Mechanistically, the transport of transmembrane folate is facilitated by both receptors and specific carriers active across cell membranes [ 40 ]. The polyglutamyl form of tetrahydrofolate THF formed either from FA or normal dietary folate is the central folate acceptor molecule in the one-carbon cycle.
Thus, the entire FA metabolism is modulated by several folate coenzymes. Mechanistically, the central role of this coenzyme is to modulate the metabolic pathway by accepting or donating one-carbon units [ 44 ]. Key genes in this pathway that are involved in transferring the methyl group to homocysteine, and have been most extensively studied include methylenetetrahydrofolate reductase MTHFR , methionine synthase reductase MTRR , reduced folate carrier RFC , along with vitamin B dependent methionine synthase MTR [ 45 ].
Thus, further studies on FA induced methylation and detailed analysis of the folate pathway and its role in mammalian neural tube closure could give us more insights in coming years. Summary of folate metabolism simplified. The possible impact of nutritional supplements, for example FA, on the mammalian genome can have long lasting effects in human health without any underlying genetic change.
The availability of many dietary components involved in one-carbon metabolism including vitamin B6, choline, betanine, methionine, vitamin B12 and folate can result in alterations in the DNA methylation and histone modification. Mechanistically, the modulation of methylation patterns depends on the level of two metabolites of one-carbon metabolism: S -adenosylmethionine SAM , a methyl donor and S -adenosylhomocysteine SAH , a product inhibitor of methyltranferases [ 47 ]-[ 49 ].
Thus, nutrient epigenetic factors such as FA, a cofactor in one-carbon metabolism during gestation can affect the fetal programming and may modulate the genome-wide methylation pattern of DNA and cause dysregulation in the expression of genes [ 50 ]. The epigenetic impact of FA along with other one-carbon metabolites is best studied in the agouti mouse A vy experiment that has shown that the dietary methyl donors, including FA, has no affect on the A vy methylation in the mother but clearly affected the A vy methylation and phenotype of developing offspring [ 51 ].
In addition, several epidemiologic and molecular evidences also link folate supplementation and epigenetic alteration by DNA methylation with neural growth and recovery, including the activation of folate receptor Folr1 , in spinal cord regeneration [ 53 ],[ 54 ]. Recently, our study has shown that FA supplementation dysregulates expressions of several genes including FMR1 in lymphoblastoid cells [ 56 ], and a follow up study in a mouse model has also identified widespread alteration in the methylation pattern of the brain epigenome in offspring from high maternal FA during gestation [ 57 ].
The alterations in the methylation pattern were exhibited both in CpG and non-CpG regions resulting in differences in the expression of several key developmental and imprinted genes. In addition, we also found that the methylation and expression of several genes are altered in a gender-specific manner. Thus, it is clear that folate plays a key role in epigenetic regulation of fetal developmental programming. In the future, more studies on the role of folate deficiency or over supplementation on epigenetic alterations will establish causality of the amount of FA and DNA methylation in diseases.
The clinical significance of the chronic or high intake of FA is not well established. Post fortification epidemiological studies have reported an increase of approximately twice the amount in the intake of FA than previously projected. Concern has been raised regarding the potential health effects, since in addition to the fortified products there is prevalence of using widespread supplementation including over-the counter prenatal vitamins as well as energy drinks which are substantially enriched with various vitamins [ 58 ],[ 59 ].
Recently, our study in the mouse model has found that ten-fold increase in maternal FA supplementation during gestation altered the expression of several genes in the frontal cortex of day old pups [ 60 ]. Moreover, continuation of such higher amounts of FA throughout the post-weaning period exhibited alterations in behaviors compared to offspring from mothers having lower doses of gestational FA supplementation.
Mechanistically, such changes of behavioral outcomes may possibly result from alterations of gene expression as a result of aberrant methylation.
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 lesions [ 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 ].
Moreover, a study from children participating in the Northern California Childhood Leukemia Study NCCLS further revealed no significant association of folate concentration at birth with childhood acute myeloid leukemia Additional file 1 : Table S1.
In contrast, several RCT and meta-anlayis have reported that prenatal multivitamins containing FA -are associated with a significant protective effect on pediatric cancers: leukemia, pediatric brain tumors and neuroblastoma [ 65 ], Additional file 1 : Table S1.
In addition, recent ecological studies provided support for a decrease in Wilms tumour, neuroblastoma, primitive neuroectodermal tumours and ependymomas after Canadian and United States FA fortification [ 66 ],[ 67 ], Additional file 1 : Table S1. Although controversial, over-supplementation is also reported to be involved in certain chronic disease and found not to reduce cardiovascular disease [ 68 ],[ 69 ].
In addition, acute folate intake is also found to result in significant down-regulation of folate transporters in kidney, and thus dysregulated the renal folate uptake process [ 70 ]. Moreover, several RCT and observational studies suggested that maternal intake of multivitamins including FA during pregnancy may modulate pregnancy related outcomes [ 71 ]-[ 75 ] including developmental outcome of offspring Additional file 1 : Table S1.
The causal link between the maternal FA supplementation and the development of childhood asthma has been of interest as asthma is considered to be an interaction of both genetic and environmental risk factors, and concern has arisen as epidemiological studies have also shown that increased folate in pregnancy may influence poor respiratory health in children [ 76 ],[ 77 ].
Several studies, including RCT and observational studies were conducted to reveal such associations, however conflicting results were found in these studies.
While some studies found positive association between FA exposure and increase in risk of childhood asthma, other studies found no such association Additional file 1 : Table S1. In addition, studies in humans, also reported to have found higher blood folate concentration of unmetabolized FA and naturally occurring folates [ 78 ]. To gain a better understanding if maternal supplementation of FA modulates pregnancy related outcomes, much focus has been given to reveal the role of FA supplementation in the increased incidence of dizygotic twining.
This followed after the report of a Swedish study suggested a possible association of FA supplementation with the increase in the twining rate [ 79 ]. However, Berry et al. This was further supported by a Norwegian study that found no evidence for an association between preconceptional folate supplements and twinning after exclusion of known in vitro fertilization pregnancies, and accounting for under-reporting of both in vitro fertilization pregnancies and folate use [ 82 ].
Thus it is clear that FA intake during pregnancy and during daily life plays a significant role in modulating gene expression and disease related outcome. In the future, more clinical and basic studies to decipher the link between over supplementation and normal development will help us to understand the discordances between benefit and possible harm. For a better understanding of the effect of maternal FA, we systematically reviewed recent published literature — in order to assess the outcome of maternal FA supplementation on the health of newborn infants [ 83 ]-[ ] Additional file 1 : Table S1.
While results of several cohort and observational studies in USA, Canada, Chile, Australia, several countries in Europe and Asia have reported the clinical significance of FA supplementation, the direction of the beneficial effect was not in favorable terms in all the cases.
Therefore, several countries have mandatory regulated FA fortifications, and despite its efficacy there is no universal agreement based on the published data to date [ ].
The concern regarding the appropriate dose and potential side effects are still a matter of debate [ 16 ],[ ]. As maternal FA can induce potential epigenetic effects on the genome of the offspring which may vary with the metabolic ability of individual race, sex, geographical locations or interactions with other nutrients, one possible reason of inconsistency between studies may be due to differences in the design of the study.
In the future there is definitely a need of global collaboration to accumulate scientific evidence from a clinical perspective, and to interpret these intervention studies and potential effect in large cohorts. Determining the level and distribution of the methylation profile of the brain epigenome may reveal the mechanism and downstream consequences of various neuropsychiatric and imprinted disorders including autism.
Moreover as the level of folate status can influence methylation, in the future more studies are needed to explore the systemic differences in the DNA methylation profile in relation to timing and dose between different populations and between genders.
Studies and careful monitoring of the consequences of FA intake in global perspectives will help clinicians to determine a proper therapeutic strategy and the best preventive measures to improve the overall public health, moreover to precisely differentiate the evaluation of this vitamin in nutrition, in fortification and in supplementation. A representative integrative model of possible epigenetic influence on pregnancy outcomes.
Maternal intake of FA may result in epigenetic modulation in the offspring brain methylome with overall or site specific alterations of methylation in genomic DNA, non-coding RNA and histone modifications. These effects may alter gene expression of several imprinted, candidate autism susceptibility and key developmental genes.
Such changes may impact other biological processes, and associate with the overall developmental outcome. Scientific artwork adapted from [ ],[ ]. Jaenisch R, Bird A: Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet.
Am J Clin Nutr. Arch Dis Child. Li D, Rozen R: Maternal folate deficiency affects proliferation, but not apoptosis, in embryonic mouse heart. J Nutr. Nat Rev Neurosci. J Oncol. BMC Public Health. CDC: Ref Type: Report. Pitkin RM: Folate and neural tube defects. Dev Disabil Res Rev. Curr Probl Pediatr. PubMed Article Google Scholar. Eur J Clin Nutr. Blom HJ: Folic acid, methylation and neural tube closure in humans. But experts do know that it's vital to the development of DNA.
As a result, folic acid plays a large role in cell growth and development, as well as tissue formation. How can women of childbearing age — and especially those who are planning a pregnancy — get enough folic acid every day? The U. Food and Drug Administration FDA requires food-makers to add folic acid to their enriched grain products. Check the product's label for this information. But for most women, eating fortified foods isn't enough.
To reach the recommended daily level, you'll probably need a vitamin supplement. During pregnancy, you need more of all of the essential nutrients than you did before you became pregnant.
Prenatal vitamins shouldn't replace a well-balanced diet. But taking them can give your body — and your baby — an added boost of vitamins and minerals. Folic acid is a B vitamin.
Our bodies use it to make new cells. Think about the skin, hair, and nails. These—and other parts of the body — make new cells each day. Folic acid is the synthetic that is, not generally occurring naturally form of folate used in supplements and in fortified foods such as rice, pasta, bread, and some breakfast cereals.
When the baby is developing early during pregnancy, folic acid helps form the neural tube. Learn more about the recommended intake level of folic acid here. Every woman of reproductive age needs to get folic acid every day, whether she is planning to get pregnant or not, to help make new cells.
Folate is a general term to describe many different types of vitamin B9. Food fortification is a way to add vitamins or minerals, or both, to foods.
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