Folate Balance Research Articles

Folate in maternal rheumatoid arthritis-filial autism spectrum disorder continuum

Rheumatoid Arthritis (RA) is an inflammatory autoimmune disease that affects women three times more than men. Epidemiological studies found that the incidence of Autism Spectrum Disorder (ASD), a neurological and developmental disorder, in children born to mothers suffering from RA is higher compared with the control population. Considering that the pathogenesis of ASD could be traced back to pregnancy and in uterine conditions, and the evidence of reduced folate levels in the brain of ASD-affected children, we aimed to study the role of folate, as an important nutritional factor during pregnancy, in associating maternal RA to ASD development in the offspring. Folate balance during RA could be influenced twice, initially during the immune activation associated with disease onset, and later during the treatment with anti-folate drugs, with a potential consequence of folate deficiency. Maternal folate deficiency during pregnancy could increase homocysteine levels, oxidative stress, and global DNA hypomethylation, all known risk factors in ASD pathogenesis. These effects could be intensified by genetic polymorphisms in the folate system, which were also found as genetic risk factors for both RA and ASD. The available evidence suggests that folate level as an important factor during RA, pregnancy and ASD could have pathological and therapeutical significance and should be carefully monitored and investigated in the RA-pregnancy-ASD axis.

Evaluation of methylenetetrahydrofolate reductase and S-adenosyl-methionine level in male infertility: A case-control study.

BackgroundMethylenetetrahydrofolate reductase enzyme (MTHFR) plays a key role in regulating folate balance, converting homocysteine to methionine, and producing s-adenosylmethionine (SAM) that plays a role in the methylation process.ObjectiveThis study aimed to determine MTHFR activity and SAM level in men with normozoospermia and oligozoospermia.Materials and Methods30 oligozoospermic and 30 normozoospermic men as controls were enrolled in this case-control study. Semen analysis was conducted according to the world health organization criteria. All semen samples were collected after 3-5 days of sexual abstinence. The sperms were evaluated by sperm test video software. All subjects SAM level was measured by enzyme-linked immunosorbent assay kit, and MTHFR were measured manually.Results2 groups had a significant difference in sperm morphology (p = 0.02), concentration (p = 0.02) and motility (p = 0.03). The MTHFR activity in normozoospermic and oligozoospermic groups had significantly differences (p = 0.01). The level of SAM in the semen of oligozoospermic men was statistically lower than normozoospermic men (p = 0.03). Also, there was a positive association between MTHFR enzyme activity and SAM level in the normozoospermia group (p = 0.02, β = 0.67) and oligozoospermia group (p = 0.03, β = 0.54).ConclusionMTHFR activity and SAM concentration were statistically lower in oligozoospermia men. It seems they can affect sperm concentration, morphology, and motility.

Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies.

Metformin is the first-line treatment for many people with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to maintain glycaemic control. Recent evidence suggests metformin can cross the placenta during pregnancy, thereby exposing the fetus to high concentrations of metformin and potentially restricting placental and fetal growth. Offspring exposed to metformin during gestation are at increased risk of being born small for gestational age (SGA) and show signs of ‘catch up’ growth and obesity during childhood which increases their risk of future cardiometabolic diseases. The mechanisms by which metformin impacts on the fetal growth and long-term health of the offspring remain to be established. Metformin is associated with maternal vitamin B12 deficiency and antifolate like activity. Vitamin B12 and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B12 imbalance induced by metformin may lead to genomic instability and aberrant gene expression, thus promoting fetal programming. Mitochondrial aerobic respiration may also be affected, thereby inhibiting placental and fetal growth, and suppressing mammalian target of rapamycin (mTOR) activity for cellular nutrient transport. Vitamin supplementation, before or during metformin treatment in pregnancy, could be a promising strategy to improve maternal vitamin B12 and folate levels and reduce the incidence of SGA births and childhood obesity. Heterogeneous diagnostic and screening criteria for GDM and the transient nature of nutrient biomarkers have led to inconsistencies in clinical study designs to investigate the effects of metformin on folate:vitamin B12 balance and child development. As rates of diabetes in pregnancy continue to escalate, more women are likely to be prescribed metformin; thus, it is of paramount importance to improve our understanding of metformin’s transgenerational effects to develop prophylactic strategies for the prevention of adverse fetal outcomes.

Variations in vitamin B12 and folate balance: implications for cognitive function? Findings from The Irish Longitudinal Study on Ageing (TILDA)

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Impact of MTHFR polymorphisms on methylation of MGMT in glioma patients from Northeast China with different folate levels

Hypomethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter in glioma cells has been associated with temozolomide resistance. S-adenosylmethionine (SAM), which is produced during folate metabolism, is the main source of methyl groups during DNA methylation. As a key enzyme during folate metabolism, polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) may regulate folate end-products. We investigated the effect of typical polymorphisms of MTHFR (C677T and A1298C) on MGMT methylation based on different serum folate levels in patients with glioma from Northeast China. A total of 275 patients with glioma and 329 without malignant tumors were tested. Serum folate concentration was assayed by using the electrochemiluminescence immunoassay. MTHFR polymorphisms were detected by Taqman-Fluorescence quantitative polymerase chain reaction (PCR). Methylation-specific PCR was used to assess MGMT methylation. The constituent ratio of glioma patients below the serum folate biological reference value was significantly higher than that of the control population (P < 0.001). In patients with oligodendroglioma and glioblastoma, heterozygotes for the A1298C mutation were found in higher frequency than homozygotes or wild types (oligodendroglioma, P < 0.001; glioblastoma, P < 0.01). When grouped by the median or biological reference value of serum folate, only homozygotes for C677T with low levels of folate were significantly associated with decreased methylation of MGMT (median, P < 0.001; biological reference value, P = 0.036). These data suggest that, in combination with a negative folate balance in glioma patients, T/T genotypes in MTHFR C677T may be associated with MGMT demethylation.

Changes in Homocysteine and 8-iso-PGF2a Levels in Football and Hockey Players After a Match

The aim of the present study was to evaluate the levels of homocysteine and 8-iso PGF2a in football and hockey players before and soon after a match, on the predisposition for development of atherosclerosis. We measured 8-iso-PGF2a and homocysteine in 21 football athletes aged 21.8 ± 3.7 years old and 18 hockey athletes 22.2 ± 3.3 years old, respectively. All the athletes presented significant increases in serum homocysteine levels following the match (p = 0.001 for football and p = 0.001 for hockey players) Also a statistically significant increase of 8-iso-PGF2a levels was found in hockey and football athletes following the match (p < 0.001 and p = 0.071). Our findings suggest that strenuous exercise such as a football or a hockey match causes a marked increase in serum homocysteine and 8-iso-PGF2a. Due to the fact that homocysteine and 8-iso-PGF2a are contributing to atheromatosis, it may be useful to follow a restoration exercise program that involves mild exercise and to pay special attention to folate, vitamin B6, and vitamin B12 balance during the first 24 h after the match.

Study of folate in psoriasis: blood levels, intestinal absorption and cutaneous loss.

SUMMARY Serum, red cell and squame folate content have been measured in fifty cases of psoriasis with extensive lesions. Reduced serum and red cell folate have been found in 44% of the patients. Folic acid absorption, studied in twenty-six patients, was impaired in four and significantly increased in all the others. Squame folate content has been found too low to explain the folate deficiency. Malabsorption is a possible hypothesis but it occurs too rarely (four cases). The most likely explanation of folate deficiency seems to be an increased utilization of folate by the skin epidermal cells as a result of the rapid turnover rate. The increased absorption found in most cases investigated could be a compensatory mechanism to equilibrate folate balance.

Uracil misincorporation into DNA of leukocytes of young women with positive folate balance depends on plasma vitamin B 12 concentrations and methylenetetrahydrofolate reductase polymorphisms. A pilot study

Changes in the folate and vitamin B 12 status in the body influence the extent of uracil misincorporation (UrMis) into DNA, which is one of the biomarkers of genomic stability and, thus, portends a risk of cancer. In our study, the level of UrMis into DNA was evaluated by the comet assay (using the specific DNA repair enzyme, uracil DNA glycosylase) in leukocytes from blood donated by healthy young women with positive folate balance achieved by 4 weeks of folic acid supplementation (400 μg/day). The nutritional status was evaluated on the basis of nine food diaries recorded by the subjects during two winter months. The data were computerized, and the intake of nutrients and micronutrients was estimated using the DIETA 2 program (Food and Nutrition Institute, Warsaw, Poland) linked to recently updated Polish food tables. The plasma folate and vitamin B 12 concentration, as well as methylenetetrahydrofolate reductase (MTHFR) polymorphisms, were evaluated to determine their influence on the level of UrMis into DNA. The mean value of B 12 intake for all subjects reached 100% of the Polish recommended dietary allowances (RDA), whereas the mean value of folate intake, before folate supplementation, was 50%, suggesting moderate deficiency. Folic acid supplementation brought the folate intake way above the RDA, and plasma folate concentration in each individual was above the deficient range (mean value 14.67 ng/ml). The UrMis did not correlate with the plasma folate concentration, but the level of UrMis was significantly lower in subjects with plasma vitamin B 12 concentration above 400 pg/ml ( P=.02) only after folic acid supplementation. The concentration of folate in plasma correlated ( P≤.05) with the wild-type MTHFR homozygote 1298 AA but not with the MTHFR 677 genotype. When subjects were grouped according to genotype, the mean concentration of folate in plasma was significantly lower in subjects with the MTHFR 677 (CT+TT) polymorphism, which was accompanied by a lower UrMis, compared to individuals with the CC genotype. The significantly higher concentrations of folate in serum, accompanied by increased UrMis, were seen in subjects with the combined MTHFR 1298 (AC+CC) genotype, as compared to the 1298 AA wild type. Our results suggest that more than 400 pg/ml of vitamin B 12 in plasma in subjects with a positive folate balance is critical for genomic stability and indicate that the amount of UrMis into DNA is related to the MTHFR genotype.

The role of folates in squamous cell carcinoma of the head and neck

The primary objective of this review is to explore the hypothesis that folate insufficiency may be important in the pathogenesis of squamous cell carcinomas of the head and neck (SCCHN) and that folate repletion may be an effective component of chemoprevention. The main results are that folate insufficiency disrupts DNA global and specific gene methylation patterns such that the activity of certain tumor suppressor genes such as p16 and possibly p53 may be lost. Folate pool imbalance and impaired repair mechanisms may contribute to DNA instability and strand breaks. Sensitive methods exist for identification of individuals with folate insufficiency in contrast to the relatively insensitive conventional serum or red cell folate assays with broad “normal” ranges. The impact of folate supplementation can thus be quantified. Folate imbalance may result from alterations in folate cellular uptake by the reduced folate carrier (RFC) and/or the folate receptor (FR) and polymorphisms in enzymes important in folate retention such as folylpolyglutamate synthetase and in folate modification such as methylene tetrahydrofolate reductase (MTHFR). Known predisposing factors for SCCHN such as alcohol and tobacco carcinogens may influence folate balance. Folate supplementation may reduce primary or secondary risk of cancer. Formal studies of folate sufficiency in persons at risk for or diagnosed and treated for SCCHN are needed to define the role of folate supplementation in the prevention of these cancers.

Folate Status in Women of Childbearing Age Residing in Southern California after Folic Acid Fortification

Objective: The purpose of this study was to investigate folate status in healthy, nonpregnant women (18 to 45 years) following folic acid (FA) fortification of the food supply.Design: This was a cross-sectional study design in which a fasting blood sample was obtained from socio-economically advantaged (n=85) and disadvantaged (n=50) women residing in Southern California who had not consumed supplemental FA within the past 12 months. Serum folate (SF), red cell folate (RCF) and plasma homocysteine (tHcy) concentrations were measured and methylene tetrahydrofolate reductase (MTHFR) genotype (C677T) was determined.Results: SF and RCF concentrations (mean±SD) for socio-economically advantaged (54±18, 1387±329 nmol/L, respectively) and disadvantaged women (41±18, 1172±342 nmol/L, respectively) greatly exceeded the levels deemed acceptable for SF (≥13.6 nmol/L) and RCF (≥362 nmol/L). Moreover, 95% of socio-economically advantaged women and 78% of disadvantaged women achieved RCF concentrations ≥906 nmol/L, which are associated with very low risk of neural tube defects (NTD). Plasma tHcy concentrations for both socio-economically advantaged (5.2 ± 1.6 μmol/L) and disadvantaged women (6.1±1.6 μmol/L) were within the lower limit of normal range and indicative of adequate folate status. For the combined groups (n=135), the frequency of the C/C, C/T and T/T genotype was 56.0, 37.3 and 6.7%, respectively. MTHFR genotype was not associated with SF, RCF or tHcy.Conclusions: These data suggest that women of childbearing age are achieving positive folate balance and RCF concentrations associated with reduced risk of NTD following FA fortification of the food supply.

Minimum effective dose of folic acid for food fortification to prevent neural-tube defects

Although a daily supplement of 400 micrograms folic acid has been shown to prevent neural-tube defects (NTD), most women do not take the recommended supplement. Thus, food fortification is to be introduced in the USA and is being considered in the UK. Because of safety concerns, the USA has chosen a level of fortification that will increase the average woman's intake by only 100 micrograms. Such an increase, although safe, may be ineffective; but a trial to assess its efficacy would be unethical. Because women with red-cell folate concentrations above 400 micrograms/L have a very low risk of NTD, we undertook a randomised trial of several folic acid doses to find out how much is needed to reach this protective concentration. We screened 323 women. 172 with red-cell folate between 150 micrograms/L and 400 micrograms/L were invited to take part in the trial. 121 women were randomly assigned placebo or 100 micrograms, 200 micrograms, or 400 micrograms daily of additional folic acid. Compliance was monitored by having the women sign a dated sheet when taking the tablet. 95 women completed the 6-month study. There were significant increases in red-cell folate in all folic acid groups. The placebo group showed no significant change. The median incremental changes and median post-treatment concentrations were 67 micrograms/L (95% CI 43-120) and 375 micrograms/L (354-444) in the 100 micrograms/day group, 130 micrograms/L (108-184) and 475 micrograms/L (432-503) in the 200 micrograms/day group, and 200 micrograms/L (125-312) and 571 micrograms/L (481-654) in the 400 micrograms/day group. A fortification programme that delivered 400 micrograms folic acid daily to women would protect against NTD, but at the expense of unnecessarily high exposure for many people. Delivery of 200 micrograms daily is also effective against NTD and safer for the general population. Based on projections from the positive folate balance in the group that received 100 micrograms daily, this dose taken continually, as it will be in fortified food, will also produce an important decrease in NTD.

Folate economy in pregnancy

Pregnant women are prone to becoming folate deficient because there is a significant increase in folate requirement during pregnancy and folate intakes of pregnant women are often insufficient. Reduced folate levels in blood and neutrophilic hypersegmentation reflect a negative folate balance. Possible consequences of a low maternal folate status may be pregnancy complications such as abortion, abortus imminens, abruptio placentae, and congenital malformations. The role of folic acid in the etiology of neural tube defects has been discussed for decades. The importance of an adequate maternal folate status in the prevention of neural tube defects has been demonstrated by observational and controlled intervention trials. However, the mechanism of the protective effect of periconceptional folate supplementation is not completely understood. Metabolic disorders are probably involved in the pathogenesis of neural tube defects so that a relative folate shortage rather than folate deficiency seems to be responsible for the disturbed neural tube development, which can be compensated for by a higher folate intake.

Predictors of Red Cell Folate Level in Women Attempting Pregnancy

Brown, Judith E.; Jacobs, David R. Jr; Hartman, Terryl J.; Barosso, Geralyn M.; Stang, Jamie S.; Gross, Myron D.; Zeuske, Melanie A. Author Information

Predictors of red cell folate level in women attempting pregnancy.

To identify predictors of red cell folate level in women attempting to become pregnant. Cohort study. A health maintenance organization serving the Minneapolis-St Paul, Minn, area. A total of 189 healthy, primarily white women aged 22 to 35 years enrolled in the Diana Project, a population-based prospective study of preconceptional and prenatal risks to reproductive outcomes. The sample represents 189 of 219 enrolled women who were sequentially selected from the total Diana Project sample to receive additional laboratory analyses. Red cell folate level. Folic acid supplements, folic acid intake from fortified cereals, vitamin C supplements, and serum zinc level (inverse) were found to predict red cell folate levels. Previous research has shown that red cell folate levels higher than 906 nmol/L (400 ng/mL) may be optimal for the prevention of folate-responsive neural tube defects. For folic acid supplement users, folate intakes of 450 microg per day and higher corresponded to these protective levels of red cell folate. In nonusers of supplements, intakes of more than 500 microg of folate per day from foods and folic acid-fortified cereals may be needed to attain red cell folate levels higher than 906 nmol/L (400 ng/mL). Red cell folate levels higher than 906 nmol/L (400 ng/mL) were primarily found in women who took folic acid supplements. Only 1 in 4 women had red cell folate levels higher than 906 nmol/L (400 ng/mL), while 1 in 8 had red cell folate levels indicative of a negative folate balance. Addition of a daily, 400-microg folic acid supplement to the usual diet would result in red cell folate levels over 906 nmol/L (400 ng/mL) in a majority of women in this study. Supplementation of diets of women of childbearing potential with 400 microg of folic acid per day would effectively raise red cell folate to levels associated with a low risk of folate-responsive neural tube defects. Protective levels of red cell folate may also be obtained by ample consumption of vegetables, fruits, and folic acid-fortified breakfast cereals. Efforts to increase folic acid supplement use and folate consumption among women of childbearing potential must go beyond fortification of refined cereal and grain products and reach women within all educational and income groups.

Making sense of laboratory tests of folate status: folate requirements to sustain normality.

The first event in the sequence leading to nutrient deficiency is development of negative nutrient balance, i.e., nutrient utilization, requirement, catabolism, and excretion exceeds nutrient ingestion, absorption, and anabolism. Persistent negative nutrient balance produces a sequence of stages or degrees along a continuum of nutrient depletion which are not always clearly demarcated one from the next but show an increasing deficiency, usually marked by sequential appearance of various biochemical and clinical deficits. In the case of folate, the continuum from normality to folate-deficiency megaloblastic anemia begins with negative folate balance and proceeds through three sequential stages, or degrees, of folate depletion, each defined by the appearance of specific biochemical and/or hematologic markers (Table 1, Fig. 1).

Erythrocyte folate before and during treatment with lithium

AbstractWe determined erythrocyte folate in normal subjects (blood donors) as well as in manic‐‐depressive patients before the start of prophylactic lithium treatment and at various times during the treatment. Before treatment the patients' erythrocyte folate was 25 per cent lower and after 6 months of treatment it was 10 per cent lower than the control value. Thereafter patient values and control values did not differ. Lithium treatment accordingly normalised on abnormal folate balance, but it is also possible that lithium in itself may have elevated erythrocyte folate. This is supported by animal data. Rats were given ordinary food and food containing lithium. After eight weeks erythrocyte folate was 27 per cent higher in the lithium‐treated rats than in the controls. Our study does not support the notion that folate supplements are required during lithium therapy.

Folic acid binding protein and folate balance in uremia

Folic acid binding protein and folate balance in uremia

Folic Acid Binding Protein and Folate Balance in Uremia

To determine the incidence and importance of folate deficiency in uremia, we studied 41 patients who had chronic uremia but who were not receiving hemodialysis. Serum folate level was assayed by microbiological, whole serum radioassay, and heat-extracted radioassay techniques. Mean serum folate level, as determined with the Lactobacillus casei method, was 6.9 ng/ml (normal, more than 3.0 ng/ml). The mean heat-extracted radioassay serum folate level was 6.6 ng/ml. Only 10% of our patients had subnormal serum folate values, as determined with these techniques. No cases of megaloblastic anemia were discovered, and the hematologic profiles correlated with L casei and heat-extracted radioassay serum folate values. The mean serum folic acid binding protein (FABP) level was significantly greater for the uremic patients than for control patients (26% vs 9.9%, respectively; P = .0005). Our results show that elevated levels of serum FABP spuriously depress the serum folate level, as determined with the whole serum radioassay technique, but apparently do not retard delivery of folate to the tissue in vivo.

ACUTE FOLATE DEFICIENCY IN SURGICAL PATIENTS ON AMINOACID/ETHANOL INTRAVENOUS NUTRITION

Acute folate deficiency with pancytopenia and megaloblastic hæmopoiesis developed in four patients after abdominal operations; all four responded to folic acid over 3-9 days. Three of them had been given intravenous nutrition with aminoacid/ethanol before the blood changes developed. A prospective study of twenty-five surgical patients with gastrointestinal diseases revealed a high frequency of acutely developing negative folate balance. Megaloblastic hæmopoiesis and consequent blood changes were found in five patients. Treatment with intravenous nutrition correlated strongly with a fall in serum-folate and megaloblastic hæmopoiesis. Some surgical patients develop acute folate deficiency which may proceed to megaloblastic arrest of hæmopoiesis. Patients receiving intravenous nutrition containing ethanol are especially prone to this complication, which may be life-threatening if untreated. It is not yet known whether other forms of intravenous nutrition carry a similar risk.

Oral contraceptive hormones, folate metabolism, and the cervical epithelium

The currently available evidence concerning disorders of folate metabolism in women taking oral contraceptives has been reviewed. A disturbance in folate balance serious enough to cause symptoms (i.e., megaloblastic anemia) occurs very rarely. In some series, but not in others, serum and/or red cell folate concentrations have been reduced in oral contraceptive users. It is doubtful whether sex steroids affect polyglutamate folate absorption. About 20 percent of women taking contraceptive hormones manifest mild megaloblastic changes on Papanicolaou smears of the cervicovaginal epithelium which disappear after folic acid therapy. The current evidence, however, would not indicate that any significant benefit would ensue from routine folate supplementation in women on oral contraceptives.