (PFAS) was realized. Experiments on the activation of nine different human nuclear receptors by PFAS were finished in the LivSys pilot phase. It was shown that these substances predominantly activate the nuclear receptor PPARa and the other receptors were activated – if at all – only to a minor degree. These data will be correlated with gene expression data as soon as these are available.
Section overview
Subjects
- Biotechnology
- Toxicology
