Strain-dependent alterations in the expression of folate pathway genes following teratogenic exposure to valproic acid in a mouse model
✍ Scribed by Finnell, Richard H.; Wlodarczyk, Bogdan C.; Craig, Johanna C.; Piedrahita, Jorge A.; Bennett, Gregory D.
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 230 KB
- Volume
- 70
- Category
- Article
- ISSN
- 0148-7299
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✦ Synopsis
The molecular basis for the well-established hierarchy of susceptibility to valproic acidinduced neural tube defects in inbred mouse strains was examined using in situ transcription and anti-sense RNA amplification methodologies with both univariate and multivariate analyses of the resulting gene expression data. The highly sensitive SWV strain demonstrated a significant reduction in the expression of the folate binding protein (FBP-1) following the teratogenic insult at gestational day 8:18, while the more resistant LM/Bc embryos were upregulating this gene in response to valproic acid treatment. More importantly, at all 3 gestational timepoints spanning the period of murine neural tube closure examined in this study, the LM/Bc embryos had significantly higher MTHFR (5,10-methylenetetrahydrofolate reductase) gene expression levels compared to the SWV embryos. As this folate pathway enzyme is important in homocysteine and methionine metabolism, it suggests that the SWV embryos may be hypomethylated, and essential gene expression during critical periods of neural tube closure is compromised by the teratogenic exposure to valproic acid. This study represents the first evidence of a strain difference in transcriptional activity in response to a teratogenic exposure that might be causally related to the development of the teratogeninduced congenital malformations.