High-dose folic acid supplementation in rats: effects on gestation and the methionine cycle

Br J Nutr. 2000 Feb;83(2):177-83.


There is new evidence that a good folate status may play a critical role in the prevention of neural-tube defects and in lowering elevated homocysteine concentrations. This adequate folate status may be achieved through folic acid dietary supplementation. Folate is a water-soluble vitamin with a low potential toxicity. However, the possible consequences of long-term high-dose folic acid supplementation are unknown, especially those related to the methionine cycle, where folate participates as a substrate. With the aim of evaluating such possible effects, four groups of Wistar rats were classified on the basis of physiological status (virgin v. pregnant) and the experimental diet administered (folic-acid-supplemented, 40 mg/kg diet v. control, 2 mg folic acid/kg diet). Animals were fed on the diets for 3 weeks. Results showed that gestation outcome was adequate in both groups regardless of the dietary supplementation. However, there were reductions (P < 0.001) in body weight and vertex-coccyx length in fetuses from supplemented dams v. control animals. Folic acid administration also induced a higher (P < 0.01) S-adenosylmethionine: S-adenosylhomocysteine value due to increased S-adenosylmethionine synthesis (P < 0.01). However, hepatic DNA methylation and serum methionine concentrations remained unchanged. Serum homocysteine levels were reduced in supplemented dams (P < 0.05). Finally, pregnancy caused lower serum folate, vitamin B6 and vitamin B12 levels (P < 0.05). Folic acid administration prevented the effect of pregnancy and raised folate levels in dams, but did not change levels of vitamins B12 and B6. These new findings are discussed on the basis of potential benefits and risks of dietary folic acid supplementation.

MeSH terms

  • Animals
  • Dietary Supplements*
  • Female
  • Fetal Weight / drug effects
  • Folic Acid / administration & dosage*
  • Folic Acid / blood
  • Folic Acid / pharmacology
  • Methionine / metabolism*
  • Methylation
  • Nutritional Status
  • Pregnancy
  • Pregnancy Outcome
  • Rats
  • Rats, Wistar
  • S-Adenosylmethionine / biosynthesis


  • S-Adenosylmethionine
  • Folic Acid
  • Methionine