Preliminary evidence of phenytoin-induced alterations in embryonic gene expression in a mouse model

Musselman, Andrea C.; Bennett, Gregg; Greer, Kimberly A.; Eberwine, James; Finnell, Richard H.

doi:10.1016/0890-6238(94)90078-7

Cited by 19 publications

(2 citation statements)

References 44 publications

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“…□ A deficiency of the microsomal enzyme epoxide hydrolase in the mother and the embryo, leads to the accumulation of teratogenic epoxide metabolites in the presence of agents such as carbamazepine or phenytoin (Raymond 1995, Omtzigt 1993. TGF-β, NT3 and WNT1) (Musselman 1994). It can thus interfere with cell function and even lead to cell death (Wells 1997).…”

Section: "Damage Mechanisms"mentioning

confidence: 99%

Epilepsy and antiepileptic medications

Chambers¹,

Schaefer²

2015

Drugs During Pregnancy and Lactation

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Section: "Damage Mechanisms"mentioning

confidence: 99%

Epilepsy and antiepileptic medications

Chambers¹,

Schaefer²

2015

Drugs During Pregnancy and Lactation

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“…Diphenylhydantoin exposure seems to decrease the expression of mRNAs for important growth factors including TGF-ß, NY3, and WNT1 [106]. Boric acid when administered to pregnant rats on days 9-10 of gestation induces axial skeleton malformations similar to those produced by VPA or RA exposure, suggesting a possible effect on the homeobox code controlling vertebral specification [107].…”

Section: Thalidomidementioning

confidence: 99%

Gene-Teratogen Interactions in Chemically Induced Congenital Malformations

Giavini

Menegola²

2004

Neonatology

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Exposure of the embryo to environmental chemicals can result in congenital malformations or abortion. Although experimental teratology data are considered sufficient for risk assessment, only knowledge of their mechanisms of action permits a justifiable extrapolation of animal data to humans. Mechanistic studies of some teratogenic agents such as retinoic acids, valproic acid, diethylstilbestrol, and cyclopamine provided evidence of interference with regulation of genes controlling the embryonic development. The new genomic technologies are important tools in this field and may represent a real improvement in understanding the mechanisms of action of chemical teratogens.

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Phenytoin-induced alterations in craniofacial gene expression

1999

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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. Teratology 59:23–34, 1999. © 1999 Wiley‐Liss, Inc.

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Preliminary evidence of phenytoin-induced alterations in embryonic gene expression in a mouse model

Cited by 19 publications

References 44 publications

Epilepsy and antiepileptic medications

Epilepsy and antiepileptic medications

Gene-Teratogen Interactions in Chemically Induced Congenital Malformations

Phenytoin-induced alterations in craniofacial gene expression

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