PMID- 9118846
OWN - NLM
STAT- MEDLINE
DCOM- 19970423
LR  - 20190813
IS  - 0013-9580 (Print)
IS  - 0013-9580 (Linking)
VI  - 38
IP  - 4
DP  - 1997 Apr
TI  - Phenytoin-induced teratogenesis: a molecular basis for the observed developmental 
      delay during neurulation.
PG  - 415-23
AB  - PURPOSE: We wished to determine whether chronic phenytoin (PHT) exposure could 
      impair neural development and if any morphological alterations could be linked to 
      changes in gene expression. METHODS: Pregnant SWV mice were chronically 
      administered PHT 40 mg/kg/day from gestational day (GD) 0:12 (day:h) until they 
      were killed at various timepoints throughout neural tube closure (NTC). At each 
      timepoint, embryos from both treated and control dams were collected and scored 
      for their progression through NTC. The neural tubes were then isolated and 
      subjected to in situ transcription (IST) and antisense RNA amplification 
      procedures. Using these techniques, we examined the expression of 10 genes: 
      N-cadherin (Ncad), collagen type IV (col-IV), bcl-2, c-jun, PAX-3, collular 
      retinol binding protein-2 (CRBP-2), retinoic acid receptor alpha (RAR alpha), 
      transforming growth factor(beta2) (TGF(beta2)), wee-1, and EMX-2. RESULTS: 
      Chronic PHT exposure not only caused a delay in NTC whereby exposed embryos 
      lagged behind the controls at each collection timepoint, but also significantly 
      altered the expression of specific genes at distinct times during NTC. Early in 
      NTC, PHT induced a significant reduction in the expression of N-cad, col-IV, and 
      c-jun in exposed embryos as compared with controls. In contrast, during the 
      midstages of NTC, the only significant molecular alterations observed in the 
      PHT-exposed embryos was the continued decreased expression of col-IV and an 
      increase in CRBP-2 expression. Finally, in the latter stages of NTC, PHT caused a 
      significant reduction in the expression of bcl-2, RAR alpha, TGF(beta2), EMX-2, 
      and PAX-3. CONCLUSIONS: These results show that although the effects of PHT are 
      morphologically subtle, causing a delay in the development of the neural tube, 
      this delay is accompanied by alterations in critical genes at crucial times of 
      neural development that may account for the observed neurological deficits often 
      associated with PHT exposure.
FAU - Bennett, G D
AU  - Bennett GD
AD  - Department of Veterinary Anatomy and Public Health, College of Veterinary 
      Medicine, Texas A&M University, College Station 77843-4458, USA.
FAU - Lau, F
AU  - Lau F
FAU - Calvin, J A
AU  - Calvin JA
FAU - Finnell, R H
AU  - Finnell RH
LA  - eng
GR  - DE11303/DE/NIDCR NIH HHS/United States
GR  - ES07165/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Epilepsia
JT  - Epilepsia
JID - 2983306R
RN  - 0 (Cadherins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (PAX3 Transcription Factor)
RN  - 0 (Paired Box Transcription Factors)
RN  - 0 (Rbp2 protein, mouse)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinol-Binding Proteins)
RN  - 0 (Retinol-Binding Proteins, Cellular)
RN  - 0 (Transcription Factors)
RN  - 0 (empty spiracles homeobox proteins)
RN  - 138016-91-8 (Pax3 protein, mouse)
RN  - 6158TKW0C5 (Phenytoin)
RN  - 9007-34-5 (Collagen)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Wee1 protein, mouse)
SB  - IM
MH  - Abnormalities, Drug-Induced/*etiology/genetics
MH  - Animals
MH  - Cadherins/biosynthesis/genetics
MH  - *Cell Cycle Proteins
MH  - Central Nervous System/drug effects/embryology
MH  - Collagen/biosynthesis/genetics
MH  - DNA-Binding Proteins/biosynthesis/genetics
MH  - Female
MH  - Gene Amplification
MH  - Gene Expression/drug effects
MH  - Genes, jun/drug effects/genetics
MH  - Homeodomain Proteins/biosynthesis/genetics
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Nerve Tissue Proteins/biosynthesis/genetics
MH  - Neural Tube Defects/*chemically induced/genetics
MH  - *Nuclear Proteins
MH  - PAX3 Transcription Factor
MH  - Paired Box Transcription Factors
MH  - Phenytoin/*toxicity
MH  - Pregnancy
MH  - Protein-Tyrosine Kinases/biosynthesis/genetics
MH  - Receptors, Retinoic Acid/biosynthesis/genetics
MH  - Retinol-Binding Proteins/biosynthesis/genetics
MH  - Retinol-Binding Proteins, Cellular
MH  - *Transcription Factors
EDAT- 1997/04/01 00:00
MHDA- 2000/05/16 09:00
CRDT- 1997/04/01 00:00
PHST- 1997/04/01 00:00 [pubmed]
PHST- 2000/05/16 09:00 [medline]
PHST- 1997/04/01 00:00 [entrez]
AID - 10.1111/j.1528-1157.1997.tb01730.x [doi]
PST - ppublish
SO  - Epilepsia. 1997 Apr;38(4):415-23. doi: 10.1111/j.1528-1157.1997.tb01730.x.