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Neural Tube Defects, Folic Acid and Methylation  [PDF]
Apolline Imbard,Jean-Fran?ois Benoist,Henk J. Blom
International Journal of Environmental Research and Public Health , 2013, DOI: 10.3390/ijerph10094352
Abstract: Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects.
No Effect of Folic Acid Supplementation on Global DNA Methylation in Men and Women with Moderately Elevated Homocysteine  [PDF]
Audrey Y. Jung, Yvo Smulders, Petra Verhoef, Frans J. Kok, Henk Blom, Robert M. Kok, Ellen Kampman, Jane Durga
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024976
Abstract: A global loss of cytosine methylation in DNA has been implicated in a wide range of diseases. There is growing evidence that modifications in DNA methylation can be brought about by altering the intake of methyl donors such as folate. We examined whether long-term daily supplementation with 0.8 mg of folic acid would increase global DNA methylation compared with placebo in individuals with elevated plasma homocysteine. We also investigated if these effects were modified by MTHFR C677T genotype. Two hundred sixteen participants out of 818 subjects who had participated in a randomized double-blind placebo-controlled trial were selected, pre-stratified on MTHFR C677T genotype and matched on age and smoking status. They were allocated to receive either folic acid (0.8 mg/d; n = 105) or placebo treatment (n = 111) for three years. Peripheral blood leukocyte DNA methylation and serum and erythrocyte folate were assessed. Global DNA methylation was measured using liquid chromatography-tandem mass spectrometry and expressed as a percentage of 5-methylcytosines versus the total number of cytosine. There was no difference in global DNA methylation between those randomized to folic acid and those in the placebo group (difference = 0.008, 95%CI = ?0.05,0.07, P = 0.79). There was also no difference between treatment groups when we stratified for MTHFR C677T genotype (CC, n = 76; CT, n = 70; TT, n = 70), baseline erythrocyte folate status or baseline DNA methylation levels. In moderately hyperhomocysteinemic men and women, long-term folic acid supplementation does not increase global DNA methylation in peripheral blood leukocytes. ClinicalTrials.gov NCT00110604
Weekly Iron-Folic Acid Supplementation with Regular Deworming Is Cost-Effective in Preventing Anaemia in Women of Reproductive Age in Vietnam  [PDF]
Gerard J. Casey, Davide Sartori, Susan E. Horton, Tran Q. Phuc, Luong B. Phu, Dang T. Thach, Tran C. Dai, Giovanni Fattore, Antonio Montresor, Beverley-A. Biggs
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023723
Abstract: Background To estimate the cost and cost-effectiveness of a project administering de-worming and weekly iron-folic acid supplementation to control anaemia in women of reproductive age in Yen Bai province, Vietnam. Methods and Findings Cost effectiveness was evaluated using data on programmatic costs based on two surveys in 2006 and 2009 and impact on anaemia and iron status collected in 2006, 2007, and 2008. Data on initial costs for training and educational materials were obtained from the records of the National Institute of Malariology, Parasitology and Entomology and the Yen Bai Malaria Control Program. Structured questionnaires for health workers at district, commune and village level were used to collect ongoing distribution and monitoring costs, and for participants to collect transport and loss of earnings costs. The cost per woman treated (defined as consuming at least 75% of the recommended intake) was USD0.76 per annum. This estimate includes financial costs (for supplies, training), and costs of health care workers' time. Prevalence of anaemia fell from 38% at baseline, to 20% after 12 months. Thus, the cost-effectiveness of the project is assessed at USD 4.24 per anaemia case prevented per year. Based on estimated productivity gains for adult women, the benefit:cost ratio is 6.7:1. Cost of the supplements and anthelminthics was 47% of the total, while costs of training, monitoring, and health workers' time accounted for 53%. Conclusion The study shows that weekly iron-folic acid supplementation and regular de-worming is a low-cost and cost-effective intervention and would be appropriate for population-based introduction in settings with a high prevalence of anaemia and iron deficiency and low malaria infection rates.
Folate Status of Reproductive Age Women and Neural Tube Defect Risk: The Effect of Long-Term Folic Acid Supplementation at Doses of 140 μg and 400 μg per Day  [PDF]
Nicola A. Hursthouse,Andrew R. Gray,Jody C. Miller,Meredith C. Rose,Lisa A. Houghton
Nutrients , 2011, DOI: 10.3390/nu3010049
Abstract: Primary prevention of most folate-responsive neural tube defects (NTDs) may not require 400 μg folic acid/day but may be achieved by attaining a high maternal folate status. Using RBC folate ≥ 906 nmol/L as a marker for NTD risk reduction, the study aimed to determine the change in blood folate concentrations in reproductive age women in response to long-term folic acid supplementation at 400 μg/day and 140 μg/day (dose designed to mimic the average daily folic acid intake received from New Zealand’s proposed mandatory bread fortification program). Participants were randomly assigned to a daily folic acid supplement of 140 μg ( n = 49), 400 μg ( n = 48) or placebo ( n = 47) for 40?weeks. RBC folate concentrations were measured at baseline, and after 6, 12, 29 and 40?weeks. At 40 weeks, the overall prevalence of having a RBC folate < 906 nmol/L decreased to 18% and 35% in the 400 μg and 140 μg groups, respectively, while remaining relatively unchanged at 58% in the placebo group. After 40 weeks, there was no evidence of a difference in RBC folate between the two treatment groups ( P = 0.340), nor was there evidence of a difference in the odds of a RBC folate < 906 nmol/L ( P = 0.078). In conclusion, the average daily intake of folic acid received from the proposed fortification program would increase RBC folate concentrations in reproductive age women to levels associated with a low risk of NTDs.
Circulating Unmetabolized Folic Acid: Relationship to Folate Status and Effect of Supplementation  [PDF]
Carolyn Tam,Deborah O'Connor,Gideon Koren
Obstetrics and Gynecology International , 2012, DOI: 10.1155/2012/485179
Abstract: There are increasing concerns that exposure to unmetabolized folic acid, which results from folic acid intakes that overwhelm the liver's metabolic capacity, may be associated with adverse effects. In this paper, we examined the folic acid status of women of reproductive age in relation to dietary intake and the effect of folic acid supplementation (1.1?mg or 5?mg). Plasma unmetabolized folic acid was not significantly correlated with folate intake estimated by food frequency questionnaire or biomarkers. The proportion of women with detectable levels of unmetabolized folic acid increased from 65% to 100% after twelve weeks of supplementation ( ); however, the increase in concentrations did not reach statistical significance and the effect was not sustained. Moreover, there were no significant differences between the two doses. This suggests that there are mechanisms by which the body adapts to high folic acid intakes to limit exposure to unmetabolized folic acid. 1. Introduction The term “folate” describes the group of B vitamers that share the same vitamin activity based on the parent structure of folic acid. The parent structure consists of an aromatic pteridine ring joined by a methylene bridge to para-aminobenzoic acid (PABA), which in turn is attached to glutamic acid by a peptide bond (Figure 1) [1]. Folate vitamers differ in the oxidation state of the pteridine ring and substitution on the N5 and/or N10 nitrogen atoms. In addition, a polyglutamate tail consisting of up to nine glutamate residues, each one joined via amide linkage to the γ-carboxyl group of the preceding residue, may be added [1, 2]. Figure 1: Structure of folic acid [ 1]. The three parts of the parent structure include 2-amino-4-oxo-pteridine, p-aminobenzoic acid, and glutamic acid. Substitutions (one-carbon groups) occur at the N5 and/or N10 positions. By convention, the term “folic acid” refers specifically to the fully oxidized and most stable form of the vitamin that is used in supplements and fortified foods. Biologically, these groups of vitamins are critical in DNA synthesis and repair, and as cofactors in biological reactions involving folate sources. Folate exists naturally in foods as reduced folate polyglutamate conjugates. In addition, folic acid is added as a fortificant to certain foods. As of 2007, fifty-two countries worldwide had national regulations mandating folic acid fortification of wheat flour [3]. Folic acid is also found in supplements and multivitamins. In general, the bioavailability of folic acid is higher than that of the naturally occurring food
Effects of Altered Maternal Folic Acid, Vitamin B12 and Docosahexaenoic Acid on Placental Global DNA Methylation Patterns in Wistar Rats  [PDF]
Asmita Kulkarni,Kamini Dangat,Anvita Kale,Pratiksha Sable,Preeti Chavan-Gautam,Sadhana Joshi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017706
Abstract: Potential adverse effects of excess maternal folic acid supplementation on a vegetarian population deficient in vitamin B12 are poorly understood. We have previously shown in a rat model that maternal folic acid supplementation at marginal protein levels reduces brain omega-3 fatty acid levels in the adult offspring. We have also reported that reduced docosahexaenoic acid (DHA) levels may result in diversion of methyl groups towards DNA in the one carbon metabolic pathway ultimately resulting in DNA methylation. This study was designed to examine the effect of normal and excess folic acid in the absence and presence of vitamin B12 deficiency on global methylation patterns in the placenta. Further, the effect of maternal omega 3 fatty acid supplementation on the above vitamin B12 deficient diets was also examined. Our results suggest maternal folic acid supplementation in the absence of vitamin B12 lowers plasma and placental DHA levels (p<0.05) and reduces global DNA methylation levels (p<0.05). When this group was supplemented with omega 3 fatty acids there was an increase in placental DHA levels and subsequently DNA methylation levels revert back to the levels of the control group. Our results suggest for the first time that DHA plays an important role in one carbon metabolism thereby influencing global DNA methylation in the placenta.
Homocysteine, an indicator of methylation pathway alternation in Down syndrome and its regulation by folic acid therapy  [cached]
Hala M El-Gendy,Hala M Mokhtar
Journal of Research in Medical Sciences , 2007,
Abstract: BACKGROUND: Down syndrome (DS) is a complex genetic disease. Some clinical features of patients with this syndrome could be related to functional folate deficiency. The purpose of this study was to evaluate the total homocysteine (T-Hcy) metabolism in DS children and to determine whether the supplementation with folic acid therapy would shift the genetically induced metabolic imbalance or not. METHODS: Thirty-five infants with DS, with the mean age of 17.66 ± 12.24 months were included in this study. They were selected from those attending the Genetic Outpatients Clinic in Children hospital. RESULTS: Our results revealed that Down syndrome children had a significant decrease in serum plasma T-Hcy level after the treatment with folic acid [11.79 ± 0.92 vs. 14.41 ± 4.93 μmol/L]. A significant negative correlation was found between T-Hcy and folic acid serum levels [r = -0.112; P<0.05].CONCLUSIONS: We concluded that the regulation of methylation pathways in Down syndrome patients becomes important in the light of possible normalization of the metabolic imbalance and the detection of increased sensitivity to therapeutic interventions. KEY WORDS: Down syndrome, hyperhomocysteine, folic acid, vitamin B-12.
Spina Bifida Defying Folic Acid Supplementation  [PDF]
Raveenthiran V
Journal of Neonatal Surgery , 2012,
Abstract: Pre-conceptional supplementation of folic acid is well known to reduce the incidence of spina bifida. But Athena is frequently perplexed to see this anomaly occurring despite folate supplementation. In a largest Canadian study, De Wal et al [1] screened 1.9 million live births to study the effect of mass fortification. On comparing pre and post fortification periods they noted only 46% reduction in the incidence of neural tube defects (NTD). What happens to the remaining 54%? Why do they defy “folic acid” logics? Recently several publications have shed more light on this intriguing question.
Folic Acid Supplementation Promotes Mammary Tumor Progression in a Rat Model  [PDF]
Shaidah Deghan Manshadi, Lisa Ishiguro, Kyoung-Jin Sohn, Alan Medline, Richard Renlund, Ruth Croxford, Young-In Kim
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0084635
Abstract: Folic acid supplementation may prevent the development of cancer in normal tissues but may promote the progression of established (pre)neoplastic lesions. However, whether or not folic acid supplementation can promote the progression of established (pre)neoplastic mammary lesions is unknown. This is a critically important issue because breast cancer patients and survivors in North America are likely exposed to high levels of folic acid owing to folic acid fortification and widespread supplemental use after cancer diagnosis. We investigated whether folic acid supplementation can promote the progression of established mammary tumors. Female Sprague-Dawley rats were placed on a control diet and mammary tumors were initiated with 7,12-dimethylbenza[a]anthracene at puberty. When the sentinel tumor reached a predefined size, rats were randomized to receive a diet containing the control, 2.5x, 4x, or 5x supplemental levels of folic acid for up to 12 weeks. The sentinel mammary tumor growth was monitored weekly. At necropsy, the sentinel and all other mammary tumors were analyzed histologically. The effect of folic acid supplementation on the expression of proteins involved in proliferation, apoptosis, and mammary tumorigenesis was determined in representative sentinel adenocarcinomas. Although no clear dose-response relationship was observed, folic acid supplementation significantly promoted the progression of the sentinel mammary tumors and was associated with significantly higher sentinel mammary tumor weight and volume compared with the control diet. Furthermore, folic acid supplementation was associated with significantly higher weight and volume of all mammary tumors. The most significant and consistent mammary tumor-promoting effect was observed with the 2.5x supplemental level of folic acid. Folic acid supplementation was also associated with an increased expression of BAX, PARP, and HER2. Our data suggest that folic acid supplementation may promote the progression of established mammary tumors. The potential tumor-promoting effect of folic acid supplementation in breast cancer patients and survivors needs further clarification.
Homocysteine: An Indicator of Methylation Pathway Alternation in Down Syndrome Children and its Regulation by Folic Acid Therapy  [PDF]
Hala D. El-Gindi,Hala M. Hussien
Journal of Medical Sciences , 2007,
Abstract: The purpose of this research was to evaluate the total homocysteine (t-Hcy) metabolism in Down Syndrome (DS) children and to determine whether the supplementation with folic acid therapy would shift the genetically induced metabolic imbalance. Thirty-five infants with DS (17 male and 18 females), their mean age 17.66"12.24 months were included in this study. They were selected among those attending the Genetic out Patients Clinic, Children Hospital. Present results revealed that Down syndrome=s children had a significant increase of serum folic acid after treatment with folic acid therapy (18.91±3.59 vs 11.95±1.55 ng mLG1), while no significant change in vitamin B12 (323.17±38.42 vs 358.36±57.43 pg mLG1). There was a significant decrease in plasma t-Hcy level after treatment with folic acid therapy (11.79±0.92 vs 14.41±4.93 μ mol LG1). A significant negative correlation was found between t-Hcy and folic acid serum levels (r = -0.112; p< 0.05). The present study concluded that, the regulation of methylation pathways in Down syndrome becomes important in light of possible normalization of the metabolic imbalance and the detection of increased sensitivity to therapeutic interventions.
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