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Molecular Pharmacology

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Research ArticleArticle

Valproic Acid Increases Formation of Reactive Oxygen Species and Induces Apoptosis in Postimplantation Embryos: A Role for Oxidative Stress in Valproic Acid-Induced Neural Tube Defects

Emily W. Y. Tung and Louise M. Winn
Molecular Pharmacology December 2011, 80 (6) 979-987; DOI: https://doi.org/10.1124/mol.111.072314
Emily W. Y. Tung
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Louise M. Winn
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Abstract

Exposure to the anticonvulsant valproic acid (VPA) during the first trimester of pregnancy is associated with an increased risk of congenital malformations including heart defects, craniofacial abnormalities, skeletal and limb defects, and, most frequently, neural tube defects (NTDs). The mechanisms by which VPA induces teratogenic effects are not fully understood, although previous studies support a role for oxidative stress. To investigate the effects of VPA on early development, a whole-embryo culture model was used to evaluate the protective effects of antioxidants, measure intracellular reactive oxygen species (ROS) levels, and assess markers of oxidative damage and apoptosis. Furthermore, in vivo teratological evaluations of antioxidant protection were also completed. VPA (0.60 mM in embryo culture, 400 mg/kg in vivo) induced significant decreases in embryonic growth and increases in NTDs. Of the antioxidants tested, catalase provided partial protection against VPA-mediated reductions in morphological and developmental growth parameters in both whole-embryo culture and in vivo systems. VPA exposure resulted in an increase in ROS staining in the head region, as assessed by whole-mount staining with 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate. Markers of embryonic oxidative damage including 8-hydroxyguanosine, 4-hydroxynonenal adducts, and 3-nitrotyrosine were not affected by VPA treatment. Increased ROS levels were correlated with increased staining for apoptotic markers, as assessed by Western blotting and immunohistochemistry. Addition of catalase to the medium attenuated VPA-induced increases in ROS formation and apoptosis. These studies identify regions of the embryo susceptible to ROS and apoptosis induced by VPA, thus establishing a possible molecular pathway by which VPA exerts teratogenicity.

Footnotes

  • This work was supported by the Canadian Institutes of Health Research [Grant MOP 86593].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.072314.

  • ABBREVIATIONS:

    VPA
    valproic acid
    NTD
    neural tube defect
    ROS
    reactive oxygen species
    SOD
    superoxide dismutase
    GD
    gestational day
    PEG
    polyethylene glycol
    NAC
    N-acetylcysteine
    CM-H2DCFDA
    5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate
    TBST
    Tris-buffered saline with 0.1% Tween 20
    PARP
    poly(ADP-ribose) polymerase
    DAB
    3,3′-diaminobenzidine
    HDAC
    histone deacetylase.

  • Received March 19, 2011.
  • Accepted August 25, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (6)
Molecular Pharmacology
Vol. 80, Issue 6
1 Dec 2011
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Research ArticleArticle

Valproic Acid: Oxidative Stress and Neural Tube Defects

Emily W. Y. Tung and Louise M. Winn
Molecular Pharmacology December 1, 2011, 80 (6) 979-987; DOI: https://doi.org/10.1124/mol.111.072314

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Research ArticleArticle

Valproic Acid: Oxidative Stress and Neural Tube Defects

Emily W. Y. Tung and Louise M. Winn
Molecular Pharmacology December 1, 2011, 80 (6) 979-987; DOI: https://doi.org/10.1124/mol.111.072314
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