Folate Supplementation: Too Much of a Good Thing?

Article · March 2006with23 Reads
DOI: 10.1158/1055-9965.EPI-152CO · Source: PubMed
Abstract
Folate is critical for nucleotide synthesis and methylation reactions and has been associated with a number of health benefits. The accumulation of good news—ranging from the established reduction of neural tube defects to the putative prevention of several types of cancer, cardiovascular disease
Commentary
Folate Supplementation: Too Much of a Good Thing?
Cornelia M. Ulrich and John D. Potter
Fred Hutchinson Cancer Research Center, Cancer Prevention Program, Seattle, Washington
Folate is critical for nucleotide synthesis and methylation
reactions and has been associated with a number of health
benefits. The accumulation of good news—ranging from the
established reduction of neural tube defects to the putative
prevention of several types of cancer, cardiovascular disease,
and possibly dementia—has made it seem a ‘‘wonder drug’’
that is not only inexpensive, but also safe for use as a
chemopreventive agent. Although research to date supports
several of these claims, some warning lights have appeared
recently, challenging us to adopt a more nuanced view of
folate use and raising the need for investigations of the
potential health hazards of excessive intakes. Recent data also
suggest the need to distinguish between naturally occurring
folates and folic acid, the synthetic form added to supplements
and fortified foods, further complicating the already complex
story of a potent vitamin.
History of Folate and Fortification
Folate was isolated in 1941 from spinach and named after the
Latin word folium (= leaf; ref. 1). Although the initial impetus
for research on folate metabolism was to find a cure for
anemia, it was soon recognized that the administration of
folate enhanced the growth of existing tumors and that folate
metabolism may be a promising target for anticancer drug
design (2). Already developed by the late 1940s, folate
antagonists, such as methotrexate, have rapidly become a
mainstay of cancer chemotherapy (3). Because of the role of
folate in nucleotide synthesis, deficiency affects primarily
rapidly dividing tissues, such as the epithelium of the
gastrointestinal tract, hematopoietic cells, and tumors. This
increased need of proliferating tissues for folate explains why
macrocytic anemia is one of the clinical manifestations of folate
deficiency. Similarly, the crucial role of folate in preventing
neural tube defects may be attributed to the high fetal
requirement for folate to sustain rapid cell division; clinical
trials have shown a clear reduction in neural tube defects with
periconceptional folic acid administration (4-6). This success
story led policy makers, including the USPHS in 1992 and the
Institute of Medicine in 1998, to recommend that all women of
reproductive age consume 400 Ag folic acid daily from
supplements or fortified foods (7, 8). Unfortunately, health
promotion efforts targeting childbearing women have been
largely unsuccessful in achieving this level of intake. There-
fore, policy makers opted for generalized folic acid fortification
of flour and uncooked cereal grain products at a targeted level
of 140 Ag/100 g. This level of fortification was mandatory in
the United States by January 1998 and was also implemented
in Canada (9, 10). Initial data suggest that this public health
measure was successful, resulting in a substantial reduction in
the prevalence of neural tube defects (11-14).
Biomarker studies postfortification showed dramatic
increases in blood measurements of folate and a concurrent
decrease in plasma homocysteine (which is inversely associ-
ated with folate status; refs. 15, 16). Although these reports
were reassuring in that the population fraction with low serum
folate was minimized (from 16% to 0.5%; ref. 16), they also
raised concerns that fortification exceeded the original daily
intake target by as much as 2-fold (17-19). This intake of folic
acid from fortified food (f100 to 200 Ag/d) coincides today
with high consumption of nutritional supplements in the U.S.
population (f400 Ag/standard multivitamin; ref. 20) as well
as increased availability and marketing of nutrition bars,
drinks, and other fortified foods (often supplemented at 400
Ag/serving), resulting in a markedly elevated intake of folic
acid in the population from multiple sources.
Folic Acid in Supplements—Above the Tolerable
Upper Level?
The safety of chronic very high intakes of folic acid is largely
unknown. The Institute of Medicine recommends a tolerable
upper intake level for folic acid from supplements or fortified
foods of 1,000 Ag/d for adults and between 300 and 400 Ag/d
for children between the ages 1 and 8 (21). These upper intake
levels were developed primarily to avoid masking the anemia
and missing the neuropathy of vitamin B12 deficiency because
very few data were available on other possible adverse effects
of chronic high intakes (21). Putting the upper intake level in
context, an adult who consumes two standard multivitamins
daily (at 400 Ag each) can easily exceed the daily upper intake
level, as can a child who consumes substantial amounts of
breakfast cereals (which are often supplemented at a level of
400 Ag/serving). However, the clinical significance of the upper
intake levels is not well established (see research needs below)
and they were instituted as a first attempt to raise awareness
that not all levels may be safe.
The use of nutritional supplements in the United States is
high and probably increasing (20, 22, 23). Supplement use is
greatest among older individuals, and more common among
women and those who are White or Asian, with distinct
regional differences (20, 22, 24). National Health and Nutrition
Examination Survey reports that 63% of individuals over age 60
years take a dietary supplement: 40% take folic acidcontain-
ing multivitamins, 7% B-complex vitamins, and 2% folic acid
supplements (20). Among female supplement users, 55% take
multiple supplements and 17% take four or more supplements
(20). The INTERMAP study of middle-aged participants
reports that folate intakes among supplement users are f2-
fold higher than among non supplement users (f600 versus
f300 Ag/d; ref. 24). Thus, it is not surprising that more than
half of women over age 60 years (the group with highest
supplement use) in National Health and Nutrition Examination
Survey have serum folate levels in excess of 40 nmol/L (16).
The potential health effects of these high concentrations are
189
Cancer Epidemiol Biomarkers Prev 2006;15(2). February 2006
Cancer Epidemiol Biomarkers Prev 2006;15(2):189 93
Grant support: NIH grants CA105437 and CA59045 (C.M. Ulrich).
The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
Requests for reprints: Neli Ulrich, Cancer Prevention Program, Fred Hutchinson Cancer
Research Center, P.O. Box 19024, M4-B402, Seattle, WA 98109-1024. Phone: 206-667-7617;
Fax: 206-667-7850. E-mail: nulrich@fhcrc.org
Copyright D 2006 American Association for Cancer Research.
doi:10.1158/1055-9965.EPI-152CO
unclear; even more unclear is whether such high intakes
prevent cancer, especially among the elderly.
A Dual Role for Folate in Carcinogenesis?
An increasing body of evidence suggests that folate plays a dual
role in carcinogenesis, involving both the prevention of early
lesions and potential harm once preneoplastic lesions have
developed. Observational studies suggest that high folate
intakes reduce cancer risk, particularly for malignancies of the
colon, pancreas, esophagus, stomach, and possibly cervix and
breast. However, folate can promote the growth of existing
cancers and, as noted above, antifolate drugs are potent
chemotherapeutic agents. Initial experimental studies have
suggested that folate supplementation can enhance the carcino-
genic progression of mammary tumors (25). So where is the line
between benefit and possible harm? Elegant work by Kim et al.
(26) has shown that the dose and timing of folate interventions
may be critical. For example, in two colorectal cancer mouse
models, modest doses of folate supplementation suppressed the
development and progression of colorectal cancer. However,
this beneficial effect was observed only for folate given before
the establishment of neoplastic foci in the intestine (27, 28). Once
preneoplastic lesions were present, dietary folate enhanced the
development and progression of colorectal cancer (27, 28).
Similar results in a rat model of breast cancer suggest that
folate deficiency inhibited, rather than enhanced, cancer deve-
lopment (25, 29). Preliminary results from the first randomized-
controlled trial of folic acid for chemoprevention of colorectal
polyps have been recently reported at a national meeting (30).
More than 1,000 participants with a recent history of colorectal
adenomas were randomly assigned to 1 mg folic acid daily, with
or without aspirin. Follow-up colonoscopies were scheduled f3
years after the initial endoscopy and supplementation continued
until a second surveillance exam. In this trial, folic acid use did
not prevent the recurrence of colorectal adenomas (rate ratio,
1.04). However, participants in the folic acid group tended to
have greater adenoma multiplicity, with a significant increase
among those who continued treatment throughout the second
follow-up interval (rate ratio, 1.44; 95% confidence interval, 1.03-
2.02; ref. 30). These preliminary findings are consistent with a
role of folate in fostering the progression of premalignant
lesions. Although participants had the initial polyp removed
before study entry, the increased risk of later multiple
metachronous polyps suggests that, among a subgroup of
individuals who had multiple preneoplastic lesions, folic acid
supplementation may have promoted their growth. The results
also suggest that this effect may be modest at supplementation
below 1,000 Ag/d, but do not provide any information about the
effects on growth of existing polyps that are not detected during
a colonoscopy.
What are the possible mechanisms of a dual role for folate in
carcinogenesis that depends on timing and perhaps dose? The
function of folate in nucleotide synthesis may be central. Folate
is essential for the synthesis of thymidine via thymidylate
synthase, and of purines, as illustrated in Fig. 1. Folate defi-
ciency results in a reduced production of thymidine and misin-
corporation of uracil into DNA (31, 32). During the excision of
uracil, single-strand breaks and, eventually, double-strand
breaks can occur (32). Because of the lack of reliable biomarkers,
the effects of folate deficiency on purine synthesis and apurinic
sites in DNA are less well established. However, some epide-
miologic studies suggest that this common form of DNA
damage may be a critical mechanism linking folate to cancer risk
(33, 34). If we assume that folate deficiency in a rapidly proli-
ferating tissue (such as the colon) enhances genomic instability,
then the probability of a loss of function of genes that prevent
adenoma formation increases. Although an initial animal study
did not observe an effect of folate deficiency on the rate of APC
mutations, the sample size may have been too small to obtain
reliable results (35). After a small tumor or microadenoma has
been established, this tumor may grow more rapidly with folate
supplementation, due to the greater provision of nucleotides:
Experimental results from Melnyk et al. (36) show that folate
repletion to folate-deficient cells results in a promotional
stimulus, and that these cells, if injected into nude mice, show
greater tumorigenic potential and aggressive growth.
Howcouldoneestimatetheneteffectofthesetwo
potentially competing mechanisms of folate supplementation
190
Figure 1. Overview of folate metabolism, entry of folic acid and physiologic folates into the cell, and links to methylation reactions and
nucleotide synthesis (modified with permission from ref. 3). THF, tetrahydrofolate; DHF, dihydrofolate; RFC, reduced folate carrier; hFR,
human folate receptor; MTHFR, 5,10-methylenetetrahydrofolate reductase; DHFR, dihydrofolate reductase; GART, glycinamide ribonucleotide
transformyl ase; AICARFT, 5-amino-imidazole-4-carbo xamide ribon ucleotide transformylase; AICAR, 5-am inoimidazole-4-carboxamide
ribonucleotide; GAR, glycinamide ribonucleotide; SAM (AdoMet), S-adenosylmethionine; SAH (AdoHcy), S-adenosylhomocysteine; SHMT,
serine-hydroxy-methyltransferase; MS, methionine synthase; TS, thymidylate synthase; MT, methyltransferases.
Folate Supplementation and Health
Cancer Epidemiol Biomarkers Prev 2006;15(2). February 2006
on carcinogenesis? The epidemiologic evidence to date
suggests that higher folate intakes generally correlate with a
reduced risk, thus implying an overall reduction in risk.
(Nonetheless, it needs to be remembered that folate intake is
highly correlated with supplementary vitamin intake in
general, which raises the potential for confounding.) Building
on a previously developed mathematical model of colorectal
carcinogenesis (37), we have investigated the question of a ‘‘net
effect’’ of the putative opposing mechanisms by simulating the
effect of a folic acid intervention on reduction of mutations and
increase in tumor growth simultaneously. Initial results
suggest that the net effect of folic acid fortification on
individual colon cancer risk is modified by age: Whereas
children may be more likely to experience reduced colorectal
cancer rates in the future, rates among middle-aged adults are
likely to increase.
1
The findings of this mathematical model
clearly illustrate the need for a better quantification of the
molecular effects of folate (see below).
Folate and Carcinogenesis—Yet Another Discrepancy
between Observational Studies and Clinical Trials?
When the results from the folate polyp-prevention trial (30) are
published, it will be important to interpret them carefully and
to avoid rejecting folate as a chemoprevention agent altogeth-
er. The discrepancy between results from observational studies
and randomized controlled studies has recently been dis-
cussed in this journal (38). The story of folate adds yet another
possible explanation for such disparate findings: differences
in biological effects of potent agents depending on the stage of
carcinogenesis. Almost all chemoprevention trials aim at
prevention among those with a history of earlier lesions
(precancer or cancer), largely because of the higher risk of
subsequent tumors in such patients, and thus reduced cost and
time and increased power. However, we should not lose sight
of the limitations of this approach: As discussed above, for
folate, the experimental evidence suggests that administration
is beneficial before the appearance of preneoplastic lesions, but
potentially harmful after. Whereas a randomized trial that
evaluates the influence of folic acid administration on
recurrent polyps after a primary diagnosis will be able to
answer exactly that question, it is unlikely to provide relevant
information regarding folic acid supplementation early in life.
Primary prevention trials of folate (intervention before early
lesions) would be expensive and of long duration. We may
need to continue to rely on less explicit evidence, including
that from ecologic studies of folic acid fortification by age
cohort, observational epidemiologic studies, and animal
experiments.
Folate and Cardiovascular Disease
The discrepancy between findings from observational studies
and randomized controlled trials is now also apparent for
another possible health benefit attributed to folate. Because of
the unequivocal homocysteine-lowering effects of folic acid
supplementation and experimental data suggesting a role of
homocysteine in endothelial damage, the prevention of
cardiovascular disease was assumed to be another health
benefit of increased folate intakes (39). Unfortunately, the first
results from randomized controlled trials with actual disease
outcomes provide no evidence for such an effect (40). We may
need to be more cautious of biomarkers of disease until they
are established as being in the causal pathway.
Other Potential Deleterious Effects of High Folic Acid
Two recent studies raise concern about the implications of very
high folic acid intakes on other health outcomes. A prospective
cohort of 3,718 elderly individuals (>65 years) who participat-
ed in the Chicago Health and Aging Project investigated
cognitive decline over the course of 6 years in relation to
dietary intakes of folate and vitamin B12. Unexpectedly, high
folate intake was associated with a faster rate of cognitive
decline. Those in the highest quintile of folate intake
(comprised largely of supplement users with a mean intake
of 742 Ag/d) had a statistically significantly more pronounced
decline, and this association was particularly strong for
supplement use in excess of 400 Ag/d. Limitations of the
study were its lack of biomarker assessments and the potential
for confounding by indication. Nevertheless, these unexpected
findings urge us toward further research on the cognitive
implications of high levels of folic acid in older individuals.
An additional concern has arisen in relation to immune
function: In a preliminary cross-sectional study of 104
postmenopausal women, we reported an inverse U-shaped
relationship between folate from dietary sources and supple-
ments and natural killer cell cytotoxicity (41). Natural killer
cells are part of the innate immune response and low
cytotoxicity may increase cancer risk (42). Unmetabolized folic
acid was detected in 78% of fasting plasma samples from the
participants. This is the first study reporting the presence of
this compound in healthy individuals who are not subjected to
pharmacologic doses of folic acid. The presence of unmetab-
olized folic acid was associated with decreased natural killer
cytotoxicity, and a trend toward lower natural killer cytotox-
icity with greater amounts of folic acid in plasma was observed
among older women (>60 years). Although the study should
be considered preliminary, it highlights the need for a better
understanding of the relation of folate to immune function.
No clear mechanism for the association is established. It is possi-
ble that a low capacity to metabolize large amounts of folic
acid, perhaps caused by polymorphisms in the dihydrofolate
reductase (DHFR) gene (43), may play a role. As shown in
Fig. 1, DHFR is critical for reducing folic acid for entry into
folate metabolism.
Folic acid is inexpensive to produce and is characterized by
greater bioavailability than the natural folates (44). Never-
theless, it is not equivalent to the polyglutamated forms of
food folates and enters primarily via a different carrier system
(Fig. 1); thus, it may have different effects on folate-binding
proteins and transporters (45). Another explanation for the
possible adverse effects of excessive intakes of folate is derived
from a mathematical simulation model of folate metabolism
(46). Several enzymes in this pathway function as folate-
binding proteins, which simultaneously inhibits their enzyme
activity. The biochemical properties of the pathway, as
modeled, suggest that there is an optimum folate concentration
above which folate-reaction velocities decline. This theoretical
work requires confirmation in experimental studies, yet
illustrates how an interdisciplinary approach can help under-
stand different aspects of this complicated pathway.
Future Research Needs
It is clear that the relationships between folate and health
outcomes are complex; further, we need a better understand-
ing of the relevant biological mechanisms to avoid misinter-
pretation. For solid tumor carcinogenesis, we need experimental
studies that quantify possible effects of folate on growth of
aberrant crypt foci, polyps, and similar early lesions in other
tissues. The role of folate in hematopoietic malignancies also
needs further research: Hematopoietic cells are particularly
sensitive to folate deficiency and pediatric leukemias and
191
1
E.G. Luebeck, et al., unpublished data.
Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiol Biomarkers Prev 2006;15(2). February 2006
lymphomas are commonly treated with antifolate drugs (47).
For malignancies treated with antifolates, we also need to
understand better whether treatment efficacy is altered by
excessive supplement use.
Folate not only plays a role in nucleotide synthesis but
is also critical for the provision of S-adenosylmethionine
(Fig. 1), the universal methyl donor. DNA methylation of
promoter regions has been established as one mechanism of
gene regulation (48). A recent study of agouti mice shows
that methyl supplementation (including folic acid) can alter
the epigenetic gene regulation of offspring (49). Pennisi (50)
subsequently reported on folate supplementation as a means
of modifying morphology in tails of mice with a transpos-
able element in the axin gene. Whether there are other
effects of excessive perinatal folic acid supplementation on
epigenetic mechanisms, less benign than changes in coat
color or unkinking of tails, defines another area of research
need.
We also need more research on the safety of folic acid per se.
Because this compound is now found in the bloodstream, data
are needed on whether there are implications for the transport
of natural folates. Human studies of folic acid at multiple
levels, lasting several months or even years, and monitoring all
beneficial and adverse effects described to date are a critical
step. To understand the health effects of more chronic
long-term intakes of doses at the upper intake level, studies
ancillary to the recently completed randomized controlled
trials of cancer chemoprevention are needed, targeting the
specific outcomes of the animal and human studies described
above, particularly cognitive and immune function. This is
perhaps a unique opportunity to settle the issue of safety of
long-term high intakes.
Epidemiologic studies should expand their investigations
toward the high end of folate intakes and carefully evaluate
the potential for confounding in the interpretation of results.
Finally, there are multiple genetic polymorphisms in folate
metabolism that result in interindividual differences in
response (51). A full genetic screen of mutations in this
biological pathway has not yet been undertaken. Exploration
of the effect of multiple genetic variants, under different
dietary conditions, on critical biomarkers relevant to carcino-
genesis and other health outcomes is essential.
It remains unclear whether the possible deleterious effects of
high folic acid outweigh the known and potential benefits.
Further, this balance may differ across individuals and
populations, by genetic characteristics and by life stage.
Because of the high intake of folic acid from supplements
and fortified foods in a large fraction of the population, these
questions need answers soon.
Acknowledgments
We thank colleagues, postdoctoral fellows, and students who have
worked with us on research related to folate and health.
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Cancer Epidemiol Biomarkers Prev 2006;15(2). February 2006
    • To what extent the suggested increases in DNA methylation of tumor-related genes such as DIRAS3, NODAL, HOXB7, HOXA4, and other HOX genes may contribute to the pathogenesis of cancer cannot be concluded from the current study. Theoretically, our findings, however, support the hypothesis that folic acid and possibly other B-vitamins specifically increase cancer risk if preclinical neoplastic lesions already exist, pointing toward an effect on progression rather than development of cancer [27, 29]. Our findings may also explain the explorative results of the entire B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) study, where a slightly increased cancer risk was reported after intervention with folic acid and vitamin B 12 as compared to the placebo group (hazard ration 1.56; 95 % confidence interval 1.04-2.30)
    [Show abstract] [Hide abstract] ABSTRACT: Background: Folate and its synthetic form folic acid function as donor of one-carbon units and have been, together with other B-vitamins, implicated in programming of epigenetic processes such as DNA methylation during early development. To what extent regulation of DNA methylation can be altered via B-vitamins later in life, and how this relates to health and disease, is not exactly known. The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects. This project was part of a randomized, placebo-controlled trial on effects of supplemental intake of folic acid and vitamin B12 on bone fracture incidence (B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) study). Participants with mildly elevated homocysteine levels, aged 65-75 years, were randomly assigned to take 400 μg folic acid and 500 μg vitamin B12 per day or a placebo during an intervention period of 2 years. DNA was isolated from buffy coats, collected before and after intervention, and genome-wide DNA methylation was determined in 87 participants (n = 44 folic acid/vitamin B12, n = 43 placebo) using the Infinium HumanMethylation450 BeadChip. Results: After intervention with folic acid and vitamin B12, 162 (versus 14 in the placebo group) of the 431,312 positions were differentially methylated as compared to baseline. Comparisons of the DNA methylation changes in the participants receiving folic acid and vitamin B12 versus placebo revealed one single differentially methylated position (cg19380919) with a borderline statistical significance. However, based on the analyses of differentially methylated regions (DMRs) consisting of multiple positions, we identified 6 regions that differed statistically significantly between the intervention and placebo group. Pronounced changes were found for regions in the DIRAS3, ARMC8, and NODAL genes, implicated in carcinogenesis and early embryonic development. Furthermore, serum levels of folate and vitamin B12 or plasma homocysteine were related to DNA methylation of 173, 425, and 11 regions, respectively. Interestingly, for several members of the developmental HOX genes, DNA methylation was related to serum levels of folate. Conclusions: Long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes.
    Full-text · Article · Dec 2015
    • This has resulted in a population wide increase in the circulating concentrations of folate [3]. Even though the reviews of the safety and toxicity of folate that were published prior to initiation of FA fortification in the US concluded that FA is safe under most circumstances even at supra-physiologic amounts, concerns have been raised about possible adverse effects of current folate intakes on several diseases including cancer [5,6,7]. Despite these concerns, the debate continues about whether even more FA should be added to the food supply in the US.
    [Show abstract] [Hide abstract] ABSTRACT: Background Studies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk. Methods The study included 457 US women diagnosed with either CIN 2+ (cases) or ≤ CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN. Results The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR = 2.41, P = 0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR = 0.28, P = 0.017). Conclusions This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation.
    Full-text · Article · Oct 2014
    • Since 1998, countries like USA, Canada and Argentina (2002), have adopted flour fortification programs with extra vitamins to offset nutritional deficiencies (LeBlanc et al., 2010). Even though global public health efforts have focused on folate fortification and supplementation in order to prevent neural tube defects in early pregnancy, many countries have not adopted mandatory folic acid food fortification programs because this chemical form of the vitamin may mask early clinical manifestations of vitamin B12 deficiency (Bailey and Ayling, 2009; Morris and Tangney, 2007), alteration in the activity of the hepatic dihydrofolate reductase enzyme (Bailey and Ayling, 2009) or promote cancer (Baggott et al., 2012; Ulrich and Potter, 2006). Since natural folates, such as 5-methyltetrahydrofolate, that are normally found in foods and produced by microorganisms do not mask B12 deficiency (Scott, 1999), this folate form would be a more efficient and secure alternative than supplementation with folic acid (Lamers et al., 2006).
    [Show abstract] [Hide abstract] ABSTRACT: The ability of 55 strains from different Lactobacillus species to produce folate was investigated. In order to evaluate folic acid productivity, lactobacilli were cultivated in the folate-free culture medium (FACM). Most of the tested strains needed folate for growth. The production and the extent of vitamin accumulation were distinctive features of individual strains. Lactobacillus amylovorus CRL887 was selected for further studies because of its ability to produce significantly higher concentrations of vitamin (81.2±5.4μg/L). The safety of this newly identified folate producing strain was evaluated through healthy experimental mice. No bacterial translocation was detected in liver and spleen after consumption of CRL887 during 7 days and no undesirable side effects were observed in the animals that received this strain. This strain in co-culture with previously selected folate producing starter cultures (Lactobacillus bulgaricus CRL871, and Streptococcus thermophilus CRL803 and CRL415) yielded a yogurt containing high folate concentrations (263.1±2.4μg/L); a single portion of which would provide 15% of the recommended dietary allowance. This is the first report where a Lactobacillus amylovorus strain was successfully used as co-culture for natural folate bio-enrichment of fermented milk.
    Full-text · Article · Aug 2014
    • Intriguingly, results from several studies also suggested that folate supplementation can induce aberrant patterns of DNA methylation, and mechanistically may play a dual role in carcinogenesis. FA supplementation may prevent the early lesions, or potentially harm by enhancing the progression of established preneoplastic le- sions [61]. Studies in rodent models -have shown that supplementation of FA promotes the progression of mammary tumor, and supporting this view a study in a genetically engineered mouse model of a human cancer has shown that FA deficiency during the peri-gestational period protects or decreases medulloblastoma formation [62,63].
    [Show abstract] [Hide abstract] ABSTRACT: Maternal exposure to dietary factors during pregnancy can influence embryonic development and may modulate the phenotype of offspring through epigenetic programming. Folate is critical for nucleotide synthesis, and preconceptional intake of dietary folic acid (FA) is credited with reduced incidences of neural tube defects in infants. While fortification of grains with FA resulted in a positive public-health outcome, concern has been raised for the need for further investigation of unintended consequences and potential health hazards arising from excessive FA intakes, especially following reports that FA may exert epigenetic effects. The objective of this article is to discuss the role of FA in human health and to review the benefits, concerns and epigenetic effects of maternal FA on the basis of recent findings that are important to design future studies.
    Full-text · Article · Aug 2014
    • High plasma levels of un-metabolized folic acid can lead to a build-up of dihydrofolate in the cell, which has been shown to inhibit MTHFR [42] and thereby inhibiting remethylation of homocysteine. Thus, it has been postulated that high plasma concentrations of folic acid may lead to a " functional " folate deficiency [43] [44]. Folate supplementation in the form of 5- methylTHF has been shown to effectively raise plasma folate levels without leading to an elevation in un-metabolized folic acid [45] [46].
    [Show abstract] [Hide abstract] ABSTRACT: Folate is an essential B vitamin required for the maintenance of AdoMet-dependent methylation. The liver is responsible for many methylation reactions that are used for post-translational modification of proteins, methylation of DNA, and the synthesis of hormones, creatine, carnitine, and phosphatidylcholine. Conditions where methylation capacity is compromised, including folate deficiency, are associated with impaired phosphatidylcholine synthesis resulting in non-alcoholic fatty liver disease and steatohepatitis. In addition, folate intake and folate status have been associated with changes in the expression of genes involved in lipid metabolism, obesity, and metabolic syndrome. In this review, we provide insight on the relationship between folate and lipid metabolism, and an outlook for the future of lipid-related folate research. © 2013 BioFactors, 2013.
    Full-text · Article · May 2014
    • Taking into consideration the upper intake level, an adult who consumes two standard multivitamins daily (400 lg each) can easily exceed the daily upper intake level, as can a child who consumes substantial amounts of breakfast cereals which are usually folic acid supplemented. The intake of folic acid from fortified food (100–200 lg/d) together with the use of nutritional supplements creates a state of folate oversupplementation in a significant segment of the population (Ulrich and Potter 2006). This practice is occurring with little knowledge of the potential safety and physiologic consequences of chronic intake of such high doses of folic acid.
    [Show abstract] [Hide abstract] ABSTRACT: Folic acid is the key one-carbon donor required for de novo nucleotide and methionine synthesis. Its deficiency is associated with megaloblastic anemia, cancer and various complications of pregnancy. However, its supplementation results in reduction of neural tube defects and prevention of several types of cancer. The intake of folic acid from fortified food together with the use of nutritional supplements creates a state of folate oversupplementation. Fortification of foods is occurring worldwide with little knowledge of the potential safety and physiologic consequences of intake of such high doses of folic acid. So, we planned to examine the effects of acute and chronic folate oversupplementation on the physiology of renal folate transport in rats. Male Wistar rats were procured and divided into two groups. Rats in group I were given semisynthetic diets containing 2 mg folic acid/kg diet (control) and those in group II were given folate-oversupplemented rat diet, i.e., 20 mg folic acid/kg diet (oversupplemented). Six animals from group I and group II received the treatment for 10 days (acute treatment) and remaining six for 60 days (chronic treatment). In acute folate-oversupplemented rats, 5-[(14)C]-methyltetrahydrofolate uptake was found to be significantly reduced, as compared to chronic folate-oversupplemented and control rats. This reduction in uptake was associated with a significant decrease in the mRNA and protein levels of the folate transporters. Results of the present investigation showed that acute oversupplementation led to a specific and significant down-regulation of renal folate uptake process mediated via transcriptional and translational regulatory mechanism(s).
    Full-text · Article · Jan 2014
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