Profiling of drugs and environmental chemicals for functional impairment of neural crest migration in a novel stem cell-based test battery

Article Article scientifique Article Profiling of drugs and environmental chemicals for functional impairment of neural crest migration in a novel stem cell-based test battery eng 2014 author Zimmer B author Pallocca G author Dreser N author Foerster Sunniva 664956 author Waldmann T author Westerhout J author Julien Stéphanie 135125 Stéphanie Sgroi author Krause Karl-Heinz 23022 author van Thriel C author Hengstler J G author Sachinidis A author Bosgra S author Leist M 1109-1126 10.1007/s00204-014-1231-9 24691702 0340-5761 Developmental toxicity in vitro assays have hitherto been established as stand-alone systems, based on a limited number of toxicants. Within the embryonic stem cell-based novel alternative tests project, we developed a test battery framework that allows inclusion of any developmental toxicity assay and that explores the responses of such test systems to a wide range of drug-like compounds. We selected 28 compounds, including several biologics (e.g., erythropoietin), classical pharmaceuticals (e.g., roflumilast) and also six environmental toxicants. The chemical, toxicological and clinical data of this screen library were compiled. In order to determine a non-cytotoxic concentration range, cytotoxicity data were obtained for all compounds from HEK293 cells and from murine embryonic stem cells. Moreover, an estimate of relevant exposures was provided by literature data mining. To evaluate feasibility of the suggested test framework, we selected a well-characterized assay that evaluates 'migration inhibition of neural crest cells.' Screening at the highest non-cytotoxic concentration resulted in 11 hits (e.g., geldanamycin, abiraterone, gefitinib, chlorpromazine, cyproconazole, arsenite). These were confirmed in concentration-response studies. Subsequent pharmacokinetic modeling indicated that triadimefon exerted its effects at concentrations relevant to the in vivo situation, and also interferon-β and polybrominated diphenyl ether showed effects within the same order of magnitude of concentrations that may be reached in humans. In conclusion, the test battery framework can identify compounds that disturb processes relevant for human development and therefore may represent developmental toxicants. The open structure of the strategy allows rich information to be generated on both the underlying library, and on any contributing assay. Animals Cell Differentiation/drug effects Cell Movement/drug effects Dose-Response Relationship, Drug Embryonic Stem Cells/drug effects HEK293 Cells/drug effects Humans Mice Models, Theoretical Neural Crest/cytology Toxicity Tests/methods Dewey 616.07 137 Département de pathologie et immunologie 21F false 38 Radicaux libres et cellules souches embryonnaires 60 Archives of toxicology 88 5 2178846e-f42f-4ba2-99bc-3330a82b21ec Article (Published version) Public profiling of drugs.pdf 4520012 application/pdf openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Profiling of drugs and environmental chemicals for functional impairment of neural crest migration in a novel stem cell-based test battery	Archives of toxicology			2014	529	259

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