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Effects of Deficiencies in Labile Methyl Groups on the Growth and Development of Fetal Rats¹

Department of Pathology, University of Florida College of Medicine, Gainesville, Florida 32601

By using the "hemorrhagic kidney syndrome" of weanling rats as a bioassay, it was possible to test the nutritional adequacy of various diets in supporting methylneogenesis for the synthesis of choline. In this manner it was demonstrated that compounds which enter one-carbon metabolism at the oxidation level of formaldehyde (sarcosine and N,N-dimethylglycine) had a specific antimethyl action, and oral doses of nicotinamide potentiated the effects of mild methyl depletion. The action of sarcosine resulted in renal cortical necrosis in mature females. Adult animals, maintained on diets which resulted in graded levels of methyl deficiency, were examined to determine the effects on reproduction. The major changes were embryonic death and growth retardation, and the more deficient diets inhibited estrus and conception. Nicotinamide, which is detoxified by transmethylation, induced hydrocephalus, spina bifida and umbilical hernia even when dams received adequate amounts of folic acid, vitamin B₁₂, choline and methionine. It was observed, in this and previous experiments, that congenital abnormalities were more common when the mothers' diets were supplemented with methionine. The action of methionine is probably related to the unique finding that congenital abnormalities occurred more frequently in litters from mildly deficient dams.

Manuscript received 2 April 1970.