Phenytoin-induced alterations in craniofacial gene expression

Janee Gelineau-van Waes, Gregory D. Bennett, Richard H. Finnell

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

In utero exposure to the anticonvulsant drug phenytoin has been shown to alter normal embryonic development, leading to a pattern of dysmorphogenesis known as the Fetal Hydantoin Syndrome. This embryopathy is characterized by growth retardation, microcephaly, mental deficiency, and craniofacial malformations, although the precise mechanism(s) by which phenytoin alters normal developmental pathways remains unknown. To better understand the molecular events involved in the pathogenesis of phenytoin-induced congenital defects, alterations in gene expression were examined during critical periods of craniofacial development. Pregnant SWV mice were administered phenytoin (60 mg/kg/day) from gestational day 6.5 until they were sacrificed at selected developmental time points. Tissue from the craniofacial region of control and exposed embryos was isolated, and samples were subjected to in situ transcription, antisense RNA amplification, and hybridization on reverse Northern blots to quantitatively assess expression of 36 candidate genes. Chronic phenytoin exposure significantly altered expression of several genes at distinct times during morphogenesis. Results of these studies show that expression of the retinoic acid receptors (RAR) α, β, and γ were significantly increased by phenytoin exposure. Elevations in gene expression of lamininβ1, and the growth factors IGF-2, TGFα, and TGFβ1, were also demonstrated in the craniofacial region of phenytoin-exposed embryos. As several of these genes are transcriptionally regulated by retinoic-acid-responsive elements in their promoter regions, phenytoin-induced alterations in expression of the RAR isoforms may have severe downstream consequences in the regulation of events necessary for normal craniofacial development. Such alterations occurring coordinately at critical times during craniofacial development may account for the dysmorphogenesis often associated with phenytoin exposure.

Original languageEnglish
Pages (from-to)23-34
Number of pages12
JournalTeratology
Volume59
Issue number1
DOIs
StatePublished - 1999
Externally publishedYes

Fingerprint

Phenytoin
Gene expression
Gene Expression
Retinoic Acid Receptors
Genes
Embryonic Structures
Hydantoins
Fetal Diseases
Antisense RNA
Microcephaly
Insulin-Like Growth Factor II
Transcription
Tretinoin
Morphogenesis
Genetic Promoter Regions
Intellectual Disability
Northern Blotting
Anticonvulsants
Embryonic Development
Amplification

All Science Journal Classification (ASJC) codes

  • Developmental Biology
  • Embryology
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Phenytoin-induced alterations in craniofacial gene expression. / Gelineau-van Waes, Janee; Bennett, Gregory D.; Finnell, Richard H.

In: Teratology, Vol. 59, No. 1, 1999, p. 23-34.

Research output: Contribution to journalArticle

Gelineau-van Waes, Janee ; Bennett, Gregory D. ; Finnell, Richard H. / Phenytoin-induced alterations in craniofacial gene expression. In: Teratology. 1999 ; Vol. 59, No. 1. pp. 23-34.
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