INFLUENCE OF MATERNAL FOLATE STATUS ON THE DEVELOPMENTAL TOXICITY OF METHANOL IN THE CD-1 MOUSE

Methanol, which is detoxified via a folic acid-dependent pathway, has been shown to be teratogenic in mice. Given recent observations that t he level of dietary folic acid intake may be inversely related to the occurrence of select birth defects in humans, we tested the hypothesis that dietary folic acid intake would influence the developmental toxi city of methanol. Virgin female mice were fed one of three diets conta ining 400 (low), 600 (marginal), or 1,200 (adequate) nmol folic acid/k g diet for 5 weeks prior to and following mating. On gestation days (G D) 6-15, dams were administered by gavage either vehicle (distilled, d eionized water) or methanol at 2.0 or 2.5 g/kg body weight, twice dail y. On GD 18, mice were weighed and killed and the liver, kidneys, and gravid uteri removed and weighed. Implantation sites, live and dead fe tuses, and resorptions were counted; fetuses were weighed individually and examined for cleft palate and exencephaly. One third of the fetus es in each litter were examined for skeletal morphology. Maternal live r folate concentrations were approximately 40-50% lower in the low die tary folic acid groups than in the marginal and adequate groups; metha nol did not affect maternal liver folate concentration at term. Matern al net gestational weight gain was lowest at the lowest dietary folate level but was not affected by methanol. Gravid uterus weights were lo west in the low dietary folic acid groups exposed to the high methanol dose and the number of live fetuses per litter was lowest in the low folic acid groups. Fetal body weights were lowest in the low folic aci d groups and significantly lower in the methanol groups relative to ve hicle treated animals. Fetal crown-rump lengths were shorter in the me thanol-treated groups; this parameter was not affected by folic acid t reatment. Both methanol and low dietary folic acid increased the incid ence of cleft palate, with the highest number of affected litters in t he low dietary folic acid group. These results support the concept tha t maternal folate status can modulate the developmental toxicity of me thanol. (C) 1997 Wiley-Liss, Inc.