Document Detail

Exencephaly and axial skeletal malformations induced by maternal administration of sodium valproate in the MF1 mouse.
MedLine Citation:
PMID:  7852547     Owner:  NLM     Status:  MEDLINE    
Clinical and epidemiological studies indicate that maternal use of valproic acid (VPA) during pregnancy causes an increased risk for spina bifida in the fetus. A proportion of infants exposed to VPA in utero exhibit a characteristic pattern of facial malformations. Despite the developmental interdependence of the neural plate and paraxial mesoderm during normal morphogenesis, the possible involvement of the axial skeleton in VPA-induced NTD has not been clearly documented. So the objective of this investigation was to determine the nature and extent of involvement of the axial skeleton in VPA-induced exencephaly in the mouse. A single dose of 600 mg/kg of sodium valproate was administered (IP) to MF1 mouse on day 8 of gestation. This treatment resulted in significant increase in resorption, reduction in mean fetal weight, and exencephaly (25%) of live fetuses. Several craniofacial malformations and subcutaneous haematomas were associated with exencephaly. Alizarin red-stained skeletal preparations revealed maxillary-, mandibular hypoplasia, absence of skull vault, hypoplasia and/or agenesis of basicranial bones, and obtuse angulation of the craniovertebral junction. Hemivertebrae, longitudinal fusion of the vertebral arches and bodies, accessory ribs (cervical and lumbar), fusion of thoracic ribs, and several patterns of sternal variations were observed. Nonexencephalic VPA-treated embryos exhibited mandibular, maxillary hypoplasia, arched and cleft palates, cleft lip, kinky tail, and vertebral and sternal anomalies. Treated embryos at early stages of development revealed delay in elevation and fusion of neural folds, distended IVth ventricle, kinky spinal cord, incomplete separation of somites and growth retardation. When viewed in light of the published work on VPA action on embryonic systems, these observations suggest that abnormalities associated with VPA-induced exencephaly may be due to either a direct action of VPA on the precursors of these organs or secondary to its action on neural tube. A significantly high incidence of NTD and their consistent association with defective development of the axial skeleton suggest that this is an excellent experimental model for investigating the pathogenetic mechanism(s) of VPA induced NTD.
R Padmanabhan; M S Hameed
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of craniofacial genetics and developmental biology     Volume:  14     ISSN:  0270-4145     ISO Abbreviation:  J. Craniofac. Genet. Dev. Biol.     Publication Date:    1994 Jul-Sep
Date Detail:
Created Date:  1995-03-16     Completed Date:  1995-03-16     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8109845     Medline TA:  J Craniofac Genet Dev Biol     Country:  DENMARK    
Other Details:
Languages:  eng     Pagination:  192-205     Citation Subset:  IM    
Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
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MeSH Terms
Abnormalities, Drug-Induced / embryology*,  etiology
Abnormalities, Multiple / chemically induced
Brain / abnormalities
Fetal Growth Retardation / chemically induced
Jaw Abnormalities / chemically induced
Mice, Inbred Strains
Neural Tube Defects / chemically induced*,  embryology
Skull / abnormalities*
Spine / abnormalities
Valproic Acid / toxicity*
Reg. No./Substance:
99-66-1/Valproic Acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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