Journal Article

The Embryonic Stem Cell Test as Tool to Assess Structure-Dependent Teratogenicity: The Case of Valproic Acid

Christian Riebeling, Ralph Pirow, Klaus Becker, Roland Buesen, Daniel Eikel, Johanna Kaltenhäuser, Frauke Meyer, Heinz Nau, Birgitta Slawik, Anke Visan, Jutta Volland, Horst Spielmann, Andreas Luch and Andrea Seiler

in Toxicological Sciences

Volume 120, issue 2, pages 360-370
Published in print April 2011 | ISSN: 1096-6080
Published online January 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr001

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Teratogenicity can be predicted in vitro using the embryonic stem cell test (EST). The EST, which is based on the morphometric measurement of cardiomyocyte differentiation and cytotoxicity parameters, represents a scientifically validated method for the detection and classification of chemicals according to their teratogenic potency. Furthermore, an abbreviated protocol applying flow cytometry of intracellular marker proteins to determine differentiation into the cardiomyocyte lineage is available. Although valproic acid (VPA) is in worldwide clinical use as antiepileptic drug, it exhibits two severe side effects, i.e., teratogenicity and hepatotoxicity. These limitations have led to extensive research into derivatives of VPA. Here we chose VPA as model compound to test the applicability domain and to further evaluate the reliability of the EST. To this end, we study six closely related congeners of VPA and demonstrate that both the standard and the molecular flow cytometry-based EST are well suited to indicate differences in the teratogenic potency among VPA analogs that differ only in chirality or side chain length. Our data show that identical results can be obtained by using the standard EST or a shortened protocol based on flow cytometry of intracellular marker proteins. Both in vitro protocols enable to reliably determine differentiation of murine stem cells toward the cardiomyocyte lineage and to assess its chemical-mediated inhibition.

Keywords: valproic acid; congeners; embryonic stem cell test; structure-activity relationships; embryotoxicity; teratogenicity

Journal Article.  7288 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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