Unexpected common mechanistic pathways for embryotoxicity of warfarin and lovastatin
| Autor: | Petra Jaeckel, Gerhard P. Schwall, Martina Klemm-Manns, Wojciech Wozny, Margino Steemans, Slobodan Poznanovic, Horst Spielmann, Helmut Zengerling, Tina C. Stummann, Karlfried Groebe, Rainer Schöpf, André Schrattenholz, Werner Stegmann, Chaturvedala Sastri, Andrea Seiler, Annelieke K. Peters, Katrin Hayess |
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| Rok vydání: | 2010 |
| Předmět: |
Cell Survival
Endpoint Determination Developmental toxicity Context (language use) Computational biology Biology Animal Testing Alternatives Toxicology Proteomics Inhibitory Concentration 50 Mice Heat shock protein Toxicity Tests Animals Myocytes Cardiac Lovastatin Mode of action Embryonic Stem Cells Heat-Shock Proteins Proteomic Profiling Reproducibility of Results Cell Differentiation 3T3 Cells Embryonic stem cell Teratogens Biochemistry Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization ras Proteins Electrophoresis Polyacrylamide Gel Warfarin Stem cell |
| Zdroj: | Reproductive Toxicology. 30:121-130 |
| ISSN: | 0890-6238 |
| DOI: | 10.1016/j.reprotox.2010.05.006 |
| Popis: | Novel molecular content for fast in vitro strategies in the context of safety tests concerning developmental toxicity has a potential to substantially reduce animal experiments according to the "3R" concept (Reduce/Refine/Replace). Here we present and discuss data from a differential proteomic profiling of samples generated using embryonic stem cell derived in vitro models treated with a set of model substances. Among substance-dependent proteomic changes, potential surrogate markers were some isoforms of heat shock proteins and a component of the Ras pathway, present in several redundant isoforms due to posttranslational modifications. Both proteins are implicated in cell migration, cell survival, growth and embryonic development. Using the examples of warfarin and lovastatin, two substances with entirely different primary targets, the surrogate marker signature nevertheless indicates a common embryotoxic mode of action. We discuss these findings observed in in vitro toxicity tests, in a context of clinical validation and evidence-based toxicology. |
| Databáze: | OpenAIRE |
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