INFLUENCE OF DIETARY FOLIC-ACID ON THE DEVELOPMENTAL TOXICITY OF METHANOL AND THE FREQUENCY OF CHROMOSOMAL BREAKAGE IN THE CD-1 MOUSE

The proposed increased use of methanol (MeOH)-based fuels raises the c oncern for an increased risk for MeOH toxicity. MeOH, which is detoxif ied in part via a folate-dependent pathway, is known to be teratogenic in rodents. Previous observations have implicated maternal folate sta tus as a critical modulator for the developmental toxicity of MeOH. Th e current study extends these findings, examining the effect of matern al dietary folate intake on fetal folate stores, as well as identifyin g a possible marker for the prediction of the developmental toxicity o f MeOH. Virgin female CD-1 mice were assigned to diets containing eith er 400 (marginal) or 1200 (control) nmol folic acid (FA)/kg, and 1% su ccinylsulfathiazole for 5 weeks prior to mating and throughout breedin g and gestation. From gestation day (GD) 6 through 10 dams were given by gavage deionized, distilled water (dH(2)O) or MeOH at 2.5 g/kg body weight, twice daily. On GD 18, mice were weighed and killed and the l iver, kidneys, and gravid uteri removed and weighed. Implantation site s, live and dead fetuses, and resorptions were counted; fetuses were w eighed individually and examined for cleft palate and exencephaly. The marginal FA dietary treatment resulted in low maternal liver (50% red uction) and red cell folate (30% reduction) concentrations, as well as low fetal tissue folate concentrations (60 to 70% reduction) relative to the adequate FA dietary groups. Marginal FA treatment alone result ed in cleft palate in 13% of the litters; there were no litters affect ed with cleft palate in the adequate PA-control group. Marginal FA-MeO H treatment resulted in a further increase in the litters affected by cleft palate (72% of litters affected). The percent of litters affecte d by exencephaly was highest in the marginal FA-MeOH group. The freque ncy of micronuclei in maternal and fetal reticulocytes, a marker for c hromosomal abnormalities, was not influenced by either the marginal FA diet or by MeOH treatment. These results show that marginal folate de ficiency in pregnant dams significantly increases the teratogenicity o f MeOH. (C) 1996 Elsevier Science Inc.