Folic acid and pantothenic acid protection against valproic acid-induced neural tube defects in CD-1 mice.
In utero exposure to valproic acid (VPA) during pregnancy is associated with an increased risk of neural tube defects (NTDs). Although the mechanism by which VPA mediates these effects is unknown, VPA-initiated changes in embryonic protein levels have been implicated. The objectives of this study were to investigate the effect of in utero VPA exposure on embryonic protein levels of p53, NF-kappaB, Pim-1, c-Myb, Bax, and Bcl-2 in the CD-1 mouse. We also evaluated the protective effects of folic acid and pantothenic acid on VPA-induced NTDs and VPA-induced embryonic protein changes in this model. Pregnant CD-1 mice were administered a teratogenic dose of VPA prior to neural tube closure and embryonic protein levels were analyzed. In our study, VPA (400 mg/kg)-induced NTDs (24%) and VPA-exposed embryos with an NTD showed a 2-fold increase in p53, and 4-fold decreases in NF-kappaB, Pim-1, and c-Myb protein levels compared to their phenotypically normal littermates (P<0.05). Additionally, VPA increased the ratio of embryonic Bax/Bcl-2 protein levels (P<0.05). Pretreatment of pregnant dams with either folic acid or pantothenic acid prior to VPA significantly protected against VPA-induced NTDs (P<0.05). Folic acid also reduced VPA-induced alterations in p53, NF-kappaB, Pim-1, c-Myb, and Bax/Bcl-2 protein levels, while pantothenic acid prevented VPA-induced alterations in NF-kappaB, Pim-1, and c-Myb. We hypothesize that folic acid and pantothenic acid protect CD-1 embryos from VPA-induced NTDs by independent, but not mutually exclusive mechanisms, both of which may be mediated by the prevention of VPA-induced alterations in proteins involved in neurulation.
Dawson
Jennifer E
JE
Department of Pharmacology and Toxicology and School of Environmental Studies, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Raymond
Angela M
AM
Winn
Louise M
LM
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D005492:Folic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D005865:Gestational Age; D015151:Immunoblotting; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009436:Neural Tube Defects / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D010205:Pantothenic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014635:Valproic Acid / Q000008:administration & dosage / Q000633:toxicity*; D014803:Vitamin B Complex / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000927:Anticonvulsants; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D020598:Proto-Oncogene Proteins c-myb; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D014803:Vitamin B Complex; D010205:Pantothenic Acid; D014635:Valproic Acid; D005492:Folic Acid; D051573:Proto-Oncogene Proteins c-pim-1