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PubMed1997

Effect of folic acid supplementation on folate status and formate oxidation rate in mink (Mustela vision).

We investigated the folate-dependent toxicity of formate to mink to better understand the use of formic acid in fur animal feeds. Folic acid supplementation (0, 1, 5, 10, and 20 mg/kg of DM) in the feed of weanling mink for 4 wk resulted in hepatic tetrahydrofolate (H4folate) concentrations of 3.94, 8.51, 9.15, 10.4, and 15.0 nmol/g, respectively (SE 1.03). Oxidation tests in metabolic chambers, preceeding a single injection of sodium [14C]formate (500 mg/kg BW), showed that the nonsupplemented mink oxidized formate into CO2 at a rate 37% less than that of the supplemented mink. The oxidation rate increased with supplementation level and was maximal, 54.2 mEq.kg1.h1 (SE 3.0), at 10 mg of folate/kg; at the highest level of supplementation (20 mg/kg), CO2 production tended to be lower. Concentration of hepatic 14C increased with the hepatic H4folate, and its accumulation continued after the highest point of oxidation. These observations indicate that mink oxidize formate readily but at a slightly lower rate than do rats. However, if extra folate is not supplemented in the feed during the period of early intensive growth, hepatic H4folate level may decline to the levels found in humans and monkeys, which are susceptible to formate accumulation. Average daily weight gain improved with each increase in supplementation of folic acid; however, only the differences between the nonsupplemented diet and the two highest levels of the vitamin reached statistical significance (P < .05).

Animals↗
PubMed1999

Modulation of fluorouracil antitumor activity by folic acid in a murine model system.

The biochemical basis for modulation of fluorouracil (FU) activity by leucovorin is elevation of the metabolite methylenetetrahydrofolate, which stabilizes the inhibitory ternary complex formed between thymidylate synthase and the active metabolite of FU, 5-fluorodeoxyuridylate. Folic acid, because it can also potentially be metabolized to methylenetetrahydrofolate, was evaluated for its ability to potentiate FU antitumor activity in a dietary folic acid restricted murine model. The plasma pharmacokinetics and tissue distribution of folic acid and all stable metabolites thereof were determined in the model to establish administration schedules. FU was administered to mice implanted subcutaneously with a mammary adenocarcinoma 4 hr after folic acid administration, when the metabolites, methylenetetrahydrofolate and tetrahydrofolate, were elevated maximally in both plasma and tumor tissue. While FU alone suppressed growth 25%, folic acid in combination with FU increased growth suppression to over 70%. These results indicate that folic acid is a potent modulator of FU activity and could be considered as an alternative to leucovorin in the clinical setting.

Animals↗
PubMed2002

Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To study the effects of folic acid and zinc sulfate treatment on semen variables in fertile and subfertile men. DESIGN: Double-blind, placebo-controlled interventional study. SETTING: Two outpatient fertility clinics and nine midwifery practices in The Netherlands. PARTICIPANT(S): One hundred eight fertile and 103 subfertile men. INTERVENTION(S): Both groups were randomly assigned to receive one of four treatments for 26 weeks: folic acid and placebo, zinc sulfate and placebo, zinc sulfate and folic acid, and two placebos. Folic acid was given at a daily dose of 5 mg, and zinc sulfate was given at a daily dose of 66 mg. MAIN OUTCOME MEASURE(S): Before and after treatment, standardized semen and blood samples were obtained for determinations of sperm concentration, motility, and morphology according to World Health Organization guidelines; semen morphology according to strict criteria; and blood folate and zinc concentrations. Effects of the four interventions were evaluated separately in subfertile and fertile men. RESULT(S): Subfertile men demonstrated a significant 74% increase in total normal sperm count and a minor increase of 4% abnormal spermatozoa. A similar trend was observed in fertile men. Pre-intervention concentrations of folate and zinc in blood and seminal plasma did not significantly differ between fertile and subfertile men. CONCLUSION(S): Total normal sperm count increases after combined zinc sulfate and folic acid treatment in both subfertile and fertile men. Although the beneficial effect on fertility remains to be established, this finding opens avenues of future fertility research and treatment and may affect public health.

Adult↗
PubMed1995

[Folic acid and pregnancy. Société française de pdiatrie--Comité de nutrition].

Epidemiological studies have shown a relationship between maternal folic acid status and the incidence of neural tube defects, prematurity, abortions. Based on the actual data, the Committee of Nutrition recommends that all women at age of procreation should be encouraged to regularly eat fresh fruits and vegetables in order to increase their reserve of folic acid, and that pregnant and lactating women should be supplemented with a daily dose of 200 micrograms of folic acid. In addition, the Committee is in favour of a folacin enrichment of some food which would allow to cover the needs of pregnant and lactating women. Those women who gave birth to a child with neural tube defects must be informed of the high risk of recurrence and be encouraged to take a treatment of 4 mg/day of folic acid, ideally starting one month before the beginning of pregnancy and to be maintained during the first 3 months.

Female↗
PubMed1988

Folic acid therapy for alopecia in a Charolais calf.

A three-week old male Charolais calf which had a history of progressive hair loss and clinical signs, including crusts and brown patches similar to those in folic acid deficiency syndrome in man, was subjected to folic acid therapy. Daily oral administration of folic acid (1 mg/kg/day) resulted in the gradual disappearance of the crusts and patches within two weeks and a steady growth of hair and recovery to a normal state within two months. Folic acid, which is required for cellular turnover in a variety of tissues and organs including the hair follicle, may serve as an effective therapeutic agent in some types of alopecia triggered by a deficiency of either folic acid or the co-enzymes involved in the synthetic pathway of DNA.

Alopecia↗
PubMed2003

Folic acid and homocysteine affect neural crest and neuroepithelial cell outgrowth and differentiation in vitro.

The beneficial effect of additional folic acid in the periconceptional period to prevent neural tube defects, orofacial clefts, and conotruncal heart defects in the offspring has been shown. Folate shortage results in homocysteine accumulation. Elevated levels of homocysteine have been related to neural tube defects. We studied the behavior of neuroepithelial cells and cranial and cardiac neural crest cells in vitro. Neural tube explants were cultured for 24 and 48 hr in medium after addition of folic acid and/or homocysteine. Folic acid addition increased neuroepithelial cell outgrowth and increased neural crest cell differentiation into nerve and smooth muscle cells. Addition of homocysteine increased neural crest cell outgrowth and migration from the neural tube and inhibited neural crest cell differentiation. Our findings suggest that neural tube defects caused by folate deficiency and hyperhomocysteinemia develop due to increased neuroepithelial to neural crest cell transformation. This increased transformation leads to a shortage of neuroepithelial cells in the neural tube. Defects in orofacial and conotruncal development are explained by abnormal differentiation of neural crest cells in the presence of high homocysteine concentrations. Our findings supports a critical role for folic acid and homocysteine in the development of neural tube defects and neural crest related heart malformations.

Animals↗
PubMed1990

Effects of intramuscular injections of folic acid on serum folates, haematological status and growth performance of growing-finishing pigs.

In a first trial, 48 piglets aged 5 weeks, grouped into 6 blocks of 8 pigs each, were used to determine the effect of intramuscular injections of folic acid on serum folates, haematological status, growth performance and carcass characteristics. Each block consisted of 2 pens of 4 pigs; in one pen, pigs received, by weekly intramuscular injections, an increasing volume of a solution containing 5 mg/ml folic acid, while in the other the animals were non-injected controls. The concentration of serum folates in treated pigs was 19% higher (P = 0.005) than in controls. There was no effect of treatment (P greater than or equal to 0.29) on haemoglobin and haematocrit. During the starting period, (5-11 weeks) average daily gain was not influenced by folic acid injections but feed intake and feed conversion were decreased (P = 0.07 and P = 0.05 respectively). No effect of folic acid (P greater than or equal to 0.23) was noted from 11-23 weeks of age, suggesting that the supplement was suboptimal during the growing-finishing period. In a second trial, 72 piglets aged 9 weeks were assigned to 6 blocks of 12 animals each. The following treatments were randomly distributed in each block according to a 2 x 3 factorial design: level of feeding (restricted vs ad libitum) and weekly intramuscular injections of increasing volume of solutions containing either 0, 15 or 30 mg/ml of folic acid. The variables studied were the same as in Trial 1. Concentrations of serum folates varied quadratically (P = 0.0001) with the dose injected, a plateau being attained with injections of 15 mg/ml. There was no effect of treatment (P = 0.043) on haemoglobin and haematocrit. During the growing period (9-15 weeks), no effect (P greater than or equal to 0.72) of folic acid was noted on growth performance. However, during the finishing period (15-21 weeks), folic acid given at a dose of 30 mg/ml decreased (P = 0.006) feed intake while no effect (P greater than or equal to 0.13) of the vitamin supplementation was noted on average daily gain and feed conversion. In both trials, there was no effect (P greater than or equal to 0.21) of any treatments on carcass characteristics. These results indicate that a supplement of folic acid administered by intramuscular injections was effective in increasing concentration of serum folates of starting or growing-finishing pigs. This supplement may be associated with a decrease in feed intake.

Animal Feed↗
PubMed2002

[Frequency of hyperhomocysteinemia in hemodialysis patients with folic acid supplementation].

BACKGROUND: It is known that hyperhomocystinemia is an independent risk factor for development of atherosclerosis. In end stage renal disease the frequency of hyperhomocystinemia is much greater than in normal populations. AIM: In this study homocystein (Hcy), folic acid and vitamin B12 concentrations were determined in 125 chronic renal failure patients being on folic acid supplementation (3 mg/day). In 107 patients the frequency of C667T polymorphism of methylene tetrahyrofolate reductase (MTHFR) was also determined. The relationships between these parameters were also studied. RESULTS: It was found that in these patients who are under continuous folic acid supplementation the mean level of homocysteine was 16.8 +/- 7.2 mumol/L, a value considerably lower than the homocysteine concentration reported for non-supplemented patients. The elevation of homocysteine concentrations was independent of gender, time spent in renal replacement therapy, and the type of renal replacement therapy (hemodialysis: 17.6 +/- 12.6; hemodiafiltration: 16.6 +/- 12.9 mumol/L). Data showed an inverse relation between plasma homocysteine concentrations and the concentrations of folic acid and vitamin B12. Moderately severe hyperhomocystinemia (Hcy > 20 mumol/L) was found in about 30% of patients. In those the frequency of patients for homozygous T677 allele of MTHFR was about 25-30%. However, in all ESRD patients the frequency of the homozygotes was the same then in the normal population. Homocysteine plasma levels correlated with MTHFR polymorphism: in the wild type group Hcy was 14 +/- 7 mumol/L, in the heterozygous group was 17.2 +/- 6.2 mumol/L, and in the homozygous group was 21 +/- 19 mumol/L. CONCLUSIONS: Long-term folic acid supplementation decreased the homocysteine level in end stage renal disease patients. However, in folic acid resistant group, who were in 30% homozygotes for C667T of MTHFR (suggesting that homocysteine-methionine remethylation cycle is disturbed), instead of the administration of folic acid, methylene tetrahydrofolate supplementation might be considered.

Adult↗
PubMed2006

Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age.

BACKGROUND: For the primary prevention of neural tube defects (NTDs), public health authorities recommend women of childbearing age to take 400 mug folic acid/d 4 wk before conception and during the first trimester. The biologically active derivate [6S]-5-methyltetrahydrofolate ([6S]-5-MTHF) could be an alternative to folic acid. OBJECTIVE: We investigated the effect of supplementation with [6S]-5-MTHF compared with that of folic acid on red blood cell folate concentration, an indicator of folate status. DESIGN: The study was designed as a double-blind, randomized, placebo-controlled intervention trial. Healthy women (n = 144) aged 19-33 y received 400 microg folic acid, the equimolar amount of [6S]-5-MTHF (416 microg), 208 microg [6S]-5-MTHF, or placebo as a daily supplement for 24 wk. Red blood cell and plasma folate concentrations were measured at baseline and at 4-wk intervals. RESULTS: The increase in red blood cell folate over time was significantly higher in the group receiving 416 microg [6S]-5-MTHF/d than in the groups receiving 400 microg folic acid/d or 208 microg [6S]-5-MTHF/d (P < 0.001). No plateau was reached in red blood cell folate concentration in the 3 treatment groups during 24 wk of intervention; however, plasma folate plateaued after 12 wk. CONCLUSIONS: We showed that administration of [6S]-5-MTHF is more effective than is folic acid supplementation at improving folate status. In addition, the study indicates that the recommended period for preconceptional folic acid supplementation should be extended to >4 wk for maximal prevention of NTDs based on folate concentrations. [6S]-5-MTHF might be an efficient and safe alternative to folic acid.

Adult↗
PubMed2007

Effects of folic acid supplementation on hearing in older adults: a randomized, controlled trial.

BACKGROUND: Age-related hearing loss is a common chronic condition of elderly persons. Low folate status has been associated with poor hearing. OBJECTIVE: To determine whether folic acid supplementation slows age-related hearing loss. DESIGN: Double-blind, randomized, placebo-controlled trial conducted from September 2000 to December 2004. SETTING: The Netherlands. PARTICIPANTS: 728 older men and women recruited from municipal and blood bank registries with plasma total homocysteine concentrations 13 micromol/L or greater serum and vitamin B12 concentrations 200 pmol/L or greater at screening, and no middle ear dysfunction, unilateral hearing loss, or pathologic ear conditions unrelated to aging. INTERVENTION: Daily oral folic acid (800 microg) or placebo supplementation for 3 years. MEASUREMENTS: 3-year change in hearing thresholds, assessed as the average of the pure-tone air conduction thresholds of both ears of the low (0.5-kHz, 1-kHz, and 2-kHz) and high (4-kHz, 6-kHz, and 8-kHz) frequencies. RESULTS: Initial median hearing thresholds were 11.7 dB (interquartile range, 7.5 to 17.5 dB) for low frequencies and 34.2 dB (interquartile range, 22.5 to 50.0 dB) for high frequencies. Sixteen participants (2%) were lost to follow-up. After 3 years, thresholds of the low frequencies increased by 1.0 dB (95% CI, 0.6 to 1.4 dB) in the folic acid group and by 1.7 dB (CI, 1.3 to 2.1 dB) in the placebo group (difference, -0.7 dB [CI, -1.2 to -0.1 dB]; P = 0.020). Folic acid supplementation did not affect the decline in hearing high frequencies. LIMITATIONS: The strict criterion for participation on the basis of serum homocysteine concentrations limits extrapolation to the general population. Folic acid fortification of food was prohibited in the Netherlands during the study, so baseline folate levels in participants were about half of those found in the U.S. population. CONCLUSIONS: Folic acid supplementation slowed the decline in hearing of the speech frequencies associated with aging in a population from a country without folic acid fortification of food. The effect requires confirmation, especially in populations from countries with folic acid fortification programs. Clinicaltrials.gov identifier: NCT00110604.

Aged↗
PubMed1996

Folic acid fortification.

The relationship of folic acid to neural tube defects has provided us with one of the richest case studies in nutrition science policy of this half century. The concepts of nutritional adequacy in the periconceptual period, the power of well-designed and controlled intervention trials, the challenges of altering the intake of a critical nutrient, the risks and benefits of food fortification, proper targeting with supplementation, and the effectiveness of achieving dietary change are all elements of this case study that we will continue to explore throughout the pages of this journal in the months ahead.

Female↗
PubMed2002

Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease.

Fortification of food with folic acid to prevent neural-tube defects in babies also lowers plasma total homocysteine, which is a risk factor for vascular disease. We investigated the effect of folate and vitamin B12 on homocysteine concentrations. 30 men and 23 women received sequential supplementation with increasing doses of folic acid. After supplementation, the usual dependency of homocysteine on folate diminished, and vitamin B12 became the main determinant of plasma homocysteine concentration. This finding suggests that a fortification policy based on folic acid and vitamin B12, rather than folic acid alone, is likely to be much more effective at lowering of homocysteine concentrations, with potential benefits for reduction of risk of vascular disease.

Adult↗
PubMed1997

Relationship of plasma folic acid and status of DNA methylation in human gastric cancer.

To evaluate the anti-cancer effects of folic acid at the molecular level, we determined plasma folic acid concentration by radioimmuno-assay and the degree of total genomic DNA methylation by incubating DNA with 3H-S-adenosylmethionine (3H-SAM) in the presence of a methylase, and analyzed the methylation status of the c-myc and c-Ha-ras oncogenes by Southern blotting in 21 patients with advanced gastric cancer. The degree of total genomic DNA methylation of cancerous tissues was significantly lower than that of paracancerous and non-cancerous tissues; c-myc and c-Ha-ras oncogenes from cancerous (10/21, 5/10) and paracancerous (13/21, 4/10) tissues were hypomethylated. The plasma folic acid concentration in patients who showed hypomethylation was lower than that patients showing normal methylation. These findings suggest that a decrease in folic acid, and the subsequent DNA hypomethylation, may be involved in human gastric carcinogenesis.

Adenocarcinoma↗
PubMed2006

Promoting pre-conceptional use of folic acid to Hispanic women: a social marketing approach.

OBJECTIVE: To develop a culturally appropriate communication initiative in an effort to promote the use of pre-conceptional folic acid among Hispanic women of childbearing age. The materials were designed to communicate information about the risks of neural tube defects and the value of folic acid supplementation before conception. METHODS: The initiative was developed using a social marketing approach. A series of focus groups were conducted with Hispanic women, particularly Mexican and Mexican-American women, to gain an understanding of their knowledge, attitudes, and behaviors regarding birth defects and folic acid. Additionally focus groups assessed women's preferences for existing folic acid education materials. Qualitative analysis of coded transcripts revealed key themes which were incorporated into a multi-media initiative. RESULTS: Critical themes of the research highlighted the need to include the role of partners and a sense of family in the promotions aimed at these groups. Another key component was the need to dispel myths which act as barriers to pre-conceptional folic acid use. Other important elements included in the media products were the need for Spanish and English versions, an explanation of neural tube defects, and a reference to the cost of the supplements. CONCLUSION: The final products of the initiative included Spanish and English versions of a brochure, photo-novella, and radio public service announcement. Pre-testing results showed women understood the message, thought the message was for women like them, and expected to begin taking a folic acid supplement. Results of the overall evaluation of the initiative are on-going.

Adolescent↗
PubMed1963

FOLIC ACID DERIVATIVES SYNTHESIZED DURING GROWTH OF DIPLOCOCCUS PNEUMONIA.

Sirotnak, F. M. (Sloan-Kettering Institute for Cancer Research, New York, N.Y.), Gloria J. Donati, and Dorris J. Hutchison. Folic acid derivatives synthesized during growth of Diplococcus pneumoniae. J. Bacteriol. 85:658-665. 1963.-Under cultural conditions permitting synthesis of folic acid in an amount greatly in excess (20- to 30-fold) of that required for maximal growth of Diplococcus pneumoniae, 85 to 90% of the growth factor accumulated as polyglutamates. Approximately equal amounts of mono- and diglutamates made up the remaining 10 to 15% found in culture material. Most of the polyglutamates occurred intracellularly, in a proportion of triglutamates to higher glutamates of about two to one. Only 10 to 15% of all folic acid derivatives (mono-, di-, and polyglutamates) found had folinic acid (5-formylfolate-H(4)) activity for Pediococcus cerevisiae. Practically all synthesis of the glutamyl-peptide moieties of folate seems to occur at an enzymatic step prior to folic acid, since no appreciable peptide formation occurred under conditions blocking folate synthesis. Sulfanilamide inhibition of growth by a block in folate synthesis was reversed by the addition of dihydrofolic acid, but not folic acid. The examination of two genetically distinct amethopterin-resistant mutant strains has revealed no gross differences in folate accumulation during growth when compared with the wild strain.

Antimetabolites↗
PubMed1989

Folic acid supplementation to diets of gestating-lactating swine over multiple parities.

Crossbred gilts (n = 59) were utilized in a three-parity study to evaluate the effects of dietary additions of folic acid for reproducing swine and to ascertain if responses were dependent on the presence of a sulfonamide in the diet. The four dietary treatments were 1) control, a 14% crude protein corn-soybean meal diet with 110 ppm tylosin, 2) diet 1 plus 110 ppm sulfamethazine, 3) diet 1 plus 1 ppm folic acid and 4) diet 2 plus 1 ppm folic acid. Gilts were allotted to dietary treatment based on age, weight and ancestry within 15 d postbreeding and remained on the assigned dietary treatment continuously. Folic acid supplementation of the diet improved (P less than .05) total (11.17 vs 10.23) and live pigs born (10.79 vs 9.86) per litter; however, when litters were weaned at 28 d, the folic acid advantage was not significant (P greater than .20, 9.34 vs 9.03). No dietary effects (P greater than .10) were observed for pig birth weight or weaning weight. Number of breedings required per female farrowed tended (P less than .12) to be less for females fed folic acid-supplemented diets (1.07 vs 1.16). These results demonstrate improved sow performance through an increase in pigs born and possibly an improved conception rate when folic acid is supplemented to cornsoybean meal diets.

Animals↗
PubMed1987

Folic acid: effect on zinc absorption in humans and in the rat.

The effect of folic acid on zinc absorption and utilization was studied in humans and in rats. Serum Zn response curves after a 25-mg oral dose of Zn was measured for 4 h with and without 10 mg folic acid. The increase in serum Zn expressed as AUC (area under the curve) was 57 mumol/L for Zn alone and 65 mumol/L with folate. Zn intragastric intubation experiments with rats showed that adding 4.4 or 176 micrograms of folate to test meals containing 13 micrograms Zn did not affect the bioavailability of Zn as measured by the retention of 65Zn by the liver and kidney. A 3-wk feeding test carried out with diets containing either 6 or 12 mg Zn/kg diet showed that adding either 2 or 160 mg of folic acid had no effect on growth or Zn uptake by the femur. These results do not indicate any inhibition of Zn utilization by folic acid.

Absorption↗
PubMed1995

Evaluating food fortification options: general principles revisited with folic acid.

OBJECTIVES: This article uses folic acid as an example to illustrate some of the complex issues and general principles that emerge when evaluating fortification of the food supply as one possible means to address a public health recommendation. METHODS: Distributions of current daily folate intakes from conventional foods and dietary supplements were estimated. Intakes that might result from fortification of cereal-grain products and ready-to-eat cereals at various levels for eight age-gender groups were also estimated by using the US Department of Agriculture's 1987-1988 Nationwide Food Consumption Survey. RESULTS: The results illustrate that fortification of the US food supply tends to increase folate intakes of consumers at the high end of the intake distribution curves in the general population to a greater extent than it affects consumers at the low end of the intake distribution curves in the target population. CONCLUSIONS: The effectiveness of food fortification options for a target population and the safety for the general population impose conflicting challenges that must be considered concurrently when making decisions about fortifying the US food supply.

Adolescent↗