Protective Effect Of Folic Acid Research Articles

A Polymorphism, R653Q, in the Trifunctional Enzyme Methylenetetrahydrofolate Dehydrogenase/Methenyltetrahydrofolate Cyclohydrolase/Formyltetrahydrofolate Synthetase Is a Maternal Genetic Risk Factor for Neural Tube Defects: Report of the Birth Defects Research Group

Women who take folic acid periconceptionally reduce their risk of having a child with a neural tube defect (NTD) by >50%. A variant form of methylenetetrahydrofolate reductase (MTHFR) (677C-->T) is a known risk factor for NTDs, but the prevalence of the risk genotype explains only a small portion of the protective effect of folic acid. This has prompted the search for additional NTD-associated variants in folate-metabolism enzymes. We have analyzed five potential single-nucleotide polymorphisms (SNPs) in the cytoplasmic, nicotinamide adenine dinucleotide phosphate-dependent, trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1) for an association with NTDs in the Irish population. One SNP, R653Q, in this gene appears to be associated with NTD risk. We observed an excess of the MTHFD1 "Q" allele in the mothers of children with NTD, compared with control individuals. This excess was driven by the overrepresentation of QQ homozygotes in the mothers of children with NTD compared with control individuals (odds ratio 1.52 [95% confidence interval 1.16-1.99], P=.003). We conclude that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival.

Protective Effects of the Folic Acid and Vitamin B12 against Chromosome Damage Induced by Manganese Sulfate in Cultured Mouse Spleen Cells.

The present study was carried out to evaluate the cytogenetic effect of manganese sulfate (MnSO4) in cultured mouse spleen cells and the possible protective effect of folic acid (FA) and/or vitamin B12 (VB12) on cell cultures treated with MnSO4. Cultured mouse spleen cells were treated with MnSO4 at 4 concentrations (10-6, 5×10-6, 10-5, 10-4). FA at 10-5, 5×10-5 and 10-4M, and VB12 at 5×10-6, 10-5 and 5×10-5 M were used for testing the protective effect on chromosome damage induced by MnSO4. The highest dose (10-4 M) of MnSO4 were treated simultaneously with FA and/or VB12. The cultures were set up for 24 h. The results indicate that MnSO4 alone induced a concentration-related increase in the percentage of chromosome aberrations. Both FA and VB12 reduced the percentage of aberrant cells in a significant (p<0.01) and dose-dependent manner. However, FA combined with VB12 caused a highest percentage of reduction (62.20-71.94%). Under the present experimental conditions, FA and VB12 are capable of reducing the cytogenetic damage induced by MnSO4 and appear to be an antimutagenic agent.

Folate, homocysteine and neural tube defects: an overview.

Folate administration substantially reduces the risk on neural tube detects (NTD). The interest for studying a disturbed homocysteine (Hcy) metabolism in relation to NTD was raised by the observation of elevated blood Hcy levels in mothers of a NTD child. This observation resulted in the examination of enzymes involved in the folate-dependent Hcy metabolism. Thus far, this has led to the identification of the first and likely a second genetic risk factor for NTD. The C677T and A1298C mutations in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with an increased risk of NTD and cause elevated Hcy concentrations. These levels can be normalized by additional folate intake. Thus, a dysfunctional MTHFR partly explains the observed elevated Hcy levels in women with NTD pregnancies and also, in part, the protective effect of folate on NTD. Although the MTHFR polymorphisms are only moderate risk factors, population-wide they may account for an important part of the observed NTD prevalence.

Do we need another randomized controlled trial of folic acid alone?

As a public health strategy to help prevent neural tube defect-affected pregnancies, enriched flour and pasta in the United States and Canada are being fortified with folic acid, and women are being advised to take supplementary folic acid around the time of pregnancy to ensure an adequate intake. But in spite of the recently published results of a public health campaign in China, the burden of proof that folic acid alone is responsible for a decreased risk of these birth defects rests on the results of a randomized controlled trial conducted by the Medical Research Council of the United Kingdom. Supporting evidence comes primarily from studies that have shown a protective effect of multivitamins containing folic acid as one of many nutrients. Based on a striking and potentially hazardous type of non-compliance observed in an earlier study in which a participant took multiple vitamin doses simultaneously and a suggestion of similar incidents in the Medical Research Council study, we conclude that a further randomized controlled trial of the protective effect of folic acid alone may be necessary.

Protective effect of folic acid against oxidative stress produced in 21-day postpartum rats by maternal-ethanol chronic consumption during pregnancy and lactation period

In this paper we show the protective effect of folic acid on oxidative stress in offspring caused by chronic maternal ethanol consumption during pregnancy and the lactation period. Glutathione reductase (GR) specific activity was assayed in liver and pancreas of offspring and mothers. In the offspring, these tissues were also assayed for markers of oxidative damage to lipids and proteins. The results show that ethanol exposure during pregnancy and lactation increased the specific activity of GR in tissues of the mothers (32–34% increase) as well as in the liver of their progeny (24%). Thiobarbituric acid reactive substances (TBARS) were also increased in the liver and pancreas of 21-day-old rats (37- and 54%, respectively). Alcohol also increased the amount of carbonyl groups in proteins in both tissues. These measures of ethanol-mediated oxidative stress were mitigated when pregnant rats were treated with folic acid concomitantly to ethanol administration. The antioxidant capacity of folic acid seems to be involved in its protective effect. The results obtained in the present work suggest that folic acid may be useful in the prevention of damage and promotion of health of the progeny of ethanol-treated rats.

The folic acid analogue methotrexate protects frog embryo cell membranes against damage by the potato glycoalkaloid α-chaconine

As part of an effort to improve the safety of plant foods, a need exists to more clearly delineate the mechanisms of toxicities of glycoalkaloids, which may be present in Solanum plant species such as potatoes, tomatoes and eggplants. α-Chaconine is a major glycoalkaloid present in potatoes. To assess the possible influence of structure of pteridine derivatives on toxicity of potato glycoalkaloids, a previous study that demonstrated the protective effects of folic acid against the Solanum glycoalkaloid α-chaconine-induced toxicity on Xenopus laevis frog embryo cell membranes was extended to two folate analogues—a synthetic compound widely used as a therapeutic agent methotrexate, and naturally occurring l-monapterin. Adverse effects on embryos were evaluated by observing changes in membrane potentials with an electrochromic dye, di-4-ANEPPS, as a fluorescent probe for the integrity of the membranes. Methotrexate decreased α-chaconine-induced polarization, as did folic acid. This decrease may result from an alteration of membrane conformations that prevents the binding of the glycoalkaloid to the membrane receptor sites, and/or from effects on folic acid metabolism. In contrast, l-monapterin did not significantly reduce the α-chaconine-induced toxicity. The possible significance of these results to food safety is discussed.

Prevention of Neural Tube Defects by Periconceptional Use of Folic Acid

Prevention of Neural Tube Defects by Periconceptional Use of Folic Acid

Open or closed

In this valedictory address the research of the Nijmegen homocysteine team on birth defects and vascular disease is presented. Hyperhomocysteinemia was found in women with neural tube defect (NTD) offspring, other birth defects and vascular disease. Raised homocysteine levels in the blood plasma can be explained by lack of B-vitamins (folic acid), mutation of the 5,10-methylenetetrahydrofolate reductase genes or both. Genetic mutations were found on the first chromosome (677 C→T and 1298 A–C) and can explain up to 50% of the NTD protective effect of folic acid. The inborn error of methionine-homocysteine metabolism was also found in cases with recurrent early pregnancy loss, schisis, congenital heart defects and vascular problems like placental abruption, infarcts and fetal growth retardation. One of the most exciting medical findings of the last years is that folic acid can prevent NTD defects. This might also hold for other birth defects and vascular disease.

Folic acid for the prevention of congenital anomalies.

Paediatricians need to be aware of the broad implications that sufficient maternal folic acid intake has on the wellbeing of the embryo and fetus. There is now strong evidence that adequate periconceptional maternal folic acid supplementation during critical periods of organ formation is associated with reduction in both the occurrence and recurrence of neural tube defects, congenital heart defects (particularly conotruncal heart defects), obstructive urinary tract anomalies, limb deficiencies, orofacial clefts and congenital hypertrophic pyloric stenosis. Inadequate maternal folic acid intake is associated with preterm deliveries, intra-uterine growth retardation, placental abruption and infarction, while maternal folic acid supplementation is associated with a reduction in preterm deliveries and intra-uterine growth retardation. Recently adequate folic acid intake in adults has been associated with a reduction in adult cardiovascular disease and some cancers. A common mutation in the 5,10 methylenetetrahydrofolate reductase gene has been identified which produces a thermolabile variant of 5,10 methylenetetrahydrofolate reductase with reduced enzyme activity. The common mutation is a risk factor both for neural tube defects and adult cardiovascular diseases. Folic acid acts to increase the activity of the variant methylenetetrahydrofolate reductase thereby reducing plasma homocysteine levels. However the polymorphism does not explain all of the protective effects of folic acid. Primary prevention of birth defects by adequate periconceptional folic acid supplementation is a major public health opportunity and has wide implications in reducing both mortality and morbidity due to birth defects and several adult diseases. It follows that there would also be a curbing of health care costs related to those disorders.

Elevated midtrimester serum methylmalonic acid levels as a risk factor for neural tube defects

The role of folic acid in the primary prevention of neural tube defects (NTDs) is well established. However, questions related to the protective mechanism remain unanswered. To help answer these questions, we designed a case-control study to assess the role of folate- and cobalamin-related metabolites in the pathogenesis of NTDs. Concentrations of folate, cobalamin, and 14 other related metabolites were measured by gas chromatography/mass spectrometry in midtrimester serum specimens from 32 women with an NTD-affected pregnancy and from 132 control women, and in serum specimens from 46 nonpregnant women who had a history of NTD-affected pregnancy and from 43 nonpregnant control women. Log-transformed means of metabolites were compared between case and control women for both the midtrimester and nonpregnant groups. In the pregnant group, serum methylmalonic acid (MMA) concentrations were higher among case women than among control women (130 vs 105 nM). There was a strong dose-response relationship between midtrimester serum MMA level and the risk for an NTD-affected pregnancy, with the relative risk increasing 13-fold for women with MMA levels > 90th percentile. In the nonpregnant group, there was no difference in serum MMA levels between case and control women (140 vs 140 nM). Thus, the serum MMA levels of women in the midtrimester of pregnancies unaffected by NTDs were significantly lower than the levels of nonpregnant women, whereas the levels of women whose pregnancies were affected by NTDs were similar to those of nonpregnant women. The finding of elevated MMA serum concentrations among women in the midtrimester of NTD-affected pregnancies suggests that cobalamin may be involved in the etiology of NTDs. The possible role of cobalamin in relation to the protective effect of folic acid needs further evaluation.

Aging

Recent investigations have demonstrated a protective role for folic acid in dysplasia and neoplasia, through an unknown mechanism. The current study was designed to evaluate whether the protective role of folic acid is due, in part, to its antiproliferative properties. In addition, because colorectal neoplasia is more common with increasing age, we have compared results in both old (22 months) and young (3 months) rats. Colorectal mucosal explants of rats treated with the known carcinogen methylazoxymethanol, were supplemented with folic acid. Ornithine decarboxylase was then measured as an index of cellular proliferative activity. We observed that supplemental folic acid suppressed carcinogen-induced ornithine decarboxylase activity by 64% in the old and 74% in the young rats. Furthermore, a similar phenomenon was observed for tyrosine kinase, which was measured for comparison. The suppression of hyperproliferative activity by supplemental folic acid may contribute to the protective effect of folic acid in colorectal neoplasia.

Ameliorative Effect of Folic Acid on Pyrimethamine Teratogenesis in Pigs

The effects of oral dosing of folic acid (FA) on pyrimethamine (PYR) teratogenesis were examined in Goettingen minipigs. PYR (3.6 mg/kg/day) was orally administered in the feed to sows with or without FA (2.5, 10 or 50 mg/kg/day) for 12 days, (days 11 - 22 of gestation). Major malformations, such as cleft palate, cleft lips, micrognathia and clubfoot, were observed in all treated groups. The incidence of malformed fetuses decreased dose-dependently as the FA level was raised. This new finding suggests FA administration may prevent newborns from PYR induced malformations. This result contrasts in the observations in rats, in which PYR teratogenesis was potentiated by the concurrent oral dosing of FA. Neither PYR blood concentrations nor plasma protein binding was significantly affected by FA dosing in nonpregnant sows. These results suggest a mechanism other than pharmacokinetic modification was responsible for the protective effect of FA on PYR teratogenesis in minipigs.

Arsenate-induced neural tube defects not influenced by constant rate administration of folic acid.

Serious suggestions have been made that dietary supplementation with folic acid (FA) and perhaps other vitamins during pregnancy may reduce the incidence of neural tube defect (NTD) in human newborns. The purpose of these experiments was to evaluate the effect of continuous infusion of FA on the incidence of NTDs induced by arsenate. This teratogen induces NTDs in up to 90% of golden hamster fetuses when administered acutely during critical stages of embryogenesis. FA was administered by subcutaneously implanted osmotic minipumps beginning on the 6th day of gestation, 48 h before an acutely administered dose of sodium arsenate. The protective effect of FA was examined at three teratogenic dose levels of arsenate: optimal, with 905 NTDs, intermediate, with 38% NTDs, and low, with 20% NTDs. Fetuses were recovered at day 13 of gestation and examined for NTDs and other malformations. Maternal red cell folate levels were determined on day 8, 48 h after implantation of the pumps. The results show that the maternal red blood cell level of FA can be significantly increased within 48 h by chronic infusion to levels which are almost two times (550 ng/ml) control levels. There was no significant protection against arsenate-induced NTDs following FA supplementation at any of three levels of this teratogen.