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

  • M. Achón (a1), E. Alonso-Aperte (a1), L. Reyes (a1), N. Úbeda (a1) and G. Varela-Moreiras (a1)...

Abstract

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.

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Corresponding author

*Corresponding author: Dr Gregorio Varela-Moreiras, fax +34 91 3510475, email gvarela@ceu.es

References

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Alonso-Aperte, E (1997) Methionine metabolism in pregnant rats: effects of dietary folic acid intake and valproate administration. Doctoral Thesis, San Pablo-CEU University, Madrid, Spain.
Alonso-Aperte, E, Úbeda, N, Achón, M, Pérez de Miguelsanz, J and Varela-Moreiras, G (1999) Impaired methionine synthesis and hypomethylation in rats exposed to valproate during gestation. Neurology 52, 750757.
Alonso-Aperte, E and Varela-Moreiras, G (1996) Brain folates and DNA methylation in rats fed a choline deficient diet or treated with low doses of methotrexate .International Journal of Vitamin and Nutrition Research 66, 232236.
Andersson, ABrattstrom, LIssakson, AIsraelsson, B and Hultberg, B (1989) Determination of homocysteine in plasma by ion-exchange chromatography. Scandinavian Journal of Clinical and Laboratory Investigation 49, 445450.
Bailey, LB (1998) Dietary intakes for folate: the debut of dietary folate equivalents. Nutrition Reviews 56, 294299.
Balaghi, MHorne, DW and Wagner, C (1993) Hepatic one carbon metabolism in early folate deficiency in rats. Biochemical Journal 291, 145149.
Balaghi, MHorne, DWWoodward, SC and Wagner, C (1992) Methyl group metabolism in the pancreas of folate deficient rats. Journal of Nutrition 122, 145149.
Center for Disease Control (1991) –. Use of folic acid for prevention of spina bifida and other neural tube defects 1983–1991 .Morbidity and Mortality Weekly Report 40, 513516.
Christman, JKWeich, NSchoenbrun, BSchneideman, N and Asc, G (1980) Hypomethylation of DNA during differentiation of Friend erythroleukemia cells. Journal of Cellular Biology 86, 366379.
Clifford, AJBills, NDPeerson, JM Müller HG, Burk, GE and Rich, KD (1993) A depletion-repletion folate bioassay based on growth and tissue folate concentrations of rats .Journal of Nutrition 123, 926932.
Clifford, AJWilson, DS and Bills, ND (1989) Repletion of folate-depleted rats with amino acid based diet supplemented with folic acid. Journal of Nutrition 119, 19561961.
Coelho, CND and Klein, NW (1990) Methionine and neural tube closure in cultured rat embryos: morphological and biochemical analyses. Teratology 42, 437451.
Coelho, CND, Weber, JAKlein, NWDaniels, WG and Hoagland, TA (1989) Whole rat embryos require methionine for neural tube closure when cultured on cow serum. Journal of Nutrition 119, 17161725.
Czeizel, AE and Dudás, I (1992) Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. New England Journal of Medicine 327, 18321835.
Czeizel, AEToth, M and Rockenbauer, M (1996) Population based case-control study of folic acid supplementation during pregnancy .Teratology 53, 345351.
de Bree, A van Dusseldorp, MBrouwer, IAvan het Hof, KH and Steegers-Theunissen, RPM (1997) Folate intake in Europe: recommended, actual and desired intake. European Journal of Clinical Nutrition 51, 643660.
Department of Health (1992) Folic Acid and the Prevention of Neural Tube Defects, Report from Expert Advisory Group. Heywood: Health Publications Unit.
Department of Health and Human Services (1992) –. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. Morbidity and Mortality Weekly Report 41, 17.
Dierkes, JKroesen, M and Pietrzik, K (1998) Folic acid and vitamin B6 supplementation and plasma homocysteine concentrations in healthy young women. International Journal of Vitamin and Nutrition Research 68, 98103.
European Community Council (1986) Directional Guides Related to Animal Housing and Care. Official Bulletin of European Communities, 18.12.86 N L358/1-N L358/28. Barcelona: European Community Council.
Fell, DBenjamin, LE and Steele, RD (1985) Determination of adenosine and adenosyl derivatives of sulfur amino acids in rat liver by high performance liquid chromatography. Journal of Chromatography 345, 150156.
Finkelstein, JD (1990) Methionine metabolism in mammals. Journal of Nutritional Biochemistry 1, 228237.
Food and Drug Administration (1993) (197), –. Notice. Food labeling: health claims and label statements; folate and neural tube defects. Federal Register 58, 1325413295.
Health Council/Food and Nutrition Council (1992) Report on the Relationship Between Folic Acid and Neural Tube Defects. The Hague: Netherlands Food and Nutrition Council.
Health Council/Food and Nutrition Council (1993) Follow up report on the relationship between folic acid and neural tube defects. The Hague: Netherlands Food and Nutrition Council.
Hoffman, DRCornatzer, WE and Duerre, JA (1979) Relationship between tissue levels of S-adenosylmethionine, S-adenosylhomocysteine, and transmethylation reactions. Canadian Journal of Biochemistry 57, 5665.
Hook, EB and Czeizel, AE (1997) Can terathanasia explain the protective effect of folic acid supplementation on birth defects?. Lancet 350, 513515.
Lachance, AP (1998) Overview of key nutrients: micronutrient aspects Nutrition Reviews 56(Suppl. 4), 34S39S.
Li, EBestor, TH and Jaenisch, R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915926.
Loscalzo, J (1996) The oxidant stress of hyperhomocyst(e)inemia. Journal of Clinical Investigation 98, 57.
McNulty, HMcPartlin, JMWeir, DG and Scott, JM (1993) Folate catabolism is increased during pregnancy in rats .Journal of Nutrition 123, 10891093.
McPartlin, JMHalligan, AScott, JMDarling, M and Weir, DG (1993) Accelerated folate breakdown in pregnancy. Lancet 341, 148149.
Malinow, MRDuell, PBHess, DLAndersson, PHKrugger, WDPhillipson, BEGluckman, RABlock, PC and Upson, BM (1998) Reduction of plasma homocysteine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. New England Journal of Medicine 338, 10091015.
Miller, JWNadeau, MRSmith, JSmith, D and Selhub, J (1994) Folate deficiency induced homocysteinemia in rats: disruption of S-adenosylmethionine's coordinate regulation of homocysteine metabolism. Biochemical Journal 298, 415419.
Mills, JLScott, JMKirke, PNMcPartlin, JMConley, MRWeir, DGMolloy, AM and Lee, YJ (1996) Homocysteine and neural tube defects. Journal of Nutrition 126, 756S760S.
MRC Vitamin Study Research Group (1991) –. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study Lancet 338, 131137.
National Research Council (1995) Nutrient requirements of the laboratory rat. In Nutrient Requirements of Laboratory Animals, 4th ed., pp. –. Washington, DC: National Academy Press. 1180.
Santhosh-Kumar, CR, Deutsch, JCRyder, JW and Kolhouse, JF (1997) Unpredictable intraindividual variations in serum homocysteine levels on folic acid supplementation. European Journal of Clinical Nutrition 51, 188192.
Selhub, J & Rosenberg, I (1996) Folic acid. In Present Knowledge in Nutrition, 7th ed., pp. 206219 [Ziegler, EE, and Filer, LJ, editors]. Washington, DC: ILSI Press.
Kang, SS (1996) Treatment of hyperhomocyst(e)inemia. Physiological basis. Journal of Nutrition 126, 1273S1275S.
Steegers-Theunissen, RPM, Boers, GHTrijbels, FJM, Finkelstein, JDBlom, JGThomas, CMG, Borm, GFWouters, MGAJ and Eskes, TKAB (1994) Maternal hyperhomocysteinemia: a risk factor for neural tube defects?. Metabolism, Clinical and Experimental 43, 14751480.
Ubbink, JB (1994) Vitamin requirements for the treatment of hyperhomocysteinemia in humans. Journal of Nutrition 124, 19271933.
Van Aerts, LAGJM, Blom, HJDe Abreu, RATrijbels, FJM, Eskes, TKAB, Copius Peereboom-Stegeman, JHJ and Noordhoeck, J (1994) Prevention of neural tube defects by and toxicity of L-homocysteine in cultured postimplantation rat embryos .Teratology 50, 348360.
Varela-Moreiras, G, Alonso-Aperte, E, Rubio, MGassó, M, Deulofeu, RAlvarez, LCaballería, J, Rodés, J and Mato, JM (1995) Carbon tetrachloride induced hepatic injury is associated with global DNA hypomethylation and homocysteinemia: effects of S-adenosylmethionine treatment .Hepatology 22, 13101315.
Varela-Moreiras, G, Ragel, C and Pérez de Miguelsanz, J (1995) Choline deficiency and methotrexate treatment induces marked but reversible changes in hepatic folate concentrations, serum homocysteine and DNA methylation rates in rats .Journal of the American College of Nutrition 14, 480485.
Varela-Moreiras, G and Selhub, J (1992) Long term folate deficiency alters folate content and distribution differentially in rat tissues. Journal of Nutrition 122, 986991.
Walzem, RL and Clifford, AJ (1988) Folate deficiency in rats fed diets containing free amino acids or intact proteins. Journal of Nutrition 118, 10891096.
Welch, GN and Loscalzo, J (1998) Homocysteine and atherothrombosis. New England Journal of Medicine 338, 10421050.

Keywords

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

  • M. Achón (a1), E. Alonso-Aperte (a1), L. Reyes (a1), N. Úbeda (a1) and G. Varela-Moreiras (a1)...

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