Pre- and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the United States

Gibson, Todd M.; Weinstein, Stephanie J.; Pfeiffer, Ruth M.; Hollenbeck, Albert R.; Subar, Amy F.; Schatzkin, Arthur; Mayne, Susan T.; Stolzenberg‐Solomon, Rachael Z.

doi:10.3945/ajcn.110.002659

Cited by 79 publications

(72 citation statements)

References 59 publications

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“…These concerns include increased tumor growth (Cole et al, 2007;Mason et al, 2007;Lawrance et al, 2009), although this has been refuted by other investigations (Gibson et al, 2011;Stevens et al, 2011) and perturbations in immune function (Troen et al, 2006;Halsted, 2008). There is also evidence that high maternal folate concentrations can be associated with greater adiposity and higher insulin resistance in the offspring, which could increase the risk for type 2 diabetes (Yajnik et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Moderately high intake of folic acid has a negative impact on mouse embryonic development

Mikael

Deng

Paul

et al. 2012

Birth Defects Research

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BACKGROUND:The incidence of neural tube defects has diminished considerably since the implementation of food fortification with folic acid (FA). However, the impact of excess FA intake, particularly during pregnancy, requires investigation. In a recent study, we reported that a diet supplemented with 20-fold higher FA than the recommended intake for rodents had adverse effects on embryonic mouse development at embryonic days (E)10.5 and 14.5. In this report, we examined developmental outcomes in E14.5 embryos after administering a diet supplemented with 10-fold higher FA than recommended to pregnant mice with and without a mild deficiency of methylenetetrahydrofolate reductase (MTHFR). METHODS: Pregnant mice with or without a deficiency in MTHFR were fed a control diet (recommended FA intake of 2 mg/kg diet for rodents) or an FA-supplemented diet (FASD; 10-fold higher than the recommended intake [20 mg/kg diet]). At E14.5, mice were examined for embryonic loss and growth retardation, and hearts were assessed for defects and for ventricular wall thickness. RESULTS: Maternal FA supplementation was associated with embryonic loss, embryonic delays, a higher incidence of ventricular septal defects, and thinner left and right ventricular walls, compared to mothers fed control diet. CONCLUSIONS: Our work suggests that even moderately high levels of FA supplementation may adversely affect fetal mouse development. Additional studies are warranted to evaluate the impact of high folate intake in pregnant women. Birth Defects Research (Part A) 97:47À52,

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Section: Introductionmentioning

confidence: 99%

Moderately high intake of folic acid has a negative impact on mouse embryonic development

Mikael

Deng

Paul

et al. 2012

Birth Defects Research

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“…They estimated that there were between four and six additional cases of CRC per 100 000 of the population post-folic-acid fortification and suggested that the increase could result from an acceleration of progression of adenoma to carcinoma. A more recent prospective cohort study provides some reassurance that the level of folic acid fortification in the US is not detrimental (26) . The authors considered the relative risk of CRC pre-and post-the introduction of folate fortification and found similar inverse associations between the total folate intake and CRC risk both before and after the introduction of mandatory folic acid fortification.…”

Section: Colorectal Cancer and Its Molecular Classificationmentioning

confidence: 99%

Folate, colorectal cancer and the involvement of DNA methylation

Williams

2012

Proc. Nutr. Soc.

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Diet is a major factor in the aetiology of colorectal cancer (CRC). Epidemiological evidence suggests that folate confers a modest protection against CRC risk. However, the relationship is complex, and evidence from human intervention trials and animal studies suggests that a highdose of folic acid supplementation may enhance the risk of colorectal carcinogenesis in certain circumstances. The molecular mechanisms underlying the apparent dual modulatory effect of folate on colorectal carcinogenesis are not fully understood. Folate is central to C 1 metabolism and is needed for both DNA synthesis and DNA methylation, providing plausible biological mechanisms through which folate could modulate cancer risk. Aberrant DNA methylation is an early event in colorectal carcinogenesis and is typically associated with the transcriptional silencing of tumour suppressor genes. Folate is required for the production of S-adenosyl methionine, which serves as a methyl donor for DNA methylation events; thereby folate availability is proposed to modulate DNA methylation status. The evidence for an effect of folate on DNA methylation in the human colon is limited, but a modulation of DNA methylation in response to folate has been demonstrated. More research is required to clarify the optimum intake of folate for CRC prevention and to elucidate the effect of folate availability on DNA methylation and the associated impact on CRC biology.Colorectal cancer: Folate: Folic acid: DNA methylation Colorectal cancer (CRC) occurs as a consequence of a complex series of genetic and epigenetic events leading to uncontrolled cell proliferation of malignant cells. Although the genetic events leading to neoplasia are well defined, an appreciation of the importance of epigenetic factors is relatively recent. Aberrant DNA methylation has been recognised as an early event in CRC and has been the focus of considerable research. As with other epigenetic events, DNA methylation is potentially reversible making aberrant DNA methylation in cancer a particularly attractive target for chemotherapeutics and chemoprevention. Diet is known to have a significant impact on risk of CRC and there is some suggestion of an inverse association between folate and CRC risk. Folate is a methyl donor for DNA methylation and consequently DNA methylation has received attention in attempts to elucidate the mechanism whereby folate may modify CRC risk. This review focuses on our current knowledge and understanding of the interaction between folate, CRC and the possible involvement of DNA methylation. Colorectal cancer and its molecular classificationCRC is the third most common cancer in the world, accounting for 10% of all cancers and for approximately 20% of all deaths in the developed world (1) . It is an agerelated disease with peak incidence in the seventh decade of life. The majority of CRC cases are sporadic; however, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer are two forms of early onset hereditary CRC that account for approxi...

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“…Large trials of FA supplementation with doses up to 10 times higher than the average intake confirms that such a policy is safe [18,56,67,68]. Reports on increased colon cancer risk that appeared in 1996 almost simultaneously with the approval of food fortification by the FDA [69] were not confirmed later [70] or even by controlled trials using FA supplementation [68,[71][72][73]. Considering results from controlled trials and data from countries applying fortification programs since 1998, there is no evidence that cancer risk can be attributed to or altered by (i.e., increased or decreased) low or moderate intake of FA.…”

Section: Folate Aging and Populationattributable Risk Of Diseasesmentioning

confidence: 96%

Folate status and health: challenges and opportunities

Obeid¹,

Oexle

Rißmann

et al. 2016

Journal of Perinatal Medicine

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Abstract:Each year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated after prenatal diagnosis. The prevalence of neural tube defects (NTDs) has been significantly lowered in more than 70 countries worldwide by applying fortification with folic acid. Periconceptional supplementation of folic acid also reduces the risk of congenital heart diseases, preterm birth, low birth weight, and health problems associated with child mortality and morbidity. All European governments failed to issue folic acid fortification of centrally processed and widely eaten foods in order to prevent NTDs and other unwanted birth outcomes. The estimated average dietary intake of folate in Germany is 200 μg dietary folate equivalents (DFE)/day. More than half of German women of reproductive age do not consume sufficient dietary folate to achieve optimal serum or red blood cell folate concentrations ( > 18 or 1000 nmol/L, respectively) necessary to prevent spina bifida and anencephaly. To date, targeted supplementation is recommended in Europe, but this approach failed to reduce the rate of NTDs during the last 10 years. Public health centers for prenatal care and fortification with folic acid in Europe are urgently needed. Only such an action will sufficiently improve folate status, prevent at least 50% of the NTD cases, reduce child mortality and morbidity, and alleviate other health problems associated with low folate such as anemia.

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Pre- and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the United States

Cited by 79 publications

References 59 publications

Moderately high intake of folic acid has a negative impact on mouse embryonic development

Moderately high intake of folic acid has a negative impact on mouse embryonic development

Folate, colorectal cancer and the involvement of DNA methylation

Folate status and health: challenges and opportunities

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