Gd. Bennett et al., Valproic acid-induced alterations in growth and neurotrophic factor gene expression in murine embryos, REPROD TOX, 14(1), 2000, pp. 1-11
Although the teratogenicity of valproic acid (VPA) has been well establishe
d, the mechanism(s) by which this anticonvulsant drug induces malformations
remains controversial. Using the combined molecular techniques of in situ-
transcription (IST) and antisense RNA (aRNA) amplification we analyzed VPA-
induced alterations in the gene expression for 10 genes within the neural t
ubes of embryos from two murine strains that have been shown to differ in t
heir susceptibility to VPA-induce neural tube defects (NTD). Pregnant dams
from both SWV (susceptible) and LM/Bc (resistant) strains were either treat
ed with saline (control) or VPA (600 mg/kg) on gestational day (GD) 8:12 (d
ay:hour). Neural tubes were isolated from control or VPA exposed embryos at
three gestational time points, which represented the beginning (GD 8:18),
middle (GD 9:00), and end (GD 9:12) of neural tube closure (NTC) in both of
these murine strains. Using univariant statistics we demonstrated that in
LM/Bc embryos with NTDs, the expression of bdnf, ngf; and trk, ngf-R were s
ignificantly elevated at all three time points, and the cytokine, cntf was
significantly decreased at GD 9.00. In contrast, the major gene alterations
observed in SWV embryos were a significant increase in tfg alpha: and tgf
beta 1-3 at GD 9.00. In an effort to better define the more intricate inter
actions between VPA exposure and the expression of these genes, we analyzed
our data using Principal Component Analysis. The results from this analysi
s demonstrated that embryos from these two stains behaved differently, not
only in response to a VPA exposure, but also under control conditions, whic
h may explain the multifactorial nature of NTDs in these mice. (C) 2000 Pub
lished by Elsevier Science Inc. All rights reserved.