STRAIN-DEPENDENT ALTERATIONS IN THE EXPRESSION OF FOLATE PATHWAY GENES FOLLOWING TERATOGENIC EXPOSURE TO VALPROIC ACID IN A MOUSE MODEL

The molecular basis for the well-established hierarchy of susceptibili ty to valproic acid-induced neural tube defects in inbred mouse strain s was examined using in situ transcription and anti-sense RNA amplific ation methodologies with both univariate and multivariate analyses of the resulting gene expression data. The highly sensitive SWV strain de monstrated a significant reduction in the expression of the folate bin ding protein (FBP-1) following the teratogenic insult at gestational d ay 8:18, while the more resistant LM/Bc embryos were up-regulating thi s gene in response to valproic acid treatment. More importantly, at al l 3 gestational timepoints spanning the period of murine neural tube c losure examined in this study, the LM/Bc embryos had significantly hig her MTHFR (5,10-methylenetetrahydrofolate reductase) gene expression l evels compared to the SWV embryos, As this folate pathway enzyme is im portant in homocysteine and methionine metabolism, it suggests that th e SWV embryos may be hypomethylated, and essential gene expression dur ing critical periods of neural tube closure is compromised by the tera togenic exposure to valproic acid, This study represents the first evi dence of a strain difference in transcriptional activity in response t o a teratogenic exposure that might be causally related to the develop ment of the teratogen-induced congenital malformations. (C) 1997 Wiley -Liss, Inc.