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Purpose: The aim of the present study was to examine the association between intake of folate, and specific folate vitamers, and the risk of advanced and total prostate cancer. Methods: The association between dietary folate and prostate cancer risk was evaluated in The Netherlands Cohort Study (NLCS) on diet and cancer, conducted among 58,279 men ages 55-69 years at baseline. Information on diet was collected at baseline by means of food frequency questionnaires. Incident cases were identified by record linkage with regional cancer registries and the Dutch National Database of Pathology Reports. After 17.3 years of follow-up, 3,669 incident prostate cancer cases, of which 1,290 advanced cases, and 2,336 male subcohort members were available for case-cohort analyses. Results: Dietary folate was not associated with prostate cancer risk, nor with the risk of advanced prostate cancer, among men in the NLCS cohort (HR = 1.05, 95 % CI: 0.87-1.26 and HR = 1.09, 95 % CI: 0.88-1.35, respectively, for the highest quintile of folate intake vs. the lowest quintile). Specific folate vitamers were neither associated with the risk of prostate cancer or risk of advanced prostate cancer. Conclusions: Our results do not support an association of dietary folate or specific folate vitamers on the risk of prostate cancer, or advanced prostate cancer. © 2012 Springer Science+Business Media Dordrecht.

Objective: Studies of folate intake and colorectal cancer risk have been inconsistent. We examined the relation with colon cancer risk in a series of 13 prospective studies. Methods: Study-and sex-specific relative risks (RRs) were estimated from the primary data using Cox proportional hazards models and then pooled using a random-effects model. Results: Among 725,134 participants, 5,720 incident colon cancers were diagnosed during follow-up. The pooled multivariate RRs (95% confidence interval [CI]) comparing the highest vs. lowest quintile of intake were 0.92 (95% CI 0.84-1.00, p-value, test for between-studies heterogeneity = 0.85) for dietary folate and 0.85 (95% CI 0.77-0.95, p-value, test for between-studies heterogeneity = 0.42) for total folate. Results for total folate intake were similar in analyses using absolute intake cutpoints (pooled multivariate RR = 0.87, 95% CI 0.78-0.98, comparing ≥560 mcg/days vs. <240 mcg/days, p-value, test for trend = 0.009). When analyzed as a continuous variable, a 2% risk reduction (95% CI 0-3%) was estimated for every 100 μg/day increase in total folate intake. Conclusion: These data support the hypothesis that higher folate intake is modestly associated with reduced risk of colon cancer. © 2010 Springer Science+Business Media B.V.

Milk products are only moderate sources of folate. Nevertheless, they are of interest due to their content of folate-binding proteins (FBP), which in some studies have been reported to increase folate bioavailability. The effect of FBP on folate bioavailability has been widely discussed. The aim of this study was to investigate the bioaccessibility of folic acid and (6S)-5-methyltetrahydrofolate (5-CH3-H4folate) from fortified yogurt using a dynamic in vitro gastrointestinal model (TIM). In addition, the effect of FBP on folate bioaccessibility and the stability of FBP added to yogurt during gastrointestinal passage were investigated. Folate bioaccessibility was 82% from yogurt fortified with folic acid and 5-CH 3-H4folate. The addition of FBP to yogurt decreased (P < 0.05) folate bioaccessibility. The lowering effect of FBP was more pronounced in yogurt fortified with folic acid (34% folate bioaccessibility) than from yogurt fortified with 5-CH3-H4folate (57% folate bioaccessibility). After gastrointestinal passage, 17% of the FBP in yogurt fortified with 5-CH3-H4folate and 34% of the FBP in yogurt fortified with folic acid were recovered. No difference in folate bioaccessibility was found between folate-fortified yogurt and folate-fortified pasteurized milk (P = 0.10), whereas the lowering effect of FBP was (P < 0.05) greater in yogurt compared with pasteurized milk. In conclusion, based on the high bioaccessibility of folic acid and 5-CH3-H 4folate, yogurt without active FBP can be considered to be an appropriate food matrix for folate fortification.

Dairy products are a potential matrix for folate fortification to enhance folate consumption in the Western world. Milk folate-binding proteins (FBP) are especially interesting because they seem to be involved in folate bioavailability. In this study, folate bioaccessibility was investigated using a dynamic computer-controlled gastrointestinal model [TNO gastrointestinal model (TIM)]. We used both ultrahigh temperature (UHT)-processed milk and pasteurized milk, differing in endogenous FBP concentrations and fortified with folic acid or 5-methyltetrahydrofolate (5-CH3-H4folate). To study FBP stability during gastrointestinal passage and the effect of additional FBP on folate bioaccessibility, FBP-fortified UHT and pasteurized milk products were also tested. Folate bioaccessibility and FBP stability were measured by taking samples along the compartments of the gastrointestinal model and measuring their folate and FBP concentrations. Folate bioaccessibility from folic acid-fortified milk products without additional FBP was 58-61%. This was lower (P < 0.05) than that of the 5-CH3-H4folate-fortified milk products (71%). Addition of FBP reduced (P < 0.05) folate bioaccessibility from folic acid-fortified milk (44-51%) but not from 5-CH3-H4folate-fortified milk products (72%). The residual FBP levels in the folic acid- and 5-CH3-H4folate-fortified milk products after gastrointestinal passage were 13-16% and 0-1%, respectively, of the starting amounts subjected to TIM. In conclusion, milk seems to be a suitable carrier for folate, because both folic acid and 5-CH3-H4folate are easily released from the matrix and available for absorption. However, our results suggest that folic acid remains partly bound to FBP during passage through the small intestine, which reduces the bioaccessibility of folic acid from milk in this model. Chemicals/CAS: 5 methyltetrahydrofolic acid, 134-35-0; folic acid, 59-30-3, 6484-89-5; 5-methyltetrahydrofolate, 134-35-0; Folic Acid, 59-30-3; Tetrahydrofolates

Background: Milk products are a potential matrix for fortification with synthetic folic acid or natural 5-methyltetrahydrofolate (5-CH 3-H4folate) to enhance the daily folate intake. In milk, folate occurs bound to folatebinding proteins (FBP). Our previous studies with an in vitro gastrointestinal model showed that 70% of the initial FBP content of the milk product was retained in the duodenal lumen. While folic acid remained bound to FBP after gastric passage, 5-CH3-H4folate was mainly present as free folate in the duodenal lumen. Aim of the study: To investigate the effect of FBP on the absorption of folic acid and 5-CH 3-H4folate from the intestinal lumen. Methods: The transport of [3H]-folic acid and [14C]-5-CH 3-H4folate across enterocytes was studied in the presence or absence of bovine FBP using monolayers of Caco-2 cells grown on semi-permeable inserts in a two-compartment model. The apparent permeability coefficients (Papp) of folic acid and 5-CH3-H 4folate were determined and compared with the permeability of reference compounds for low (mannitol) and high (caffeine) permeability. Results: The transport from the apical to the basolateral side of the Caco-2 cells was higher (P < 0.05) for folic acid (Papp = 1.7*10-6 cm/s) than for 5- CH3-H4folate (Papp = 1.4*10-6 cm/s) after 2 h incubation to 1 μM folic acid or 5-CH3-H4folate test solutions (pH 7). The permeability of folic acid and 5-CH3-H4folate across Caco-2 monolayers appeared to be higher (P < 0.05) than that of mannitol (Papp = 0.5*10-6 cm/s) but lower (P < 0.05) than that of caffeine (Papp = 34*10-6 cm/s). The addition of FBP to the medium led to a lower (P < 0.05) intestinal transport and cellular accumulation of folic acid and 5-CH3-H4folate. Conclusions: Compared to the reference compounds, folic acid and 5-CH 3-H4folate showed a moderate permeability across Caco-2 cells, which indicates that folate absorption from the intestinal lumen is not likely to be complete. The intestinal transport of folic acid and 5-CH 3-H4folate was found to be dependent on the extent of binding to FBP at the luminal side of the cells. © Steinkopff Verlag 2004.

In spite of an on average adequate dietary nutrient intake and status in most European countries, for some micronutrients (e.g. folate, vitamin D, B2, B6, B12 (in elderly), iron and iodine) subgroups have been identified which may be at risk and may benefit from a higher intake, especially elderly and (pregnant) women. In this paper the argumentation and justifications for nutrient addition to ordinary foods are discussed and compared with other options to increase the nutrient intake, as well as the potential benefits and risks. Correction of an existing marginal nutrient intake/status, and disease prevention are considered as potential benefits, while the main safety issue is the risk of excessive intake and the occurrence of adverse effects. It is concluded that food supplements and fortified foods should have a place in securing an adequate intake and be considered as legitimate options for the consumer, but require (harmonized) regulation to avoid excessive intakes, especially for those nutrients for which adverse effects might be anticipated.

Despite its low natural folate concentration, milk is responsible for 10-15% of the daily folate intake in countries with a high dairy consumption. Milk products can be considered as a potential matrix for folate fortification, e.g., with synthetic folic acid, to enhance the daily intake of folate. In untreated milk, the natural folate, 5-methyltetrahydrofolate (5-CH 3-H4folate), is bound to folate-binding proteins (FBP). In this study, the extent of binding to FBP for folic acid and 5-CH 3-H4 folate was investigated in a dynamic in vitro model simulating human gastric passage. Protein binding of folic acid and 5-CH 3-H4 folate was characterized using gel-exclusion chromatography. Before gastric passage, folic acid and 5-CH3-H 4 folate were bound mainly to FBP (76-79%), whereas 7% was free. Folic acid remained bound to FBP to a similar extent after gastric passage. For 5-CH3-H4 folate, the FBP-bound fraction gradually decreased from 79 to 5% and the free fraction increased from 7 to 93%. Although folic acid enters the proximal part of the intestine bound to FBP, 5-CH 3-H4 folate appears to be present mainly as free folate in the duodenal lumen. The stability of FBP was similar in both folate/FBP mixtures, i.e., 70% of the initial FBP content was retained after gastric passage. This study indicated that FBP are partly stable during gastric passage but have different binding characteristics for folic acid and 5-CH 3-H4 folate in the duodenal lumen. This could result in different bioavailability from folic acid- and 5-CH3-H4 folate-fortified milk products.

Objective: The aim of this study was to investigate whether milk fortified with folic acid enhances the folate status of humans and whether the presence of folate-binding proteins (FBP) in pasteurised milk affects the bioavailability of folic acid from fortified milk. In untreated and pasteurised milk, folate occurs bound to FBP, while FBP is (partly) denatured in ultra-high-temperature (UHT)-treated milk. The effect of FBP on folate bioavailability is still unclear. Design, subjects and setting: Healthy, free-living subjects (n=69) aged 18-49y participated in a 4-week double-blind, placebo-controlled dietary intervention study. Intervention: In addition to a fully controlled diet, the subjects consumed each day 500 ml of pasteurised or UHT milk, either fortified or not with 200 μg folic acid. Results: Consumption of fortified milk increased folate concentrations in serum and in red blood cells (RBQ by 6.6-7.0 nmol/l (P<0.001) and 32-36nmol/l (P<0.01), respectively. Similarly, plasma homocysteine concentrations were lowered 0.88-0.89 μmol/l (P = 0.001) in subjects who consumed fortified milk. The bioavailability of folic acid from pasteurised milk relative to that of folic acid from UHT milk was 74-94% (NS), depending on the parameter used. Conclusions: Milk fortified to supply an additional 200 μg of folic acid/s substantially increased folate status, and decreased plasma total homocysteine concentrations in young, healthy subjects. Milk is therefore a suitable matrix for fortification to enhance the folate status in humans. No significant effect of endogenous FBP was found on the bioavailability of folic acid from milk. © 2005 Nature Publishing Group. All rights reserved.

Fruit and vegetable consumption produces changes in several biomarkers in blood. The present study aimed to examine the dose-response curve between fruit and vegetable consumption and carotenoid (α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein and zeaxanthin), folate and vitamin C concentrations. Furthermore, a prediction model of fruit and vegetable intake based on these biomarkers and subject characteristics (i.e. age, sex, BMI and smoking status) was established. Data from twelve diet-controlled intervention studies were obtained to develop a prediction model for fruit and vegetable intake (including and excluding fruit and vegetable juices). The study population in the present individual participant data meta-analysis consisted of 526 men and women. Carotenoid, folate and vitamin C concentrations showed a positive relationship with fruit and vegetable intake. Measures of performance for the prediction model were calculated using cross-validation. For the prediction model of fruit, vegetable and juice intake, the root mean squared error (RMSE) was 258.0 g, the correlation between observed and predicted intake was 0.78 and the mean difference between observed and predicted intake was -1.7 g (limits of agreement: -466.3, 462.8 g). For the prediction of fruit and vegetable intake (excluding juices), the RMSE was 201.1 g, the correlation was 0.65 and the mean bias was 2.4 g (limits of agreement: -368.2, 373.0 g). The prediction models which include the biomarkers and subject characteristics may be used to estimate average intake at the group level and to investigate the ranking of individuals with regard to their intake of fruit and vegetables when validating questionnaires that measure intake. Copyright © The Authors 2015.

In the Netherlands Cohort Study among 120 852 subjects aged 55-69 years at baseline (1986), the association between vitamins and carotenoids intake, vitamin supplement use, and bladder cancer incidence was examined. Exposure status was measured with a food-frequency questionnaire. After 6.3 years of follow-up, data from 569 cases and 3123 subcohort members were available for case-cohort analyses. The age-, sex-, and smoking-adjusted relative risks (RRs) for retinol, vitamin E, folate, α-carotene, β-carotene, lutein and zeaxanthin, and lycopene were 1.04, 0.98, 1.03, 0.99, 1.16, 1.11, and 1.08, respectively, comparing highest to lowest quintile of intake. Only vitamin C (RR: 0.81, 95% CI: 0.61-1.07, P-trend = 0.08), and β-cryptoxanthin intake (RR: 0.74, 95% CI: 0.53-1.03, P-trend < 0.01) were inversely associated with bladder cancer risk. The association with vitamin C disappeared after adjustment for β-cryptoxanthin but not vice versa. The RRs for supplemental use of vitamin A, C or E compared to no use were around unity. We conclude that dietary or supplemental intake of vitamin A, vitamin C, vitamin E, and intake of folate, and most carotenoids are not associated with bladder cancer. In this study, only β-cryptoxanthin intake appeared to be inversely associated. © 2001 Cancer Research Campaign.

Background: Red blood cells (RBCs) represent a storage pool for folate. In contrast to plasma, RBC folate can appear in different biochemical isoforms. So far, only the methylenetetrahydrofolate reductase (MTHFR) 677 TT genotype has been identified as a determinant of RBC folate vitamer distribution. Objective: The purpose of this study is to identify clinical and biochemical determinants of RBC folate vitamer distribution in healthy subjects. Design: In an observational study, 109 subjects, aged 18 to 65 years, were studied. Red blood cell folate vitamers were analyzed using a liquid chromatography-tandem mass spectrometry method. Other variables recorded included vitamin B2, B6 and B12 status, homocysteine, plasma and RBC S-adenosylhomocysteine and S-adenosylmethionine, renal function and the MTHFR C677T polymorphism. Results: The MTHFR C677T genotype was the dominant determinant of nonmethylfolate accumulation. The median (range) nonmethylfolate/total folate ratio was 0.58% (0-12.2%) in the MTHFR CC group (n=55), 0.99% (0-14.3%) in the CT group (n=39) and 30.3% (5.7-73.3%) in the TT genotype group (n=15), P<.001. The 95th percentile for the nonmethylfolate/total folate ratio was 2.8% for the CC group, 9.1% for the CT group and 73.3% for the TT group. In the CC and CT genotype subjects, the T-allele and total folate status were positively and independently correlated with nonmethylfolate accumulation, but the degree of nonmethylfolate accumulation in these subjects was usually minor compared with those with the TT genotype. None of the other studied variables was associated with nonmethylfolate accumulation. Conclusions: The MTHFR C677T genotype is the dominant determinant of nonmethylfolate accumulation in RBCs. In addition, high total folate status may contribute to minor to moderate nonmethylfolate accumulation in MTHFR CC and CT subjects. © 2007 Elsevier Inc. All rights reserved.

Dietary methyl donors might influence DNA methylation during carcinogenesis of colorectal cancer (CRC). Among 609 CRC cases and 1,663 subcohort members of the Netherlands Cohort Study on diet and cancer (n = 120,852), we estimated CRC risk according to methyl donor intake across genotypes of folate metabolizing enzymes and methyltransferases. Although diet-gene interactions were not statistically significant, methionine intake was inversely associated with CRC among subjects having both common rs2424913 and rs406193 DNMT3B C > T genotypes (highest versus lowest tertile: RR = 0.44; p trend = 0.05). Likewise, vitamin B2 was modestly inversely associated among individuals with the MTHFR c.665CC (rs1801133) genotype (RR = 0.66; p trend = 0.08), but with a significant reduced risk when ≤ 1 rare allele occurred in the combination of folate metabolizing enzymes MTHFR, MTRR and MTR (RR = 0.30; p trend = 0.005). Folate or vitamin B6 were neither inversely associated with CRC nor was methyl donor intake associated with the CpG island methylator phenotype (CIMP). Despite the absence of heterogeneity across genotypes, might an effect of methyl donors on CRC be more pronounced among individuals carrying common variants of folate metabolizing enzymes or DNA methyltransferases. Combining genotypes may assist to reveal diet associations with CRC, possibly because rare variants of related genes may collectively affect specific metabolic pathways or enzymatic functions. © 2010 The Author(s). methyltransferase, 9037-42-7; cytosine, 71-30-7; methionine, 59-51-8, 63-68-3, 7005-18-7; methyltransferase, 9033-25-4; pyridoxine, 12001-77-3, 58-56-0, 65-23-6, 8059-24-3; riboflavin, 83-88-5; thymine, 65-71-4

In the past decade, the understanding of folate bioavailability, metabolism and related health issues has increased, but several problems remain, including the difficulty of delivering the available knowledge to the populations at risk. Owing to the low compliance of taking folic acid supplements, for example, among women of child-bearing age who could lower the risk of having a baby with a neural tube defect, food-based strategies aimed at increasing the intake of folate and other B-group vitamins should be a priority for future research. These should include the development of a combined strategy of supplemental folate (possibly with vitamin B12), biofortification using engineered plant-derived foods and micro-organisms and food fortification for increasing folate intakes in the general population. Currently, the most effective population-based strategy to reduce NTDs remains folic acid fortification. However, the possible adverse effect of high intakes of folic acid on neurologic functioning among elderly persons with vitamin B12 deficiency needs urgent investigation. The results of ongoing randomized controlled studies aimed at reducing the prevalence of hyperhomocysteinemia and related morbidity must be available before food-based total population approaches for treatment of hyperhomocysteinemia can be recommended. Further research is required on quantitative assessment of folate intake and bioavailability, along with a more thorough understanding of physiological, biochemical and genetic processes involved in folate absorption and metabolism. © 2006 Nature Publishing Group All rights reserved.