Dietary Folic Acid Supplementation Research Articles

Effects of dietary supplements of folic acid on reproductive performance in ewes

The objective of this project was to assess the impact of periconceptional folic acid supplementation on the reproductive performance of prolific and non-prolific ewes, in the estrous and anestrous seasons. Two initial trials took place during the estrous season at two experimental sites where 38 Dorset and 39 half-Finn half-Dorset ewes (site A) as well as 80 Dorset ewes (site C) were divided into two groups receiving either 0 or 210 mg ewe-1 d-1 of folic acid over a period which extended from 21 d premating to 30 d postmating. Three other trials were conducted in the anestrous season where 80 Dorset ewes (site A), 56 half-Romanov ewes (site B) and 78 Dorset ewes (site C) were subjected to the same protocol as the one used in the breeding season. In all the trials, the folic acid supplement increased plasma and red cell folates, but had no effect on fertility, embryonic mortality, or the size or weight of the litter at birth. Folic acid supplementation did not improve the reproductive performance of prolific and non-prolific ewes, either in the estrous season or in the anestrous period. Key words: Ewes, reproduction, vitamins, folic acid, fertility, prolificacy

Gene-environment interactions reveal a homeostatic role for cholesterol metabolism during dietary folate perturbation in mice

Dietary folate supplementation can dramatically reduce the severity and incidence of several common birth defects and adult diseases that are associated with anomalies in homocysteine and folate metabolism. The common polymorphisms that adversely affect these metabolic pathways do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test involvement of folate, homocysteine, and other pathways in disease pathogenesis and treatment response, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared with the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE-deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting that homeostasis among the homocysteine, folate and cholesterol metabolic pathways contributes to the beneficial effects of dietary folate supplementation.

Effects of Folic Acid on Cardiac Myocyte Apoptosis in Rats with Streptozotocin-induced Diabetes Mellitus

The effect of folic acid on cardiac myocyte apoptosis secondary to diabetes is unknown. Diabetic rats were divided into diabetic control (DC, n = 11), low-dose (LDF, 0.4 mg/kg/day, n = 12) and high-dose (HDF, 1.2 mg/kg/day, n = 12) folic acid groups. Non-diabetic rats (n = 11) were used as the normal control (NC). After 11 weeks of treatment, compared with the NC group, the DC group showed a reduced blood levels of reactive oxygen species (ROS, P < 0.01). The rate of cardiac myocyte apoptosis in the diabetic control group was also greater than in the non-diabetic control group (P < 0.01). In folic acid-treated rats, the blood levels of ROS was higher than in the diabetic control group (P < 0.05). There was a dose-dependent reduction in the rate of cardiac myocyte apoptosis in the folic acid groups (P < 0.01), and this was accompanied by an increased level of anti-apoptotic protein Bcl-2 and decreased level of pro-apoptotic protein Bax and Fas (P < 0.01). Dietary folic acid supplementation diminishes the cardiac myocyte apoptosis in streptozotocin-induced diabetes. The apoptosis suppression is accompanied by an increase in the expression of Bcl-2 and a decrease in Bax and Fas.

Postweaning Dietary Folate Deficiency Provided through Childhood to Puberty Permanently Increases Genomic DNA Methylation in Adult Rat Liver

Folate plays an important role in the pathogenesis of several chronic diseases by its potential ability to modulate DNA methylation. We hypothesized that the postweaning period might be a highly susceptible period to dietary folate intervention for DNA methylation patterning. We determined the effects of timing and duration of dietary folate intervention provided during the postweaning period on genomic DNA methylation in adult rat liver. In study 1, weanling rats were randomized to receive an amino acid-defined diet containing 0 (deficient), 2 (control), or 8 (supplemented) mg folic acid/kg until 8 wk of age, after which all the rats were fed the control diet until 30 wk of age. In study 2, weanling rats were fed the control diet until 8 wk of age and then randomized to receive the diet containing 0, 2, or 8 mg folic acid/kg until 30 wk of age. In study 3, weanling rats were randomized to receive these diets until 30 wk of age. Dietary folate deficiency, but not supplementation, provided during the postweaning period through childhood to puberty significantly increased genomic DNA methylation by 34–48% ( P < 0.04) in rat liver that persisted into adulthood following a return to the control diet at puberty. In contrast, dietary folate deficiency or supplementation continually imposed at weaning or at puberty did not significantly affect genomic DNA methylation in adult rat liver. Our data suggest that early folate nutrition during postnatal development plays an important role in epigenetic programming that can have a permanent effect in adulthood.

Early-Life Arsenic Exposure: Methylation Capacity and Beyond

Inorganic arsenic (iAs), a toxic metalloid, affects millions of people worldwide, mainly from drinking contaminated water. Arsenic is a human carcinogen that targets skin, lung, bladder, and possibly other sites. iAs and its methylated metabolites readily cross the placenta and reach the fetus [National Research Council (NRC) 1999], producing effects ranging from developmental toxicity to cancer (NRC 1999; Waalkes et al. 2007). Thus, early-life As exposures are drawing escalating health concerns. In this issue of Environmental Health Perspectives, Li et al. (2008) report on iAs metabolism in pregnant Bangladeshi women exposed to iAs through contaminated water. iAs is metabolized to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) for urinary excretion; urinary As speciation is widely used to assess As methylation capacity. Arsenic methylation capacity can be influenced by dietary intake of cysteine, methionine, folic acid, niacin, vitamin B12, and choline (Steinmaus et al. 2005), and dietary folic acid supplementation to malnourished arsenicosis patients can decrease As burden by decreasing blood MMA and increasing urinary DMA (Gamble et al. 2007). However, despite poor micronutrient status and high As exposure, the pregnant Bangladeshi women showed remarkably efficient As methylation. The median percentage of urinary DMA (74%) is in the upper range, and MMA (11%) in the lower range of what is commonly seen in urine of individuals from developed counties with much better nutrition (Vahter 2007). Women during childbearing years are more efficient at As methylation than men (Lindberg et al. 2007), particularly during pregnancy. This is likely due to the de novo synthesis of choline by the phosphatidylethanolamine methyltransferase (PEMT) pathway (Vahter 2007), which can be up-regulated by estrogen. Thus, the PEMT pathway may function in malnourished pregnant women to increase choline production needed for fetal development, and, perhaps fortuitously for As methylation (Vahter 2007). The remarkable efficiency of As methylation in malnourished pregnant women could also be an adaptive response to As exposure. Such adaptation might increase As methylation, and thereby excretion, during pregnancy, but perhaps at the expense of later toxicity. Methyl groups from S-adenosylmethionine are essential to both As and DNA methylation. DNA methylation status is a well-recognized controlling factor in gene expression. Furthermore, alterations in DNA methylation status are a recognized epigenetic mechanism in As carcinogenesis and are linked with As exposure in various systems (Pilsner et al. 2007; Waalkes et al. 2004). Gestation is a critical period of cell differentiation and genetic programming during development, and a highly sensitive time for initiation of chemical carcinogenesis (Waalkes et al. 2007). Thus, adaptation to As methylation in malnourished pregnant women could impact fetal development via altered gene expression. Activation of the PEMT pathway through estrogen signaling is clearly beneficial for As methylation (Vahter 2007). In contrast, aberrant estrogen signaling is linked with transplacental As carcinogenesis in mice (Waalkes et al. 2004, 2007). Arsenic also has potential synergistic effects with estrogenic carcinogens (Waalkes et al. 2007). Indeed, when in utero As exposure is followed by diethylstilbestrol treatment in newborn mice, tumors at multiple sites show synergistic increases in adulthood, including various estrogen sensitive targets (Waalkes et al. 2007). Recent data show that early-life As exposure has significant impact on human health (Fry et al. 2007; Smith et al. 2006). In newborns from mothers exposed to iAs through contaminated water in Thailand, altered transcript profiles in cord blood include stress-related genes and breast cancer/estrogen-signature genes (Fry et al. 2007), suggesting an adaptive response to As and pointing toward future health issues. Smith et al. (2006) observed a remarkable increase in lung cancer incidence in young adults in Chile who had been exposed to iAs in utero; this suggests a human transplacental carcinogenic potential for As. Thus, regardless of the immediate temporal tolerance to As during pregnancy, preventing early-life As exposure of the fetus and improving nutritional status of pregnant women may be critical for the health of future generations.

Comment repérer et traiter les carences en vitamines, minéraux et oligoéléments

Bariatric surgery leads to the risk of metabolic and nutritional complications. The nutritional deficiencies observed are most often associated with malabsorption caused by the surgical technique, but the reduction in food intake and nutritional imbalance generated by food restriction are also at play. The high prevalence of iron deficiency (about one third of gastroplasty patients and more than 50% of gastric bypass patients) calls for regular monitoring of blood levels. Dietary supplements in cases of nutritional deficiency are recommended following restrictive surgery and gastric bypass procedures (GBP). Women of childbearing age who have undergone GBP must discuss regular dietary supplementation (200 mg of iron a day) with their healthcare providers. Vitamin B12 deficiency is highly prevalent after GBP, but also occurs at a significant rate after restrictive surgery (4–10%). Dietary supplements after GBP are crucial, and oral administration is possible (1,000 μg a week at 500 μg a day). Folic acid deficiency occurs in about 40% of patients after GBP. A dose of 400 μg at 1 mg a day is necessary to correct this deficiency. This must always be administered when pregnancy has been planned. Increased parathyroid hormone levels stemming from vitamin D deficiency and reduced calcium absorption, with its consequences on bone, occur frequently after GBP. Calcium and vitamin D supplements must be administered in this case (1,000–1,500 mg a day of calcium (citrate), combined with 400–1,000 UI of cholecalciferol). Symptoms of thiamine (vitamin B1) deficiency, responsible for Wernicke’s encephalopathy, are usually triggered by glucose administration in deficient patients (vomiting). Zinc and selenium deficiencies affect 25–30% of patients. Dietary supplements of iron, vitamin B12, folic acid, calcium and vitamin D, as well as comprehensive monitoring of nutritional status, are necessary after bariatric surgery, especially following gastric bypass procedures. Patients should be informed of this necessity. The assessment of patient compliance is a factor to take into account when evaluating indications.

A Tribute to Marcy Carlson Speer, 1959–2007

A Tribute to Marcy Carlson Speer, 1959–2007

Supranormal dietary folic acid supplementation: effects on methionine metabolism in weanling rats

There are nationwide folic acid (FA) fortification programmes of staple foods established or under consideration in order to prevent neural tube defects. Universal FA fortification still remains controversial because of the concern that additional FA in the diets of population groups (e.g. children and elderly) not initially targeted for fortification may suffer adverse effects. However, dietary surveys regarding folate generally deal with adults and little is known about the consumption and long-term effects of fortified food and supplements in growing individuals. Recent reports from our laboratory show several effects of high-dose folate supplementation in rats. In the present work, we studied the effect of FA on the methionine cycle in weanling (3-week-old) male rats after 4 weeks of supplementation with 40 mg FA/kg diet v. control (1 mg FA/kg diet). FA supplementation resulted in a reduction of homocysteine and creatinine concentrations v. control group. FA supplementation did not alter S-adenosylmethionine/S-adenosylhomocysteine ratio, DNA methylation, enzymatic activities or concentrations of vitamins involved in the nutritional regulation of the methionine cycle, except for folate. FA supplementation of 40 mg/kg did not lead to hepatic or renal damage. In conclusion, there were no apparent adverse effects on one-carbon metabolism after FA supplementation in the studied conditions.

Effects of Dietary Supplements of Folic Acid and Vitamin B12 on Metabolism of Dairy Cows in Early Lactation

The present experiment was undertaken to determine the effects of dietary supplements of folic acid and vitamin B12 given from 3 wk before to 8 wk after calving on lactational performance and metabolism of 24 multiparous Holstein cows assigned to 6 blocks of 4 cows each according to their previous milk production. Supplementary folic acid at 0 or 2.6 g/d and vitamin B12 at 0 or 0.5 g/d were used in a 2×2 factorial arrangement. Supplementary folic acid increased milk production from 38.0±0.9 to 41.4±1.0 kg/d and milk crude protein yield from 1.17±0.02 to 1.25±0.03 kg/d. It also increased plasma Gly, Ser, Thr, and total sulfur AA, decreased Asp, and tended to increase plasma Met. Supplementary B12 decreased milk urea N, plasma Ile, and Leu and tended to decrease Val but increased homocysteine, Cys, and total sulfur AA. Liver concentration of phospholipids was higher in cows fed supplementary B12. Plasma and liver concentrations of folates and B12 were increased by their respective supplements, but the increase in plasma folates and plasma and liver B12 was smaller for cows fed the 2 vitamins together. In cows fed folic acid supplements, supplementary B12 increased plasma glucose and alanine, tended to decrease plasma biotin, and decreased Km of the methylmalonyl-coenzyme A mutase in hepatic tissues following addition of deoxyadenosylcobalamin, whereas it had no effect when cows were not fed folic acid supplements. There was no treatment effect on plasma nonesterified fatty acids as well as specific activity and gene expression of Met synthase and methylmalonyl-coenzyme A mutase in the liver. Ingestion of folic acid supplements by cows fed no supplementary B12 increased total lipid and triacylglycerols in liver, whereas these supplements had no effect in cows supplemented with B12. The increases in milk and milk protein yields due to folic acid supplements did not seem to be dependent on the vitamin B12 supply. However, when vitamin B12 was given in combination with folic acid, utilization of the 2 vitamins seems to be increased, probably more so in extrahepatic tissues. Metabolic efficiency seems also to be improved as suggested by similar lactational performance and dry matter intake for cows fed supplementary folic acid but increased plasma glucose and decreased hepatic lipids in cows fed folic acid and vitamin B12 together.

Role of dietary supplementation of methionine and Folic acid in early atherosclerotic Changes in adult male mice

Role of dietary supplementation of methionine and Folic acid in early atherosclerotic Changes in adult male mice

Health benefits of folic acid

Folic acid, as the anionic folate, is a watersoluble vitamin B9 considered to be of immense health benefit. Folic acid is a synthetic product that can be used to supplement the naturally occurring dietary folate. Links between dietary folate deficiencies and megaloblastic anaemia provided the early impetus for a more critical review of evidence concerning the biological role of this vitamin. The current scientific evidence supports the view that good dietary folate intake and folic acid supplementation are not confined to haematopoiesis but also play important roles in cell division and cellular metabolism throughout life. The biochemical mechanisms are complex and not fully understood, although the benefits of folate/folic acid in reducing the occurrence of major congenital defects and sustaining more tolerable homocysteine plasma values should not be ignored.

HOMOCYSTEINE AND ABDOMINAL AORTIC ANEURYSMS

There is evidence to suggest that increased levels of homocysteine play a significant role in vascular disease. It has been suggested that lowering homocysteine levels by dietary folate supplementation may reduce the risk of stroke and coronary heart disease. It is plausible that homocysteine may also play a role in the pathogenesis of abdominal aortic aneurysms (AAA) and that patients with this disease may benefit from folate supplementation. Our objective was to review the published work with regard to the role of homocysteine in the pathogenesis of AAA. Searches were carried out in published work in English with the keywords 'abdominal aortic aneurysm' and 'homocysteine'. There is evidence from in vitro and animal model studies that activation of metalloproteinases by homocysteine can influence aortic wall structure. Several case-control studies report an association between increased levels of homocysteine and the presence of an AAA. There are conflicting genotypic data concerning the association between methylenetetrahydrofolate reductase gene variants and AAA. Although there is evidence for an association between homocysteine and AAA, it is not strong enough to conclude that it plays a causal role in the pathogenesis of AAA. Further research is needed, given the potential benefit that simple vitamin supplementation may have for patients with AAA.

Folic acid in general medicine and dermatology

Folic acid is a vitamin B essential for the integrity and function of DNA. Relative deficiency of folic acid may occur in conditions such as pregnancy and hyperproliferative or chronic inflammatory disorders. Folic acid supplementation has been proven to be beneficial in the prevention of neural tube defects and in limiting methotrexate side effects, and may reduce the risk of colorectal cancer. Folate is a critical vitamin in determining plasma homocysteine levels, which in turn is a major risk factor for cardiovascular diseases. The results of large clinical trials with dietary supplementation of folic acid, vitamin B12 and vitamin B6 have shown that this homocysteine‐lowering therapy is effective in the secondary prevention of non‐fatal strokes, but had no effect in the prevention of fatal cardiovascular diseases. Hyperhomocysteinemia has also been reported in age‐related neurological conditions with cognitive impairment (e.g. dementia), and psychiatric disorders such as depression. Elevated homocysteine levels are frequent in patients with chronic immune‐mediated disorders including rheumatoid arthritis, systemic lupus erythematosus, chronic plaque psoriasis and psoriatic arthritis, which have in common a tendency to an accelerated atherosclerosis leading to increased deaths from cardiovascular events. Folic acid supplementation appears as a reasonable therapeutic option in patients affected by chronic inflammatory skin diseases, such as moderate to severe psoriasis; in particular, those with concomitant hyperhomocysteinemia, low plasma folate and additional cardiovascular risk factors.

Parallel changes in metabolite and expression profiles in crooked-tail mutant and folate-reduced wild-type mice

Anomalies in homocysteine (HCY) and folate metabolism are associated with common birth defects and adult diseases, several of which can be suppressed with dietary folate supplementation. Although supplementation reduces the occurrence and severity of neural tube defects (NTDs), many cases are resistant to these beneficial effects. The basis for variable response and biomarkers that predict responsiveness are unknown. Crooked-tail (Cd) mutant mice are an important model of folate-responsive NTDs. To identify features that are diagnostic for responsiveness versus resistance to dietary folate supplementation, we surveyed metabolite and expression levels in liver samples from folate-supplemented, folate-reduced and control diets in Cd mutant and wild-type adult females. Cd homozygotes had normal total homocysteine (tHcy) levels suggesting that folate suppresses NTDs through a mechanism that does not involve modulating serum tHcy levels. Instead, parallel changes in metabolite and expression profiles in folate-supplemented Cd/Cd homozygotes and folate-reduced+/+and Cd/+mice suggest that Crooked-tail homozygotes have a defect in the utilization of intracellular folate. Then, by combining these expression and metabolite profile results with published results for other models and their controls, two clusters were found, one of which included several folate-responsive NTD models and the other previously untested and presumably folate-resistant models. The predictive value of these profiles was verified by demonstrating that NTDs of Ski-/-mutant mice, whose profile suggested resistance to folate supplementation, were not suppressed with dietary folate supplementation. These results raise the possibility of using metabolite and expression profiles to distinguish folate-responsive and resistance adult females who are at risk for bearing fetuses with an NTD.

Faulty Folic Acid Assumptions: Prenatal Supplements Not Always a Good Idea

Vol. 114, No. 10 EnvironewsOpen AccessFaulty Folic Acid Assumptions: Prenatal Supplements Not Always a Good Ideais accompanied byNeural Tube Defects and Folate Pathway Genes: Family-Based Association Tests of Gene–Gene and Gene–Environment Interactions Ernie Hood Ernie Hood Search for more papers by this author Published:1 October 2006https://doi.org/10.1289/ehp.114-a601aAboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Dietary folic acid supplementation in women of childbearing age has been a major public health success story, reducing the incidence of neural tube defects (NTDs) by an estimated 50–70%. The CDC currently recommends that all women of childbearing age eat a diet high in folic acid or take a daily multivitamin with 0.4 mg of folic acid each day, with higher intake from before conception through the first three months of pregnancy. In light of a new analysis of NTDs and folate pathway genes, however, that blanket recommendation may need to be fine-tuned [EHP 114:1547–1552; Boyles et al.].If these results are confirmed, it appears there may be a subgroup of women in whom folic acid supplementation is actually positively associated with the formation of NTDs in their offspring—a startling finding the authors acknowledge to be counterintuitive. Counterintuitive or not, the study may have uncovered individuals susceptible to adverse outcomes stemming from overactivity in the folate metabolism pathway during a critical stage of embryonic neurodevelopment.The researchers analyzed the genomes of 304 families where at least one individual had an NTD. They focused their analysis on 28 single-nucleotide polymorphisms (SNPs) in 11 genes known to be involved in the folate metabolism pathway, and stratified the genomic results by potential gene–gene interactions and by whether the mothers had taken folate-containing nutritional supplements prior to conception.The results showed that certain SNPs in the betaine-homocysteine methyltransferase (BHMT ) gene were significantly associated with NTDs, and that the significance was strongest with mothers who took folate supplements before conception. The group also found an associative gene–gene interaction: significance increased in the BHMT rs3733890 SNP when the data were stratified by preferential transmission of one particular MTHFR allele from parent to offspring. However, MTHFR, the most widely studied gene implicated in NTD research, was not found to be a significant single risk factor.The authors speculate that the stratification method they employed may have inadvertently grouped families by one or more unidentified cofactors correlated with folate supplementation, or that the BHMT polymorphism may create a genetic variant that promotes overactivity of the folate metabolic cycle, given the high folate levels achieved during supplementation. This overactivity may inappropriately silence growth factors necessary for proper neural tube closure. Whether this potentially important polymorphic anomaly is grounded in analytic methodology or in actual biology, further research is clearly indicated.NTDs are known to be complex multifactorial disorders arising from an array of genetic and environmental interactions. In their various physiologic manifestations, they are either profoundly disabling or fatal. Although the preventive effect of folic acid supplementation is undeniable, its protective mechanism of action is still poorly understood. And if the results of this study are replicated and confirmed, the public health directives concerning folic acid supplementation may need to be revised.FiguresReferencesRelatedDetailsRelated articlesNeural Tube Defects and Folate Pathway Genes: Family-Based Association Tests of Gene–Gene and Gene–Environment Interactions15 June 2006Environmental Health Perspectives Vol. 114, No. 10 October 2006Metrics About Article Metrics Publication History Originally published1 October 2006Published in print1 October 2006 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Folate Supplementation During Pregnancy Improves Offspring Cardiovascular Dysfunction Induced by Protein Restriction

Dietary protein restriction in the rat compromises the maternal cardiovascular adaptations to pregnancy and leads to raised blood pressure and endothelial dysfunction in the offspring. In this study we have hypothesized that dietary folate supplementation of the low-protein diet will improve maternal vascular function and also restore offspring cardiovascular function. Pregnant Wistar rats were fed either a control (18% casein) or protein-restricted (9% casein) diet +/-5 mg/kg folate supplement. Function of isolated maternal uterine artery and small mesenteric arteries from adult male offspring was assessed, systolic blood pressure recorded, and offspring thoracic aorta levels of endothelial nitric oxide (NO) synthase mRNA measured. In the uterine artery of late pregnancy dams, vasodilatation to vascular endothelial growth factor was attenuated in the protein-restricted group but restored with folate supplementation, as was isoprenaline-induced vasodilatation (P<0.05). In male offspring, protein restriction during pregnancy led to raised systolic blood pressure (P<0.01), impaired acetylcholine-induced vasodilatation (P<0.01), and reduced levels of endothelial NO synthase mRNA (P<0.05). Maternal folate supplementation during pregnancy prevented this elevated systolic blood pressure associated with a protein restriction diet. With folate supplementation, endothelium-dependent vasodilatation and endothelial NO synthase mRNA levels were not significantly different from either the control or protein-restricted groups. Maternal folate supplementation of the control diet had no effect on blood pressure or vasodilatation. This study supports the hypothesis that folate status in pregnancy can influence fetal development and, thus, the risks of cardiovascular disease in the next generation. The concept of developmental origins of adult disease focuses predominately on fetal life but must also include a role for maternal cardiovascular function.

Effect of dietary folic acid supplementation on egg folate content and the performance and folate status of two strains of laying hens

Enrichment of eggs with folate is possible when dietary folic acid levels are increased. However, development of optimal strategies for the production of folate-enriched eggs requires knowledge as to differences due to strain of bird and a greater understanding of the factors limiting egg folate deposition. To this end, a study was designed to determine the response of two leghorn strains that differ in production performance. Hyline W36 and W98 hens (n = 6 per diet) received a barley-based ration containing 0, 2, 4, 8, 16, 32, 64, or 128 mg/kg of crystalline folic acid for 21 d. Response criteria included production parameters, measures of blood folate status, and egg folate content. Significant (P < 0.05) main effects of folate supplementation were observed for egg folate content and plasma folate, which increased, and homocysteine concentrations, which decreased with supplementation; performance, however, was not affected. The Hyline W98 strain had significantly (P < 0.05) higher total egg and yolk weights and feed consumption when compared with the W36. Significant (P < 0.05) ration x strain interactions were observed for egg and yolk weight, egg folate content, and plasma homocysteine. The higher egg mass producing strain, Hyline W98, benefited from increased folic acid through a reduction in plasma homocysteine concentrations, suggesting that this strain has a higher requirement for folate than the W36 strain. Overall, egg folate content is maximized when crystalline folic acid is supplemented to the diet at 2 mg/kg or higher. Higher levels of egg folate are not achieved due to the saturation of the precursor pool for egg folate deposition.

Methylation of theESR1CpG island in the colorectal mucosa is an ‘all or nothing’ process in healthy human colon, and is accelerated by dietary folate supplementation in the mouse

ESR1 is frequently silenced by CGI (CpG island) methylation, both in human colorectal tumours and, in an age-dependent manner, in healthy mucosa. It is not clear, however, whether methylation of individual cytosines occurs randomly within the epithelial genome, or preferentially within individual cells as an 'all-or-nothing' phenomenon. CGI methylation can be quantified in human DNA residues recovered from faecal samples. We used bisulphite genomic sequencing of human DNA from this source and from a colorectal cancer cell line (SW48) to show that the ESR1 CGI is methylated in an allele-specific manner. This provides support for the 'all or none' mechanism for methylation of this gene, and shows how age-dependent methylation of the ESR1 CGI leads rapidly to silencing of the gene within the cells, and hence the colonic crypt within which it occurs. Preliminary studies with a rodent model suggest the rate of age-dependent methylation of ESR1 is modifiable by dietary folate.

Effects of dietary folate on the development and progression of mammary tumors in rats †

Epidemiologic studies have suggested that dietary intake and blood levels of folate may be inversely related to the risk of breast cancer. However, epidemiologic evidence has not been consistent nor has it provided unequivocal support for this purported inverse relationship. Recent evidence has also raised a concern that folate supplementation may promote carcinogenesis if provided after neoplastic foci are established in the target organ. This study investigated the effect of dietary folate deficiency and supplementation on the development and progression of mammary tumors in the N-methyl-N-nitrosourea (MNU) rat model. Weanling, female Sprague-Dawley rats were fed diets containing 0, 2 (control) or 8 mg folic acid/kg diet during the initiation or the promotion phase of MNU-induced mammary tumorigenesis. At necropsy, all macroscopic mammary tumors were identified and histologically confirmed. Dietary folate deficiency and supplementation provided during the initiation phase did not significantly modulate the development of mammary tumors. In contrast, dietary folate deficiency provided during the promotion phase significantly inhibited the rate of appearance, incidence, mean volume and weight of adenocarcinomas compared with the control and supplemental diets. Folate supplementation provided during the promotion phase did not significantly modulate mammary tumorigenesis compared with the control group. These data indicate that moderate folate deficiency inhibits, whereas dietary folate supplementation at four times the basal dietary requirement does not promote, the progression of MNU-induced mammary neoplastic foci in this rat model. However, the limitations associated with the route and dose of MNU administration preclude a definitive conclusion concerning the effect of folate status on the initiation of MNU-induced mammary tumorigenesis.

Folic Acid Supplementation Can Reduce the Endothelial Damage in Rat Brain Microvasculature Due to Hyperhomocysteinemia ,

To evaluate the effects of dietary folic acid supplementation on the cerebral vascular damage induced by hyperhomocysteinemia, rats were fed a diet containing 3.0 g/kg homocystine for 2 wk and then either 3.0 g/kg homocystine or 3.0 g/kg homocystine plus 0.008 g/kg folic acid for 8 wk. Control rats consumed the AIN-93 Maintenance diet throughout the experiment. The cerebral expression of glucose transporter-1 was measured by Western blot analysis and cerebrovascular structural alterations were evaluated by electron microscopy. The homocystine diet significantly increased the plasma levels of homocysteine and TBARS and decreased the cerebral expression of glucose transporter-1 (GLUT-1) with a concomitant increase in the percentage of damaged cerebral vessels. The inclusion of dietary folic acid for 8 wk caused plasma homocysteine levels to be the same as in control rats and it significantly upregulated the cerebral expression of GLUT-1 that was significantly reduced by hyperhomocysteinemia. Folic acid supplementation also significantly decreased the incidence of damaged vessels due to hyperhomocysteinemia. These results and the electron microscopy findings suggested that folic acid supplementation might reduce the detrimental effects on the endothelium caused by experimentally induced hyperhomocysteinemia.