Role of formate in methanol-induced exencephaly in CD-1 mice.
Mouse embryos develop exencephaly when dams are exposed by inhalation to high concentrations (> or = 10,000 ppm) of methanol on gestational day 8 (GD8; copulation plug = GD0). The present study examined the role of formate, an oxidative metabolite of methanol, in the development of methanol-induced exencephaly in CD-1 mice and cultured mouse embryos. The pharmacokinetics and developmental toxicity of sodium formate (750 mg/kg by gavage), a 6-hr methanol inhalation (10,000 or 15,000 ppm), or methanol gavage (1.5 g/kg) in pregnant CD-1 mice on GD8 were determined. Gross morphological evaluations for neural tube closure status in embryos or exencephaly in near-term fetuses were performed. Decidual swellings and maternal plasma were analyzed for methanol and formate. The mean (+/- S.E.M.) end-of-exposure plasma methanol concentration was 223 +/- 23 mM following the 6-hr, 15,000 ppm methanol inhalation. There were no changes in blood or decidual swelling formate concentrations under any of the methanol exposure conditions. Peak formate levels in plasma (1.05 +/- 0.2 mM; control 0.5 +/- 0.3 mM) and decidual swelling (2.0 +/- 0.2 mM; control 1.1 +/- 0.2 mM) from pregnant mice (GD8) given sodium formate (750 mg/kg, po) were similar to those observed following a 6-hr methanol inhalation of 15,000 ppm (plasma = 0.75 +/- 0.1 mM; decidual swelling = 2.2 +/- 0.3 mM) but did not result in exencephaly.(ABSTRACT TRUNCATED AT 250 WORDS)
Dorman
D C
DC
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27560, USA.
Bolon
B
B
Struve
M F
MF
LaPerle
K M
KM
Wong
B A
BA
Elswick
B
B
Welsch
F
F
D000818:Animals; D003656:Decidua / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D004906:Erythrocyte Count; D005260:Female; D000077604:Fomepizole; D005561:Formates / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D066298:In Vitro Techniques; D000432:Methanol / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000196:embryology; D011247:Pregnancy; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D013723:Teratogens / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*
D005561:Formates; D011720:Pyrazoles; D013723:Teratogens; C030544:formic acid; D000077604:Fomepizole; D000432:Methanol