Alcohol is known to induce
folate deficiency and impair
methionine synthase activity. Exogenous
folic acid (FA) administered periconceptionally has been shown to prevent the first occurrence and recurrence of
neural tube defects (NTD) in humans. Since
folate,
vitamin B(12) and
methionine are metabolically interrelated, it was decided to determine the effect of
methionine pre-treatment on alcohol-induced NTD and axial skeletal defects in mouse embryos. Following administration of a single dose of 70 or 150 mg/kg of
methionine, 0.03 ml/g
body weight of
ethanol solution (25% v/v of
absolute alcohol in saline) was injected intraperitoneally into pregnant mice at critical stages of neural tube development. The controls were either non-treated or saline treated and pair-fed and pair-watered. Fetuses were collected on gestation day 18. Alcohol and
methionine plus alcohol numerically enhanced embryonic resorption and induced a significant reduction in
fetal body weight. Alcohol alone caused a 3-fold increase in the background frequency of
exencephaly in gestation days 7 and 8 treatment groups. The low dose of
methionine only numerically reduced the spontaneous
exencephaly. Pre-treatment with
methionine only produced a numerical but not statistically significant reduction in alcohol-induced
exencephaly. The higher dose of
methionine did not produce a particularly beneficial effect on embryonic survival,
fetal body weight and occurrence of
exencephaly. Alcohol-induced
cleft palate and limb malformations were ameliorated by
methionine pre-treatment. Craniofacial skeleton, vertebrae and ribs were extensively malformed both in the alcohol and
methionine plus alcohol groups indicating a lack of rescue effects of
methionine. Whereas supernumerary ribs and extra sternal ribs were augmented by
methionine, occipitalization of the atlas vertebra was a malformation unique to the pre-treatment group. Plasma levels of several
amino acids including that of
methionine were significantly lowered by alcohol. Pre-treatment with
methionine produced a dose dependent enhancement of only
methionine concentration. These data suggest that pre-administration of
methionine only rescues mouse embryos of certain non-neural malformations and that the lack of ameliorative effect on NTD and axial skeletal defects may be due to the fact that alcohol lowers the concentration of a number of
amino acids and therefore, supplementation should comprise a mixture of these
amino acids and possibly FA and
vitamin B(12).