Induction of Differentiation in F9 Cells and Activation of Peroxisome Proliferator-Activated Receptor δ by Valproic Acid and Its Teratogenic Derivatives
- 1Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany (U.W., S.S., M.L., M.G.); and2Zentrumsabteilung für Lebensmitteltoxikologie, der Tiermedizinischen Hochschule, Hannover, Germany (H.N.)
Abstract
The antiepileptic drug valproic acid (VPA) is teratogenic, because it induces birth defects in some children of mothers treated for epilepsy. Cellular and molecular actions associated with teratogenicity were identified by testing differentiation of F9 embryocarcinoma cells. VPA altered cell morphology and delayed proliferation. Specific differentiation markers (e.g., c-fos and keratin 18 mRNA and particularly the activating protein-2 transcription factor protein) were induced. This pattern differs from the pattern induced by other teratogens or F9 cell-differentiating agents. Induction of differentiation correlated with teratogenicity because teratogenic derivatives of VPA, such as (S)-4-yn-VPA, induced differentiation, whereas closely related nonteratogenic compounds, such as (R)-4-yn-VPA, 2-en-VPA, and 4-methyl-VPA, did not. In the cellular signaling network, the peroxisome proliferator-activated receptor δ (PPARδ) was activated selectively by VPA and teratogenic derivatives. Depletion of PPARδ by antisense RNA expression precluded the response of F9 cells to VPA. In conclusion, our data show that VPA and its teratogenic derivatives induce a specific type of F9 cell differentiation and that PPARδ is a limiting factor in the control of differentiation.
Footnotes
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Send reprint requests to: Martin Göttlicher, Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, Hermann-von-Helmholtz-Platz 1, D-76344 Eggenstein-Leopoldshafen, Germany. E-mail: martin.goettlicher{at}itg.fzk.de
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The work was supported by the Deutsche Forschungsgemeinschaft (GO 473/2, Bonn, Germany) and the Bundesamt für Gesundheitlichen Verbraucherschutz (BGVV-ZEBET, Berlin, Germany).
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S.S. and U.W. have presented their respective contributions to this work as a diploma thesis; each contributed equally to this work.
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This work has been presented in part at the 1998 fall/winter meeting of the German Society of Pharmacology and Toxicology.
- Abbreviations:
- VPA
- valproic acid
- PPAR
- peroxisome proliferator activated receptor
- GR
- glucocorticoid receptor
- RA
- retinoic acid
- AP
- alkaline phosphatase
- AP-2
- activating protein-2
- NCC
- neural crest cell
- EMSA
- electrophoretic gel mobility shift analysis (“band-shift”)
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- Received July 26, 2000.
- Accepted January 9, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
