Valproic acid-induced alterations in growth and neurotrophic factor

• Published in: Reproductive toxicology (Elmsford, N.Y.) Vol. 14; no. 1; pp. 1 - 11
• Main Authors: Bennett, G.D, Wlodarczyk, B, Calvin, J.A, Craig, J.C, Finnell, R.H
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 2000; Elsevier
• Subjects: Animal model; Antisense RNA amplification; Biological and medical sciences; Drug toxicity and drugs side effects treatment; Gene expression; In situ-transcription; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Neural tube defects; Pharmacology. Drug treatments; Principal Component Analysis; Valproic acid; Animal model; Neural tube defects; In situ-transcription; Valproic acid; Gene expression; Antisense RNA amplification; Principal Component Analysis; Nervous system diseases; Embryo; Toxicity; Rodentia; Anticonvulsant; Strain specificity; Pregnancy; Neurotrophic factor; Vertebrata; Mammalia; Neural tube; Mouse; Malformation; Animal; Fetus; Intraspecific comparison; Teratogen; Mechanism of action; Growth factor
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/S0890-6238(99)00064-7

Although the teratogenicity of valproic acid (VPA) has been well established, 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 tubes of embryos from two murine strains that have been shown to differ in their susceptibility to VPA-induce neural tube defects (NTD). Pregnant dams from both SWV (susceptible) and LM/Bc (resistant) strains were either treated with saline (control) or VPA (600 mg/kg) on gestational day (GD) 8:12 (day: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 significantly 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 tfgα and tgfβ1–3 at GD 9:00. In an effort to better define the more intricate interactions between VPA exposure and the expression of these genes, we analyzed our data using Principal Component Analysis. The results from this analysis demonstrated that embryos from these two stains behaved differently, not only in response to a VPA exposure, but also under control conditions, which may explain the multifactorial nature of NTDs in these mice.