The effect of administration of
folinic acid,
vitamin B6 +
vitamin B12, and their combination on
valproic acid (VPA)-induced
teratogenesis was studied in NMRI mice. VPA (500 mg/kg, sc) was injected on Day 8 of gestation and the
vitamins (two dose levels) were injected ip 1 hr before, immediately before, and 1 hr after VPA administration.
Folinic acid significantly reduced VPA-induced resorptions (21-24%), and palate, rib, and sternebral malformations.
Exencephaly and
spina bifida occulta were also reduced (14 and 40%, respectively), but the difference was not statistically significant. On the other hand,
vitamin B6 +
vitamin B12 significantly reduced VPA-induced
exencephaly (23%),
spina bifida occulta (80%), palate and rib malformations, kidney abnormalities, and
fetal weight retardation. A combination of the three
vitamins was effective in reducing VPA-induced
exencephaly (23-30%),
spina bifida occulta (60%), and palate and rib malformations. The protection against VPA-induced malformations was not complete and was not always dose related, and the reduction in
exencephaly rate was only significant in the absence of a reduction in resorption rate. Full-length
cleft palate, sternebral malformations, and retarded sternebral and caudal ossification were, however, increased by the high dose of combined
vitamin administration. The present study supports the view that VPA-induced
teratogenesis may be mediated via an interaction with
folate metabolism. Although
folinic acid and
vitamin B6 +
vitamin B12 can effectively reduce VPA malformations, the protection was not complete, which may suggest the involvement of other factors. Furthermore, the dose levels should be carefully chosen since high doses of the combined
vitamins can actually increase the incidence of certain defects.