Supranormal dietary folic acid supplementation: effects on methionine metabolism in weanling rats.

There are nationwide folic acid (FA) fortification programmes of staple foods established or under consideration in order to prevent neural tube defects. Universal FA fortification still remains controversial because of the concern that additional FA in the diets of population groups (e.g. children and elderly) not initially targeted for fortification may suffer adverse effects. However, dietary surveys regarding folate generally deal with adults and little is known about the consumption and long-term effects of fortified food and supplements in growing individuals. Recent reports from our laboratory show several effects of high-dose folate supplementation in rats. In the present work, we studied the effect of FA on the methionine cycle in weanling (3-week-old) male rats after 4 weeks of supplementation with 40 mg FA/kg diet v. control (1 mg FA/kg diet). FA supplementation resulted in a reduction of homocysteine and creatinine concentrations v. control group. FA supplementation did not alter S-adenosylmethionine/S-adenosylhomocysteine ratio, DNA methylation, enzymatic activities or concentrations of vitamins involved in the nutritional regulation of the methionine cycle, except for folate. FA supplementation of 40 mg/kg did not lead to hepatic or renal damage. In conclusion, there were no apparent adverse effects on one-carbon metabolism after FA supplementation in the studied conditions.

High dietary folate supplementation: effects on diet utilization and methionine metabolism in aged rats.

BACKGROUND: Folate supplementation or food fortification is being nowadays recommended because of its effect on the prevention of neural tube defects and the lowering of homocysteine levels. We have previously reported a negative effect of high dose folate supplementation on dietary metabolic protein utilization in pregnant and virgin rats. OBJECTIVES: To determine the effects of such folate supplementation on nutritional and some biochemical markers in aged rats. DESIGN: Aged male Wistar rats were given free access either to a folate supplemented diet (40 mg/kg diet) or a control diet (1 mg/kg diet) for 29 days following a week adaptation period. Two critical periods were used for metabolic balance studies (experimental days 1 to 8 and 22 to 29), involving the determination of digestive and metabolic protein utilization. Several biochemical markers involved in the methylation cycle were also determined. RESULTS: Data show that long term high folate supplementation reduces nitrogen digestive function in aged rats (P<0,03) during the second metabolic period (days 22 to 29). However, supplementation did not alter metabolic protein utilization. Plasma homocysteine and serum vitamin B6 and B12 levels, hepatic S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) concentrations -and thus methylation ratio, SAM/SAH-, were neither affected by folate supplementation. CONCLUSION: Folate supplementation at high doses may have a negative effect on diet utilization, related to protein status.

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

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.

High dietary folate supplementation affects gestational development and dietary protein utilization in rats.

There is new evidence that good folate status may play a critical role in the prevention of neural tube defects and in the maintenance of adequate homocysteine levels, an amino acid recently identified as a risk factor for cardiovascular disease. This has led to different folate recommendations, all of them much higher than the present dietary recommendations. Folic acid is a water-soluble vitamin with a low potential toxicity. However, the possible consequences of long-term, high folate intakes are unknown. Therefore, the present study was undertaken to determine the effects of long-term, high dietary folate supplementation on gestational and nutritional markers in pregnant and virgin rats. Four groups of Wistar rats were classified on the basis of physiological status (virgin or pregnant) and the experimental diets administered (folic acid supplemented, 40 mg/kg diet; or control diet, 2 mg folic acid/kg diet). Rats were fed their respective diets for 3 wk. Two critical periods were used for metabolic balance studies (experimental d 1-5 and 17-21), which involved the determination of fat and protein digestibilities as well as metabolic protein utilization (MPU) and net protein utilization (NPU). Gestational development (number of live fetuses) was adequate in both diet groups regardless of folate supplementation. However, body weight and vertex-coccyx length in fetuses from supplemented dams were less than (P < 0.0001) in fetuses of control dams. Fat and nitrogen digestibilities were not affected by supplementation, but MPU and NPU coefficients were significantly lower (P < 0.05) in the folic acid-supplemented groups, irrespective of physiological status, compared to control rats. These new findings of macro-micronutrient interactions caused by high folate supplementation are discussed on the basis that the vitamin may act as a xenobiotic more than as a nutrient.