Promotor: Prof.dr. B. van de Water, Co-promotores: L.T.M. van der Ven, A.S. Kienhuis
|Links||Thesis in Leiden Repository|
In this thesis we showed the applicability of the zebrafish embryo as an alternative model for hepatotoxicity testing using analysis of mechanisms through toxicogenomics. By applying a variety of toxicogenomics techniques, we were able to characterize specific responses. NGS revealed that hepatotoxicity-associated gene expression remains detectable even in non-tissue specific analysis in whole body zebrafish embryo homogenates. Gene and protein expression profiling resulted in identification of a set of marker genes that could be linked to pathways and processes, which are associated with a general hepatotoxic response. Application of markers will increase the throughput of the system. Finally, we showed that the zebrafish embryo model shares similarities with in vivo and in vitro models for hepatotoxicity, where the model has more commonality with the mouse in vivo and in vitro models than with the other models. The model has the advantages of the in vitro models with the biological complexicity of an in vivo response, and we anticipate that the zebrafish embryo can contribute to the 3R strategy by reducing, refining and replacing animal studies. Our observations support that this model can have added value in a tiered approach as a pre-screen for the detection of hepatotoxic potential of compounds.