Shall we put the world on folate?

Osterhues, Anja; Holzgreve, Wolfgang; Michels, Karin B.

doi:10.1016/s0140-6736(09)61646-9

Cited by 33 publications

(24 citation statements)

References 11 publications

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“…However, the role of folate and perhaps other one-carbon nutrients in carcinogenesis may be more complex than it was initially believed [41]. Animal experiments suggest that modest supplementation of folic acid can be protective against the development of cancer, whereas higher intakes may facilitate tumor growth [42].…”

Section: Discussionmentioning

confidence: 99%

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Dietary and supplemental intake of one-carbon nutrients and the risk of type I and type II endometrial cancer: a prospective cohort study

Uccella¹,

Mariani²,

Wang³

et al. 2011

Annals of Oncology

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Background: Type I and II endometrial cancer are biologically and clinically distinct, with type II cancers having a high frequency of p53 mutations and an association with chromosomal instability. This raises the hypothesis that onecarbon nutrients (folate, methionine, and the enzymic cofactors vitamins B2, B6, and B12), which mediate chromosomal stability and DNA methylation, may be protective for type II but not type I endometrial cancer.Methods: Using a prospective cohort of 23 356 postmenopausal women followed 20 years, we estimated the relative risks (RRs) of type I (N = 471) and II (N = 71) endometrial cancers according to intake of one-carbon nutrients, adjusting for confounders.Results: No associations were observed between dietary or supplemental intake of any one-carbon nutrient and risk of type I cancer. For type II cancer, positive associations were due to supplemental, rather than dietary, intake of these nutrients: supplemental folate (RR = 1.80 for >228.6 versus 0 lg/day; P trend = 0.027) and vitamins B2 (RR = 1.94 for >1.70 versus 0 mg/day; P trend = 0.011), B6 (RR = 2.08 for >2.00 versus 0 mg/day; P trend = 0.012), and B12 (RR = 2.10 for >3.43 versus 0 lg/day; P trend = 0.0060).Conclusion: Contrary to our hypothesis, use of supplements containing folate and vitamins B2, B6, and B12 was associated with an increased risk of type II endometrial cancer.

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Section: Discussionmentioning

confidence: 99%

“…While mandatory folate fortification of enriched grain products at the population level has lead to a decline in the incidence of neural tube defects [47], this and other recent studies raise concerns about potential negative health effects of excess levels of folic acid [41] and thus need to be fully evaluated. …”

Section: Discussionmentioning

confidence: 99%

Dietary and supplemental intake of one-carbon nutrients and the risk of type I and type II endometrial cancer: a prospective cohort study

Uccella¹,

Mariani²,

Wang³

et al. 2011

Annals of Oncology

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“…The fortification aims to provide an estimated 200 μg FA/day in addition to food folate. The exposure of the entire population to additional FA is controversially discussed [87,126]. There is currently an intensive discussion on optimizing the folate status of the target population (young women) without exceeding a certain intake in the population.…”

Section: The Risk Of Neural Tube Defects Is Causally Related To Low Mmentioning

confidence: 99%

“…The purpose of the food fortification programs is to increase folate intake in young women, but the intake has been increased in the whole population [87]. Targeted administration of vitamin supplements is the most effective way to specifically increase folate intake in women of child-bearing age before and during pregnancy when folate requirements are high.…”

Section: Strategies To Prevent Ntds By Improving Maternal Folate Statusmentioning

confidence: 99%

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

Obeid

Holzgreve

Pietrzik

2013

Journal of Perinatal Medicine

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Women have higher requirements for folate during pregnancy. An optimal folate status must be achieved before conception and in the first trimester when the neural tube closes. Low maternal folate status is causally related to neural tube defects (NTDs). Many NTDs can be prevented by increasing maternal folate intake in the preconceptional period. Dietary folate is protective, but recommending increasing folate intake is ineffective on a population level particularly during periods of high demands. This is because the recommendations are often not followed or because the bioavailability of food folate is variable. Supplemental folate [folic acid (FA) or 5-methyltetrahydrofolate (5-methylTHF)] can effectively increase folate concentrations to the level that is considered to be protective. FA is a synthetic compound that has no biological functions unless it is reduced to dihydrofolate and tetrahydrofolate. Unmetabolized FA appears in the circulation at doses of > 200 μg. Individuals show wide variations in their ability to reduce FA. Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 5-MethylTHF [also known as (6S)-5-methylTHF] is the predominant natural form that is readily available for transport and metabolism. In contrast to FA, 5-methylTHF has no tolerable upper intake level and does not mask vitamin B 12 deficiency. Supplementation of the natural form, 5-methylTHF, is a better alternative to supplementation of FA, especially in countries not applying a fortification program. Supplemental 5-methylTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs.

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“…Indeed, the nature and extent of single-carbon metabolism within these cells are not understood . Given the importance attached to folic acid in the diet of intending mothers aimed, primarily, at reducing the incidence of neural tube defects (Lucock 2000, Smith et al 2008, Osterhues et al 2009, it seems surprising that so little attention has been directed towards understanding its metabolism and that of related B-vitamins by the follicle-enclosed oocyte and pre-implantation embryo. We have previously shown that human embryonic stem cells express transcripts for most of the methyl cycle enzymes illustrated in Fig.…”

Section: Introductionmentioning

confidence: 99%

Endogenous folates and single-carbon metabolism in the ovarian follicle, oocyte and pre-implantation embryo

Kwong¹,

Adamiak²,

Gwynn³

et al. 2010

Reproduction

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Maternal B-vitamin status at conception can affect fertility and the health of offspring. This study details transcript expression for genes encoding key enzymes in the linked methionine/folate cycles in the bovine oocyte, somatic cells of the ovarian follicle and pre-implantation embryo. Transcripts for all 12 enzymes that were studied and for the two folate receptors (FOLR1 and FOLR2) and reduced folate carrier (SLC19A1) were expressed in liver cells, but transcripts for betaine-homocysteine methyltransferase and methionine adenosyl transferase 1A were absent in all ovarian cells, and transcripts for FOLR2 were absent in embryonic cells. Transcripts for glycine methyltransferase were also absent/weak in cumulus and granulosa cells. The absence of these enzymes could have a profound effect on single-carbon metabolism within the ovary and pre-implantation embryo. Immunocytochemical analysis revealed SLC19A1 protein expression on the plasma and basal-lateral membranes of the pre-implantation embryo. The folate antagonist methotrexate (MTX) enters the cell via SLC19A1, and in the current study, MTX inclusion in bovine/ovine culture media at either 1 or 10 mM from the 1-cell stage inhibited embryo development beyond the 8-cell stage. Hypoxanthine and thymidine (100 mM) increased the proportion of embryos that developed to blastocysts, but the cell number was reduced by 20%. The reduced uptake of [ 35 S] methionine into intra-cellular S-adenosylmethionine and S-adenosylhomocysteine pools, together with reduced uptake of glutamate and tryptophan, was consistent with depleted intra-cellular pools of reduced folates. These data provide an insight into the importance of maternal dietary folate/B-vitamin status during the peri-conceptional period.Reproduction (2010) 139 705-715

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Shall we put the world on folate?

Cited by 33 publications

References 11 publications

Dietary and supplemental intake of one-carbon nutrients and the risk of type I and type II endometrial cancer: a prospective cohort study

Dietary and supplemental intake of one-carbon nutrients and the risk of type I and type II endometrial cancer: a prospective cohort study

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

Endogenous folates and single-carbon metabolism in the ovarian follicle, oocyte and pre-implantation embryo

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