Role of formate in methanol‐induced exencephaly in CD‐1 mice

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Abstract
Mouse embryos develop exencephaly when dams are exposed by inhalation to high concentrations (⩾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. In cultures of neurulating mouse embryos explanted on GD 8, the incidence of cephalic dysraphism observed on GD 9 + 6 hr was significantly increased relative to appropriate controls after a 12‐hr exposure to 375 mM methanol or to formate concentrations (40 mM) that exceeded those observed in vivo. These results suggest that exencephaly is a direct result of the effects of the parent compound methanol, administered at high concentrations, rather than the accumulation of formate.