Influence of maternal folate status on the developmental toxicity of methanol in the CD-1 mouse

Abstract

Methanol, which is detoxified via a folic acid‐dependent pathway, has been shown to be teratogenic in mice. Given recent observations that the 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 toxicity of methanol. Virgin female mice were fed one of three diets containing 400 (low), 600 (marginal), or 1,200 (adequate) nmol folic acid/kg diet for 5 weeks prior to and following mating. On gestation days (GD) 6–15, dams were administered by gavage either vehicle (distilled, deionized water) or methanol at 2.0 or 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. One third of the fetuses in each litter were examined for skeletal morphology. Maternal liver folate concentrations were approximately 40–50% lower in the low dietary folic acid groups than in the marginal and adequate groups; methanol did not affect maternal liver folate concentration at term. Maternal net gestational weight gain was lowest at the lowest dietary folate level but was not affected by methanol. Gravid uterus weights were lowest 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 acid groups and significantly lower in the methanol groups relative to vehicle‐treated animals. Fetal crown‐rump lengths were shorter in the methanol‐treated groups; this parameter was not affected by folic acid treatment. Both methanol and low dietary folic acid increased the incidence of cleft palate, with the highest number of affected litters in the low dietary folic acid group. These results support the concept that maternal folate status can modulate the developmental toxicity of methanol. Teratology 54:198–206 © 1997 Wiley‐Liss, Inc.

Folate depletion during pregnancy and lactation reduces genomic DNA methylation in murine adult offspring

“…Some studies did not include any run-in period [19,21], whereas others fed experimental diets for 2-8 weeks prior to mating [8,28,[33][34][35][36]. No rationale for the duration of these periods was offered.…”

Methanol exposure during gastrulation causes holoprosencephaly, facial dysgenesis, and cervical vertebral malformations in C57BL/6J mice

“…The “no observed adverse effect level” (NOAEL) in that study was 1,000 ppm. Methanol oxidation occurs in part through a folate‐dependent pathway, and folate deficiency has been shown to exacerbate some aspects of the developmental toxicity of methanol in CD‐1 mice (Fu et al, 1996; Sakanashi et al, 1996).…”

Dietary methanol and autism

“…The very strong protection from autism (almost 50%) afforded to mothers supplementing with folic acid around the time of conception [18] is a compelling link to methanol, which is detoxified via a folic acid-dependent pathway. Identical protection from developmental toxicity due to methanol poisoning has been shown by early folate supplementation in the pregnant CS-1 mouse which is considered to be closer to humans in its reaction to methanol poisoning [19] (see Figs. 1 and 2).…”