What is folate metabolism

Despite that a meta-analysis of the few studies of DS-CHD is yet not possible due to their relatively small number Table 4 , a recent meta-analysis of 18 case-control studies, that included data from In this regard, Obermann-Borst et al. The study revealed remarkably different profiles between tissues, with genes hypomethylated in heart tissue compared to blood, and genes hypomethylated in blood compared to heart tissue.

Among the 22 heart DNA samples significant differences in DNA methylation profiles were seen between fetuses with DS and fetuses with a normal karyotype. Despite that DS occurs in almost 1 on live births, the molecular mechanisms leading to maternal chromosome 21 malsegregation during oogenesis are still not fully understood. Since , it was suggested that maternal polymorphisms in folate pathway genes could contribute to the epigenetic regulation of the chromatin structure in those regions, thus acting as maternal risk factors for the birth of a child with DS James et al.

That hypothesis stimulated considerable research over the last 15 years, leading to the production of more than 50 case-control studies that, despite the conflicting nature of their results, revealed a complexity of gene-gene and gene-nutrient interactions in folate metabolism as potential maternal risk factors for having a birth with trisomy for chromosome 21 Table 1.

Furthermore, data concerning the occurrence of the meiotic error MI or MII , the maternal age at conception, as well as smoking and drinking habits, are often unavailable in case-control studies, making it impossible to evaluate their contribution during the meta-analysis Table 2. Unfortunately, our understanding of this is still in its infancy, due to scarce availability of comparison data between women who experience loss of trisomy 21 pregnancies and those with trisomic fetuses that survive up to the birth, as well as to a few epigenetic studies in DS individuals.

In this regard, evidence is accumulating concerning the possible contribution of impaired maternal folate metabolism and epigenetic changes during embryogenesis to the occurrence of DS-CHD cases Table 4.

We cannot exclude that similar mechanisms could also account for other DS comorbidities, but data are still scarce or missing. For example, Brandalize et al.

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This work was not supported by research grants and publication costs were entirely covered by the author. The author acknowledges all MDS and control mothers that took part in the studies described in this review making it possible to advance the scientific knowledge in this field.

The author also acknowledges the devotion and the scientific contribution of all the authors of the papers discussed in this review article, and encourages them to continue their work in such a complex but increasingly fascinating field.

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Blom, H. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. Methylenetetrahydrofolate reductase enzyme polymorphisms as maternal risk for Down syndrome among Turkish women.

Bosco, P. A A, — Brandalize, A. Maternal gene polymorphisms involved in folate metabolism as risk factors for Down syndrome offspring in Southern Brazil. Markers 29, 95— Cai, B. Canfield, M. Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study. Castilla, E. Preliminary data on changes in neural tube defect prevalence rates after folic acid fortification in South America.

Chadefaux-Vekemans, B. Methylenetetrahydrofolate reductase polymorphism in the etiology of Down syndrome. Chango, A. No association between common polymorphisms in genes of folate and homocysteine metabolism and the risk of Down's syndrome among French mothers. Choi, J. Contemporary issues surrounding folic acid fortification initiatives. Food Sci.

Polymorphisms in folate and homocysteine metabolizing genes and chromosome damage in mothers of Down syndrome children. Polymorphisms in folate-metabolizing genes, chromosome damage, and risk of Down syndrome in Italian women: identification of key factors using artificial neural networks. BMC Med. Genomics Nutrients 5, — Folate gene polymorphisms and the risk of Down syndrome pregnancies in young Italian women. Association of maternal polymorphisms in folate metabolizing genes with chromosome damage and risk of Down syndrome offspring.

Costa-Lima, M. Cretu, R. Cyril, C. Indian J. Relationship between polymorphisms in genes involved in homocysteine metabolism and maternal risk for Down syndrome in Brazil. A , — Dekker, A. Epigenetics: the neglected key to minimize learning and memory deficits in Down syndrome. Elsayed, G. Fedosov, S. Physiological and molecular aspects of cobalamin transport. Fenech, M. Folate vitamin B9 and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity.

Feng, Y. Maternal folic acid supplementation and the risk of congenital heart defects in offspring: a meta-analysis of epidemiological observational studies. Finkelstein, J. Metabolic regulatory properties of S-adenosylmethionine and S-adenosylhomocysteine.

Fintelman-Rodrigues, N. Markers 26, — Goh, Y. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. PubMed Abstract Google Scholar. Gopalakrishnan, S. Grillo, L. The folate in human milk. Bailey L. Dietary reference intakes for folate: the debut of dietary folate equivalents. Burdge GL, KA.

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Keshava C, Keshava, N. Inhibition of methotreate-induced chromosal damage by folinic acid in V79 cells. McGuire B, Sia, L. Pharmakokinetics of leucovorin calcium after intravenous, intramuscular, and oral administration. Moran R, Keyomarsi, K. Biochemical rationale for the synergism of 5-fluorouracil and folinic acid. Anti-toxoplasma effect of pyrimethamine, trimethoprim and sulphonamides alone and in combination: implications for therapy.

Van Delden C, Hirschel, B. Morrell M. Folic acid and epilepsy. Desmoulin S, Wang, L. Functional loss of reduced folate carrier enhances the antitumor activities of novel antifolates with selective uptake by the proton-coupled folate transporter. Battino D, Tomson, T. Management of epilepsy during pregnancy. Wilson S, Bivins, BN.

Oral contraceptive use: impact on folate, vitamin B 6 , and vitamin B 1 2 status. Czeizel A, Dudas, I. Prevention of the first occurance of neural-tube defects by periconceptional vitamin supplementation. Dec 24 ; Hodgetts V, Morris, RK. All three types of receptors have been associated with folate transport across the placenta during pregnancy Folate deficiency is most often caused by a dietary insufficiency; however, folate deficiency can also occur in a number of other situations.

For example, chronic and heavy alcohol consumption is associated with diminished absorption of folate in addition to low dietary intake , which can lead to folate deficiency Smoking is also associated with low folate status. Additionally, impaired folate transport to the fetus has been described in pregnant women who either smoked or abused alcohol during their pregnancy 14, Pregnancy is a time when the folate requirement is greatly increased to sustain the demand for rapid cell replication and growth of fetal, placental , and maternal tissue.

Conditions such as cancer or inflammation can also result in increased rates of cell division and metabolism , causing an increase in the body's demand for folate Moreover, folate deficiency can result from some malabsorptive conditions, including inflammatory bowel diseases Crohn's disease and ulcerative colitis and celiac disease Several medications may also contribute to folate deficiency see Drug interactions.

Finally, a number of genetic diseases affecting folate absorption, transport, or metabolism can cause folate deficiency or impede its metabolic functions see Disease Treatment. Clinical folate deficiency leads to megaloblastic anemia , which is reversible with folic acid treatment.

Rapidly dividing cells like those derived from bone marrow are most vulnerable to the effects of folate deficiency since DNA synthesis and cell division are dependent on folate coenzymes. When folate supply to the rapidly dividing cells of the bone marrow is inadequate, blood cell division is reduced, resulting in fewer but larger red blood cells.

This type of anemia is called megaloblastic or macrocytic anemia , referring to the enlarged, immature red blood cells. Neutrophils , a type of white blood cell, become hypersegmented, a change that can be found by examining a blood sample microscopically.

Because normal red blood cells have a lifetime in the circulation of approximately four months, it can take months for folate-deficient individuals to develop the characteristic megaloblastic anemia. Progression of such an anemia leads to a decreased oxygen carrying capacity of the blood and may ultimately result in symptoms of fatigue, weakness, and shortness of breath 1.

It is important to point out that megaloblastic anemia resulting from folate deficiency is identical to the megaloblastic anemia resulting from vitamin B 12 deficiency, and further clinical testing is required to diagnose the true cause of megaloblastic anemia see Toxicity. Individuals in the early stages of folate deficiency may not show obvious symptoms, but blood concentrations of homocysteine may increase see Disease Prevention.

Yet, the concentration of circulating homocysteine is not a specific indicator of folate status, as elevated homocysteine can be the result of vitamin B 12 and other B-vitamin deficiencies, lifestyle factors, and renal insufficiency. Traditionally, the dietary folate requirement was defined as the amount needed to prevent a deficiency severe enough to cause symptoms like anemia.

The most recent RDA ; Table 1 was based primarily on the adequacy of red blood cell folate concentrations at different levels of folate intake, as judged by the absence of abnormal hematological indicators.

Red cell folate has been shown to correlate with liver folate stores and is used as an indicator of long-term folate status. Plasma folate reflects recent folate intake and is not a reliable biomarker for folate status. Maintenance of normal blood homocysteine concentrations, an indicator of one-carbon metabolism , was considered only as an ancillary indicator of adequate folate intake. Because pregnancy is associated with a significant increase in cell division and other metabolic processes that require folate coenzymes , the RDA for pregnant women is considerably higher than for women who are not pregnant 3.

Rather, reducing the risk of NTDs was considered in a separate recommendation for women capable of becoming pregnant see Disease Prevention , because the crucial events in the development of the neural tube occur before many women are aware that they are pregnant Use of the DFE reflects the higher bioavailability of synthetic folic acid found in supplements and fortified food compared to that of naturally occurring food folates It should be noted that DFEs were determined in studies with adults and whether folic acid in infant formula is more bioavailable than folates in mother's milk has not been studied.

Use of DFEs to determine a folate requirement for the infant would not be desirable. The substitution of a cytosine C by a thymine T at nucleotide in the exon 4 of MTHFR gene leads to an alanine-to-valine transition in the catalytic domain of the enzyme. The latter is the folate coenzyme required to form methionine from homocysteine see Figure 2 above. Improving folate nutritional status in elderly women with the T allele reduced plasma homocysteine concentration An important unanswered question about folate is whether the present RDA is enough to compensate for the reduced MTHFR enzyme activity in individuals with at least one T allele, or whether those individuals have a higher folate requirement than the RDA Fetal growth and development are characterized by widespread cell division.

Neural tube defects NTDs arise from failure of embryonic neural tube closure between the 21 st and 27 th days after conception, a time when many women may not even realize they are pregnant NTDs include various malformations, such as lesions of the brain e.

The prevalence of NTDs in the United States prior to fortification of food with folic acid was estimated to be 1 per 1, pregnancies 1. These recommendations were made to all women of childbearing age because adequate folate must be available very early in pregnancy, and because many pregnancies in the US are unplanned Also, a genetic component in NTD etiology is evidenced by the increased risk in women with a family history of an NTD and also by variations in risk among ethnicities Moreover, NTD occurrence can be attributed to specific folate- gene interactions.

A meta-analysis of 25 case-control studies, including 2, case mothers and 3, control mothers, showed a positive association between the maternal MTHFR c. While maternal genotype can impact pregnancy outcome, it appears that gene-gene interactions between mother and fetus influence it further.

Finally, vitamin B 12 status has been associated with NTD risk modification in the presence of specific polymorphisms in one-carbon metabolism Congenital anomalies of the heart are a major cause of infant mortality but also cause deaths in adulthood Recent meta-analyses of 20 to 25 case-control and family-based studies observed positive associations between maternal, fetal, or paternal MTHFR c.

Additional studies are needed to elucidate the effects of gene -nutrient interactions on the risk of congenital heart defects; however, the currently available research indicates that adequate folate intake may play an important role. Epidemiological evidence supporting a role for folate in the risk of CPO is lacking.

Low birth weight has been associated with increased risk of mortality during the first year of life and may also influence health outcomes during adulthood A recent systematic review and meta-analysis of eight randomized controlled trials found a positive association between folic acid supplementation and birth weight; no association with length of gestation was observed Moreover, the maternal c. Elevated blood homocysteine concentrations have also been associated with increased incidence of miscarriage and other pregnancy complications, including preeclampsia and placental abruption A large retrospective study showed that plasma homocysteine in Norwegian women was strongly related to adverse outcomes and complications, including preeclampsia, premature delivery, and very low birth weight, in previous pregnancies A recent meta-analysis of 51 prospective cohort studies linked the c.

A large multicenter, randomized, controlled trial, the Folic Acid Clinical Trial FACT , has been initiated to evaluate whether the daily supplementation of up to 5. Adequate folate intake during pregnancy protects against megaloblastic anemia Thus, it is reasonable to maintain folic acid supplementation throughout pregnancy, even after closure of the neural tube, in order to decrease the risk of other problems during pregnancy.

Moreover, recent systematic reviews of observational studies found no evidence of an association between folate exposure during pregnancy and adverse health outcomes in offspring, in particular childhood asthma and allergies 67, The results of more than 80 studies indicate that even moderately elevated concentrations of homocysteine in the blood increase the risk of cardiovascular disease CVD 4.

Possible predispositions to vascular accidents have also been linked to genetic deficiencies in homocysteine metabolism in certain populations The mechanism by which homocysteine may increase the risk of vascular disease has been the subject of a great deal of research, but it may involve adverse effects of homocysteine on blood clotting, arterial vasodilation , and thickening of arterial walls Although increased homocysteine concentrations in the blood have been consistently associated with increased risk of CVD, it is unclear whether lowering circulating homocysteine will reduce CVD risk see Folate and homocysteine.

However, the analysis of recent clinical trials of B-vitamin supplementation has shown that lowering homocysteine concentrations did not prevent the occurrence of a second cardiovascular event in patients with existing CVD 73, Consequently, the American Heart Association recommends screening for elevated total homocysteine concentrations only in "high risk" individuals, for example, in those with personal or family history of premature cardiovascular disease, malnutrition or malabsorption syndromes , hypothyroidism , kidney failure, lupus , or individuals taking certain medications nicotinic acid, theophylline, bile acid -binding resins, methotrexate, and L-dopa.

Folate-rich diets have been associated with decreased risk of CVD , including coronary artery disease , myocardial infarction heart attack , and stroke. Of the three B-vitamins that regulate homocysteine concentrations, folic acid has been shown to have the greatest effect in lowering basal concentrations of homocysteine in the blood when there is no coexisting deficiency of vitamin B 12 or vitamin B 6 see Nutrient interactions Increasing folate intake through folate-rich food or supplements has been found to reduce homocysteine concentrations Besides, blood homocysteine concentrations have declined since the FDA mandated folic acid fortification of the grain supply in the US In particular, the effect of the c.

Although folic acid supplementation effectively decreases homocysteine concentrations, it is not yet clear whether it also decreases risk for CVD.

A recent meta-analysis of 19 randomized clinical trials , including 47, subjects with preexisting cardiovascular or renal disease, found that homocysteine lowering through folic acid and other B-vitamin supplementation failed to reduce the incidence of CVD despite significant reductions in plasma homocysteine concentrations Other meta-analyses have confirmed the lack of causality between the lowering of homocysteine and the risk of CVD , including the risk of stroke 83, Consequently, the American Heart Association removed its recommendation for using folic acid to prevent cardiovascular disease in high-risk women It should be noted that the majority of prevention trials to date have been performed in CVD patients with advanced disease.

The evidence supporting a beneficial role for folate and related B-vitamins appears to be strongest for the primary prevention of stroke Despite the controversy regarding the role of homocysteine lowering in CVD prevention, some studies have investigated the effect of folic acid supplementation on the development of atherosclerosis , a known risk factor for vascular accidents. The measurement of the carotid intima-media thickness CIMT is a surrogate endpoint for early atherosclerosis and a predictor for cardiovascular events The meta-analysis of 10 randomized trials testing the effect of folic acid supplementation showed a significant reduction in CIMT in subjects with chronic kidney diseases and in those at risk for CVD, but not in healthy participants Endothelial dysfunction is a common feature in atherosclerosis and vascular disease.

Although recent trials failed to demonstrate any cardiovascular protection from folic acid supplementation, low folate intake is a known risk factor for vascular disease, and more research is needed to explore the role of folate in maintaining vascular health Because of the important roles played by folate in DNA and RNA synthesis and methylation , it is possible that inadequate folate intake contributes to genome instability and chromosome breakage that often characterize cancer development.

In particular, DNA replication and repair are critical for genome maintenance, and the shortage in nucleotides caused by folate deficiency might lead to genome instability and DNA mutations.

A decrease in 5,methylene THF can compromise the conversion of deoxyuridine monophosphate dUMP to deoxythymidine monophosphate dTMP by the enzyme thymidylate synthase TS , causing uracil accumulation and thymine depletion. This could then lead to uracil misincorporation into DNA during replication or repair, and cause DNA damage, including point mutations and strand breaks However, this hypothesis might only be valid in a situation of folate deficiency Conversely, it was argued that folic acid supplementation could fuel DNA synthesis, therefore promoting tumor growth.

This is supported by the observation that TS can function like a tumor promoter oncogene , while a reduction in TS activity is linked to a lower risk of cancer 94, Additionally, antifolate molecules that block the thymidylate synthesis pathway are successfully used in cancer therapy Thus, folate deficiency may impair DNA and protein methylation and alter the expression of genes involved in DNA repair, proliferation and cell death.

Global DNA hypomethylation, a typical hallmark of cancer, causes genome instability and chromosome breaks reviewed in The consumption of at least five servings of fruit and vegetables daily has been consistently associated with a decreased incidence of cancer Fruit and vegetables are excellent sources of folate, which may play a role in their anti-carcinogenic effect.

Observational studies have found diminished folate status to be associated with site-specific cancers. While food fortification is mandatory in the US since ; see Sources , concerns about the impact of high folic acid intakes on health have delayed the practice in several other countries A pooled analysis of 13 prospective cohort studies , which followed a total of , individuals for a 7 to year period, revealed a modest, inverse association between dietary and total from food and supplements folate intake and colon cancer risk.

A large US prospective study , which followed , subjects, ages 50 to 71 years between and , correlated dietary folate, supplemental folic acid, and total folate intakes with a decreased colorectal cancer CRC risk However, when stratified by gender, there was no association between dietary folate intake and CRC risk in women , A lack of association between CRC risk and dietary, supplemental, and total folate intakes was also reported in another prospective study that followed more than 90, US postmenopausal women during an year period encompassing pre- and post- fortification periods These data suggest the possible influence of gender over CRC risk modification by folate.

In the latter study, a significant but transient risk elevation was also observed during the post-fortification era; however, some have asserted that this is unlikely to be caused by increased folate intake due to mandatory fortification Finally, a meta-analysis of 18 case-control studies found a slight reduction in CRC risk with folate from food However, it is important to note that the case-control studies were highly heterogeneous , and that the authors stated that dietary fiber, vitamins, and alcohol intake could have confounded their results.

While most epidemiological research shows a protective effect of folate against colorectal cancer development, it has been suggested that high doses of supplemental folic acid may actually accelerate tumor growth in cancer patients Whereas higher folate status within the normal dietary range is widely considered to be protective against cancer, some investigators remain concerned that exposure to excessively high folic acid intakes may increase the growth of pre-existing neoplasms Several clinical trials addressed the effect of folic acid supplementation in patients with a history of colorectal adenoma , with trials finding a risk reduction or no effect of supplemental folic acid A common polymorphism c.

Methionine synthase catalyzes the simultaneous conversion of homocysteine and 5-methylene THF into methionine and TFH, respectively. The recent meta-analysis of 27 case-control studies showed no association between MTR variant and cancer risk Although alcohol consumption interferes with the absorption and metabolism of folate 16 , one case-control and five prospective cohort studies have reported either reduction in CRC risk among nondrinkers compared to drinkers or a lack of association CRC risk was not increased during the post-fortification period, suggesting that it is the combination of high alcohol and low folate intake that might increase CRC risk.

Yet, another prospective study that followed more than 69, female nurses for 28 years did not report a significant increase in CRC risk with alcohol intake before and after the mandatory folic acid fortification In some studies, individuals who are homozygous for the c. Several prospective cohort and case-control studies investigating whether folate intake affects breast cancer risk have reported mixed results A meta-analysis of 15 prospective studies and one nested case-control study found no relationship with dietary folate intake Moderate alcohol intake has been associated with increased risk of breast cancer in women The results of three prospective studies suggested that increased folate intake may reduce the risk of breast cancer in women who regularly consume alcohol Thus, high folate intake might be associated with a risk reduction only in women whose breast cancer risk is raised by alcohol consumption.

A very large prospective study in more than 88, nurses reported that folic acid intake was not associated with breast cancer in women who consumed less than one alcoholic drink per day. Nevertheless, whether and how alcohol consumption increases breast cancer risk is still subject to discussion , Finally, recent meta-analyses evaluating the influence of polymorphisms in one-carbon metabolism on cancer risk found that specific variants in the gene encoding thymidylate synthase increased the risk of breast cancer in certain ethnic populations , The incidence of Wilms' tumors kidney cancer and certain types of brain cancers neuroblastoma, ganglioneuroblastoma, and ependymoma in children has decreased since the mandatory fortification of the US grain supply in However, incidence rates were unchanged between the pre- and post-fortification periods for leukemia—a predominant childhood malignancy.

Despite earlier studies linking maternal folic acid supplementation during pregnancy with the reduced risk of childhood leukemia, more recent investigations have found little evidence to support a preventive effect of folic acid Several meta-analyses have also found little to no protective effect with MTHFR polymorphisms ; however, the most recent meta-analysis of 22 case-control studies found a reduction in the risk of acute lymphoblastic leukemia ALL with the c.

Alzheimer's disease AD is the most common form of dementia , affecting more than 5 million individuals over 65 years old in the US One study associated increased consumption of fruit and vegetables, which are abundant sources of folate, with a reduced risk of developing dementia and AD in women Abstract Folate functions in multiple coenzyme forms in acceptance, redox processing and transfer of one-carbon units, including nucleotides and certain amino acids.

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