Epigenetic modifications in valproic acid-induced teratogenesis

Journal Article · Mon Nov 01 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.08.001· OSTI ID:21460226

Tung, Emily W.Y. ^[1]

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1. Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, K7L 3N6 (Canada)

Exposure to the anticonvulsant drug valproic acid (VPA) in utero is associated with a 1-2% increase in neural tube defects (NTDs), however the molecular mechanisms by which VPA induces teratogenesis are unknown. Previous studies demonstrated that VPA, a direct inhibitor of histone deacetylase, can induce histone hyperacetylation and other epigenetic changes such as histone methylation and DNA demethylation. The objective of this study was to determine if maternal exposure to VPA in mice has the ability to cause these epigenetic alterations in the embryo and thus contribute to its mechanism of teratogenesis. Pregnant CD-1 mice (GD 9.0) were administered a teratogenic dose of VPA (400 mg/kg, s.c.) and embryos extracted 1, 3, 6, and 24 h after injection. To assess embryonic histone acetylation and histone methylation, Western blotting was performed on whole embryo homogenates, as well as immunohistochemical staining on embryonic sections. To measure DNA methylation changes, the cytosine extension assay was performed. Results demonstrated that a significant increase in histone acetylation that peaked 3 h after VPA exposure was accompanied by an increase in histone methylation at histone H3 lysine 4 (H3K4) and a decrease in histone methylation at histone H3 lysine 9 (H3K9). Immunohistochemical staining revealed increased histone acetylation in the neuroepithelium, heart, and somites. A decrease in methylated histone H3K9 staining was observed in the neuroepithelium and somites, METHYLATED histone H3K4 staining was observed in the neuroepithelium. No significant differences in global or CpG island DNA methylation were observed in embryo homogenates. These results support the possibility that epigenetic modifications caused by VPA during early mouse organogenesis results in congenital malformations.

• OSTI ID: 21460226
• Journal Information: Toxicology and Applied Pharmacology, Vol. 248, Issue 3; Other Information: DOI: 10.1016/j.taap.2010.08.001; PII: S0041-008X(10)00274-7; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACETYLATION
CONGENITAL MALFORMATIONS
CYTOSINE
DNA
DRUGS
EMBRYOS
LYSINE
METHYLATION
MICE
MODIFICATIONS
TERATOGENESIS
ACYLATION
AMINES
AMINO ACIDS
ANIMALS
AZINES
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
HETEROCYCLIC COMPOUNDS
MALFORMATIONS
MAMMALS
NUCLEIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
PATHOLOGICAL CHANGES
PYRIMIDINES
RODENTS
VERTEBRATES