Protein biomarkers for in vitro testing of embryotoxicity
2009
Schrattenholz,A. | Hayess,K. | Klemm,M. | Steemans,M. | Peters,A.K. | Schwall,G. | Wozny,W. | Sastri,C. | Jaeckel,P. | Stegmann,W. | Zengerling,H. | Schoepf,R. | Poznanovic,S. | Stummann,T.C. | Seiler,A. | Spielmann,H. | Groebe,K.
German. New challenges for hazard and risk assessment in the chemical industry with regard to REACH legislation in Europe and related activities in the US and Japan require the development of novel in vitro models for toxicity tests. Developmental toxicityis regulated by guidelines, including assessments of brain morphology, behaviour, development of young animals, measurements of biomarkers for gliosis and cytotoxicity and more, requiring huge numbers of test animals. In the frame of a EuropeanFP6 project on reproductive toxicology (www.reprotect.eu) we used protein lysates from the validated embryonic stem cell test (EST) protocol and related ES models in a differential quantitative proteomic study to identify novel surrogate protein biomarkers for embryo toxicity.The combination of quantitative proteomic differences and functional data from appropriate in vitro models has generated a data set on a set of model substances assigned to four categories of embryotoxicity, i.e. "strong", "moderate", "mild", or "nonembryotoxic"based on in vivo data (selected by independent experts for the Reprotect consortium). Substance-dependent cardiomyocyte protein extracts were subjected to systematic differential proteomic profiling. Dual radioisotope labelling of proteins provided the rigorous quantitative pattern control necessary to obtain statistical significance. Moreover human and mouse embryonic stem cell models for neuronal differentiation and further substances were included to understand the general significance of our findings.The aim is to provide molecular content for novel and fast in vitro strategies for safety tests for developmental toxicity and the potential to substantially reduce animal experiments according to the 3Rs concept (Reduce/Refine/Replace).
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