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 concern for an increased risk for MeOH toxicity. MeOH, which is detoxified in part via a folate-dependent pathway, is known to be teratogenic in rodents. Previous observations have implicated maternal folate status as a critical modulator for the developmental toxicity of MeOH. The current study extends these findings, examining the effect of maternal dietary folate intake on fetal folate stores, as well as identifying a possible marker for the prediction of the developmental toxicity of MeOH. Virgin female CD-1 mice were assigned to diets containing either 400 (marginal) or 1200 (control) nmol folic acid (FA)/kg, and and 1% succinylsulfathiazole for 5 weeks prior to mating and throughout breeding and gestation. From gestation day (GD) 6 through 10 dams were given by gavage deionized, distilled water (dH2O) or MeOH at 2.5 g/kg body weight, twice daily. On GD 18, mice were weighed and killed and the liver, kidneys, and gravid uteri removed and weighed. Implantation sites, live and dead fetuses, and resorptions were counted; fetuses were weighed individually and examined for cleft palate and exencephaly. The marginal FA dietary treatment resulted in low maternal liver (50% reduction) 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 resulted in cleft palate in 13% of the litters; there were no litters affected with cleft palate in the adequate FA-control group. Marginal FA-MeOH treatment resulted in a further increase in the litters affected by cleft palate (72% of litters affected). The percent of litters affected by exencephaly was highest in the marginal FA-MeOH group. The frequency of micronuclei in maternal and fetal reticulocytes, a marker for chromosomal abnormalities, was not influenced by either the marginal FA diet or by MeOH treatment. These results show that marginal folate deficiency in pregnant dams significantly increases the teratogenicity of MeOH.
Fu
S S
SS
Department of Nutrition, University of California, Davis 95616, USA.
Sakanashi
T M
TM
Rogers
J M
JM
Hong
K H
KH
Keen
C L
CL
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D002972:Cleft Palate / Q000139:chemically induced*; D019465:Craniofacial Abnormalities / Q000139:chemically induced*; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000097:blood; D005494:Folic Acid Deficiency / Q000503:physiopathology*; D000432:Methanol / Q000633:toxicity*; D051379:Mice; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D011247:Pregnancy; D012156:Reticulocytes / Q000187:drug effects* / Q000648:ultrastructure; D012307:Risk Factors; D013723:Teratogens / Q000633:toxicity*
D009153:Mutagens; D013723:Teratogens; D005492:Folic Acid; D000432:Methanol