Synthetic Folic Acid Research Articles

5-Methyltetrahydrofolate in Maternal Diets Alters DNA Methylation Potential and Increases Later Life Weight Gain and Food Intake in Wistar Rat Dams and Female Offspring (P11-022-19)

ObjectivesDiet during pregnancy programs the mother and offspring post-weaning (PW). Folic acid (FA, synthetic folate) mediates DNA methylation (DNAm) reactions and high intakes, simulating those consumed by American women, lead to epigenetic dysregulation of energy metabolic pathways. 5-methyltetrahydrofolate (5MTHF), the bioactive folate form, has gained popularity as a supplement due to direct cellular uptake and utilization and does not increase unmetabolized FA (UMFA). However, a comparison of folate forms on in utero programming of offspring or maternal health has not been reported. Our objectives were to compare the effects of folate dose (low vs high) and form (FA vs 5MTHF) during pregnancy on DNAm potential, and the early and later PW phenotype of Wistar rat mothers and female offspring (mothers-to-be). MethodsPregnant Wistar rats (n = 22/group) were fed an AIN93G diet with recommended FA (1X, 2mg/kg diet), 5X-FA or equimolar 5MTHF. Dams were fed 1X-FA during lactation and then dams and female pups were fed a high fat diet for 19 weeks. Weight gain (WG), food intake (FI), energy expenditure (EE), insulin resistance (IR), plasma 5MTHF, UMFA, homocysteine (tHcy), and hepatic S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and DNA methyltransferases (DNMT) activity at birth and PW were measured. ResultsDams fed 5MTHF diets had lower DNMT activity at birth and female pups had higher SAM: SAH ratios (P < 0.05) indicative of altered DNAm potential compared to FA diets. Plasma 5MTHF at birth was dose dependent with 5X diets leading to higher levels than 1X diets (P < 0.001) in dams and pups. In contrast, UMFA was only higher in 5X-FA dams. 5MTHF dams had higher tHcy at birth and were more IR at 1 week PW than FA fed dams (P < 0.05). In both dams and offspring, high 5MTHF also led to higher WG (> 15%, P < 0.001) and FI (> 5%, P < 0.001) compared to high FA diets up to 19 weeks. EE (P < 0.05) was higher suggesting a compensatory response to WG. 5X-MTHF dams, but not offspring, also had greater hepatic lipids (P < 0.05) than other groups. ConclusionsFolate dose and form during pregnancy affects DNAm potential at birth and early and later phenotype of dams and female offspring. High 5MTHF increases WG, FI and hepatic lipids PW suggesting it may not be the preferred form for prenatal supplements or additions to the food supply. Funding SourcesSupported by CIHR-INMD; EP supported by NSERC-CGS D.

Dietary Intakes of Folic Acid During Pregnancy Determines Maternal Re-Set of Metabolism Post-Birth in Wistar Rat Dams (FS08-06-19)

ObjectivesNutrition during pregnancy alters the “re-set” of maternal metabolism and in turn the mother’s metabolic phenotype later in life. Folic acid (FA, synthetic folate) consumed at intakes above requirements during pregnancy by rats leads to increased weight gain and altered DNA methylation in central and peripheral pathways regulating food intake. The objectives of this study were to examine the effects of intakes below and above FA dietary requirements on the re-set of energy metabolic pathways in Wistar rat mothers early post-birth. MethodsPregnant Wistar rats (n = 12/group) were fed an AIN93G diet with 5 levels of FA: 0X, 1X (control, 2 mg FA/kg), 2.5X, 5X or 10X. Dams were fed 1X-FA during lactation up to 1-week post-weaning (PW) when maternal metabolism is thought to re-set to homeostasis and then terminated. Weekly body weight, food intake, expression of hypothalamic food-intake neurons, mRNA and protein expression of folate-related and energy metabolic genes, and glucoregulatory hormones were measured. The homeostatic model assessment of insulin resistance (HOMA-IR) was used as a surrogate index of insulin resistance. ResultsBelow (0X) and above (5X and 10X) FA requirements during pregnancy suppressed expression of hepatic folate metabolism (methyltetrahydrofolate (MTHF) reductase, and methionine synthase; P < 0.05) genes and led to higher 5-MTHF (P < 0.005) in blood compared to control suggesting dysregulation of 1-carbon pathways. Dams fed 0X- and 5X-FA also had higher plasma insulin and HOMA-IR than controls and changes in glucose and lipid metabolism-regulating genes in muscle (Glucose transporter-4, and Peroxisome-proliferator activated receptors; P < 0.05) but not liver or adipose at 1-week PW. The diets did not affect expression of hypothalamic food intake neurons nor body weight or food intake of the dams from birth to 1-week PW. ConclusionsFA below (0X) or above (5X, 10X) requirements during pregnancy induce dysregulation of 1-carbon pathways and delay re-set of energy metabolic pathways in Wistar rat dams by 4-weeks after birth, potentially programming long-term negative metabolic effects. Funding SourcesThis research was supported by: Canadian Institute of Health Research, Institute of Nutrition, Metabolism and Diabetes (CIHR-INMD); EP supported by NSERC Alexander Graham Bell Canada Graduate Scholarships-Doctoral Program (CGS D).

Supplementation with dairy matrices impacts on homocysteine levels and gut microbiota composition of hyperhomocysteinemic mice.

Several studies highlighted a correlation between folic acid deficiency and high plasma homocysteine concentration, considered a risk factor for multifactorial diseases. Natural folates represent an emerging alternative strategy to supplementation with synthetic folic acid, whose effects are controversial. The present work was, therefore, performed in hyperhomocysteinemic mice to study the impact of supplementation with dairy matrices containing natural folates on plasma homocysteine levels and faecal microbiota composition. Forty mice were divided into six groups, two of which fed control or folic acid deficient (FD) diets for 10 weeks. The remaining four groups were fed FD diet for the first 5 weeks and then shifted to a standard control diet containing synthetic folic acid (R) or a FD diet supplemented with folate-enriched fermented milk (FFM) produced by selected lactic acid bacteria, fermented milk (FM), or milk (M), for additional 5 weeks. Supplementation with dairy matrices restored homocysteine levels in FD mice, although impacting differently on hepatic S-adenosyl-methionine levels. In particular, FFM restored both homocysteine and S-adenosyl-methionine levels to the control conditions, in comparison with FM and M. Next generation sequencing analysis revealed that faecal microbiota of mice supplemented with FFM, FM and M were characterised by a higher richness of bacterial species in comparison with C, FD and R groups. Analysis of beta diversity highlighted that the three dairy matrices determined specific, significant variations of faecal microbiota composition, while hyperhomocysteinemia was not associated with significant changes. Overall, the results represent a promising starting point for the applicability of food matrices enriched in natural folates to manage hyperhomocysteinemia.

Comparative Pharmacodynamic Effect between Folate Isolated from Spinacia Oleracea Leaves and Synthetic Folic acid on Pregnant Mice

Comparative Pharmacodynamic Effect between Folate Isolated from Spinacia Oleracea Leaves and Synthetic Folic acid on Pregnant Mice

Abstract 2239: Is folic acid safe for non-muscle-invasive bladder cancer patients? An evidence-based cohort study

Abstract Background: Cancer patients are highly concerned about food choices and dietary supplements that may affect their treatment outcomes. Excess folic acid (synthetic folate) from supplements or fortification can lead to accumulation of unmetabolized folic acid in the systemic circulation and urine, and may promote cancer growth, especially among those with neoplastic alterations. Objective: We investigated the prospective association between synthetic versus natural folate intake and clinical outcomes in non-muscle-invasive bladder cancer (NMIBC), which is a highly recurrent disease. Design: In a cohort of 619 NMIBC patients, folate intake at diagnosis was assessed with a previously validated food frequency questionnaire and categorized according to tertiles. After a median follow-up of 5.2 years, 303 tumor recurrence and 108 progression events were documented from medical record review. Multivariable Cox proportional hazards and logistic models were used to estimate adjusted hazard ratios (HR) and odds ratios (OR) with 95% confidence intervals (95% CI). Results: Synthetic folic acid intake was positively associated with risk of recurrence among NMIBC patients (medium vs. low intake: HR=1.72; 95% CI=1.20, 2.48; P=0.003; high vs. low intake: HR=1.80; 95% CI=1.14, 2.84; P=0.01). Patients with higher folic acid intake were more likely to have multifocal tumors at diagnosis (medium/high vs. low: OR=2.08; 95% CI=1.08, 4.02; P=0.03). In contrast, natural folate intake tended to be inversely associated with risk of progression (medium/high vs. low: HR=0.68; 95% CI=0.44, 1.04; P=0.08). Conclusions: High intake of synthetic folic acid, in contrast to the natural forms, is associated with increased risk of recurrence in NMIBC and multifocal tumors at diagnosis, suggesting that folic acid may be unsafe for NMIBC patients. These findings provide some evidence for nutritional consultation regarding folate intake among NMIBC patients. Citation Format: Huakang Tu, Colin P. Dinney, Yuanqing Ye, Barton H. Grossman, Seth P. Lerner, Xifeng Wu. Is folic acid safe for non-muscle-invasive bladder cancer patients? An evidence-based cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2239.

MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series.

To evaluate the possibility of correcting metabolic defects in gametes and embryos due to methylene tetra hydrofolate reductase (MTHFR) isoforms C677T and A1298C, by supplementation with 5-methyl THF instead of synthetic folic acid. In these couples, high doses of folic acid lead to UMFA (un-metabolized folic acid) syndrome. Thirty couples with fertility problems lasting for at least 4years, such as recurrent fetal loss, premature ovarian insufficiency, or abnormal sperm parameters, with two thirds of them having failed assisted reproductive technology (ART) attempts were included in this program. For all couples, at least one of the partners was a carrier of one of the two main MTHFR isoforms. Most of the women had been previously treated unsuccessfully with high doses of folic acid (5mg/day), according to what is currently proposed in the literature. The couples carrying one of the isoforms were treated for 4months with 5-MTHF, at a dose of 600 micrograms per day, before attempting conception or starting another attempt at ART. The duration of treatment corresponding to an entire cycle of spermatogenesis is approximately 74days. In this first series of 33 couples, one couple was not followed-up, and two are still currently under treatment. No adverse effects were observed. Thirteen of the couples conceived spontaneously, the rest needing ART treatment in order to achieve pregnancy. Only three couples have, so far, not succeeded. The conventional use of large doses of folic acid (5mg/day) has become obsolete. Regular doses of folic acid (100-200μg) can be tolerated in the general population but should be abandoned in the presence of MTHFR mutations, as the biochemical/genetic background of the patient precludes a correct supply of 5-MTHF, the active compound. A physiological dose of 5-MTHF (800μg) bypasses the MTHFR block and is suggested to be an effective treatment for these couples. Moreover, it avoids potential adverse effects of the UMFA syndrome, which is suspected of causing immune dysfunction and other adverse pathological effects such as cancer (especially colorectal and prostate).

Dietary patterns are influenced by socio-demographic conditions of women in childbearing age: a cohort study of pregnant women.

BackgroundWomen’s health during their reproductive years and whilst pregnant has implications for their children’s health, both in utero and during childhood. Associations of women’s pre-pregnancy dietary patterns (DP) with maternal socio-demographic characteristics and nutrient intake were investigated in ProcriAr cohort study in São Paulo/Brazil, 2012.MethodsThe DPs of 454 women were investigated by principal component factor analysis, using dietary information from a validated 110-item food frequency questionnaire. Multiple linear regression models identified independent associations between DPs and maternal socio-demographic characteristics and Spearman’s correlation determined associations between DPs and nutrients intake.ResultsParticipants’ mean age was 26.1 years (standard deviation = 6.3), 10.3% had more than 8 years of formal education, 30% were migrants from outside of the Southeast of Brazil, 48% were employed, 13% were smokers, and 51% were overweight/obese. Four DPs were derived: ‘Lentils, whole grains and soups,’ ‘Snacks, sandwiches, sweets and soft drinks,’ ‘Seasoned vegetables and lean meats,’ and ‘Sweetened juices, bread and butter, rice and beans’. The ‘Lentils, whole grains and soups’ score was positively related to maternal age, being non-smoker and born in the South, North or Midwest of Brazil. The ‘Snacks, sandwiches, sweets and soft drinks’ score was positively related to higher maternal education, and negatively related to age, lack of formal work and being born in the Northeast region. The ‘Seasoned vegetables and lean meats’ score was positively related to higher maternal education. The ‘Sweetened juices, bread and butter, rice and beans’ score was positively related to unemployment and to no family history of hypertension, and negatively related to maternal overweight and obesity. Dietary intake of fruits and vegetables, foods that require preparation, nutrients from one-carbon metabolism, protein, iron, calcium and vitamin D were correlated with the ‘Seasoned vegetables and lean meats’. Dietary intake of sugar-sweetened and alcoholic beverages, industrialized and takeaway foods, and foods rich in sugar, energy, fat, and synthetic folate were correlated with the ‘Snacks, sandwiches, sweets and soft drinks’.ConclusionsFindings from this study add perspectives to be considered in the implementation of health interventions, which could improve women’s nutritional status and provide an adequate environment for the developing fetus.

Is folic acid safe for non–muscle-invasive bladder cancer patients? An evidence-based cohort study

Patients with cancer are highly concerned about food choices and dietary supplements that may affect their treatment outcomes. Excess folic acid (synthetic folate) from supplements or fortification can lead to accumulation of unmetabolized folic acid in the systemic circulation and urine and may promote cancer growth, especially among those with neoplastic alterations. We investigated the prospective association between synthetic compared with natural folate intake and clinical outcomes in non-muscle-invasive bladder cancer (NMIBC), which is a highly recurrent disease. In a cohort of 619 NMIBC patients, folate intake at diagnosis was assessed with a previously validated food-frequency questionnaire and categorized according to tertiles. After a median follow-up of 5.2 y, 303 tumor recurrence and 108 progression events were documented from medical record review. Multivariable Cox proportional hazards and logistic models were used to estimate adjusted HRs and ORs with 95% CIs. Synthetic folic acid intake was positively associated with a risk of recurrence among NMIBC patients (medium compared with low intake-HR: 1.72; 95% CI: 1.20, 2.48; P = 0.003; high compared with low intake-HR: 1.80; 95% CI: 1.14, 2.84; P = 0.01). Patients with a higher folic acid intake were more likely to have multifocal tumors at diagnosis (medium or high compared with low-OR: 2.08; 95% CI: 1.08, 4.02; P = 0.03). In contrast, natural folate intake tended to be inversely associated with the risk of progression (medium or high compared with low-HR: 0.68; 95% CI: 0.44, 1.04; P = 0.08). A high intake of synthetic folic acid, in contrast to the natural forms, is associated with an increased risk of recurrence in NMIBC and multifocal tumors at diagnosis, which suggests that folic acid may be unsafe for NMIBC patients. These findings provide some evidence for nutritional consultation with regard to folate intake among NMIBC patients.

Analysis of natural and synthetic folates in pharmaceuticals and foods: a review

This review is focused on the progress of sample pretreatment and analysis methods of natural and synthetic folates in pharmaceuticals and foods in the last decade.

Plasma metabolite profiles in healthy women differ after intervention with supplemental folic acid v. folate-rich foods

Public health authorities recommend all fertile women to increase their folate intake to 400µg/d by eating folate-rich foods or by taking a folic acid supplement to protect against neural tube defects. In a previous study it was shown that folate-rich foods improved folate blood status as effectively as folic acid supplementation. The aim of the present study was to investigate, using NMR metabolomics, the effects of an intervention with a synthetic folic acid supplement v. native food folate on the profile of plasma metabolites. Healthy women with normal folate status received, in parallel, 500µg/d synthetic folic acid from a supplement (n 18), 250µg/d folate from intervention foods (n 19), or no additional folate (0µg/d) through a portion of apple juice (n 20). The metabolic profile of plasma was measured using 1H-NMR in fasted blood drawn at baseline and after 12 weeks of intervention. Metabolic differences between the groups at baseline and after intervention were assessed using a univariate statistical approach (P≤0·001, Bonferroni-adjusted significance level). At baseline, the groups showed no significant differences in measured metabolite concentrations. After intervention, eight metabolites, of which six (glycine, choline, betaine, formate, histidine and threonine) are related to one-carbon metabolism, were identified as discriminative metabolites. The present study suggests that different folate forms (synthetic v. natural) may affect related one-carbon metabolites differently.

Calibration of Dietary Data: “Folate and Nutrients Involved in the 1-Carbon Cycle in the Pretreatment of Patients for Colorectal Adenocarcinoma in a Referral Center for Oncology in Southeastern Brazil”

Objective: Calibrate the FFQ and evaluate its performance in relation to the consumption of energy, carbohydrate, protein, fat, alcohol, folate, vitamin B2, vitamin B6, vitamin B12, methionine, choline and betaine in the study population “Folate and nutrients involved in the 1-carbon cycle in the pretreatment of patients for colorectal adenocarcinoma in a referral center for oncology in southeastern Brazil.Materials and methods: For calibration, we used three 24-hour dietary recalls (R24s; n=270) and the second FFQ (n=90) collected in a previous study. The R24 data were used as a reference method and subjected to linear regression, with β1 values used as a calibration factor for the FFQ data collected.Results: Comparing the R24 data to observed FFQ data and observed FFQ data to calibrated FFQ data; the means were significantly different for all nutrients. When comparing calibrated FFQ data to R24 values, the means were statistically similar for carbohydrates, vitamin B2, vitamin B6, natural folate, synthetic folate, DFE diet and betaine.Conclusion: The calibration coefficients were low, however the reference method used may not have been the best way to eliminate measurement errors found in the FFQ.

Recent Developments in Folate Nutrition.

The term folate (vitamin B9) refers to a group of water-soluble compounds that are nutritionally essential for the support of optimal human health and development. Folates participate in numerous one-carbon transfer reactions, including the methylation of important biomolecules (lipids, amino acids, DNA). A deficiency of folate leads to pathological outcomes including anemia and impairments in reproductive health and fetal development. Due to the linkage of impaired folate status with an increased prevalence of neural tube defects (NTDs) in babies, several jurisdictions required the fortification of the food supply with folic acid, a synthetic and stable form of folate. Data from the postfortification era have provided strong evidence for the reduction of NTDs due to folic acid fortification. However, concern is now growing with respect to the amount of synthetic folic acid within the human food supply. Excess folic acid intake has been linked to a masking of vitamin B12 deficiency, and concerns regarding the promotion of folate-sensitive cancers, including colorectal cancer. New strategies to ensure the supply of optimal folate to at-risk populations may be needed, including the use of biofortification approaches, in order to address recent concerns.

Clinical and economic feasibility study of the use of vitamin and mineral complexes in case of miscarriage

The purpose: to conduct a pharmacoeconomic analysis of two schemes of vitamin-mineral drugs in the peri-gestation period in women with habitual miscarriage and polymorphisms of folate cycle genes, giving birth to full-term children. Materials and methods: the cost-effectiveness of vitamin-mineral preparations in two groups of women was calculated. Patients of the 1st group (n=60) received pregravidno and during pregnancy a vitamin-mineral complex containing in one tablet metafolin, other vitamins of group B, vitamins C, E, PP and iodine (150 mcg) in physiological dosages, and also 200 mg of docosahexaenoic acid in a capsule intended for use from the 13th week until the end of pregnancy. Women of the 2nd group (n=54) took high doses of synthetic folic acid, vitamins B6 and B12 as part of two vitamin and mineral preparations during the pregravid preparation and gestational period. During pregnancy, the patients of both groups received an additional 100 mcg of potassium iodide daily. Results: in the 1st group, the cost-effectiveness ratio was 1.6 times lower and the clinical efficacy was significantly higher than in the 2nd group and consisted in a significant decrease in the incidence of preeclampsia, placental insufficiency, intrauterine fetal hypoxia, complications in the time of delivery, as well as the diseases in their children in the early neonatal period (1.5-3.9 times, p

Effect of Folate Supplementation on Inflammatory Markers in Individuals Susceptible to Depression: A Systematic Review

Folate has been proposed to be an efficacious treatment strategy for depression. The mandatory fortification of flour with synthetic folic acid (FA) in over 80 countries has yielded improvements in folate intake; however, depression is still a considerable public health concern. While there are established benefits of FA fortification in reducing risk of neural tube defects, the implications regarding depression are unclear, especially in individuals with certain genetic polymorphisms. Therefore, a systematic review was conducted to examine the effects of folate to treat depression. Following PRISMA guidelines, a systematic review was conducted of electronic databases (PUBMED, Scopus, CINAHL, and Cochrane Library) to identify human clinical trials examining the effects of folate (including FA) supplementation in the management or prevention of depression, the impact on inflammatory markers and if genetic polymorphisms were considered. Ten trials met the inclusion criteria. Seven trials examined effects of either adjunctive FA or L-methylfolate (L-MTHF) supplementation with antidepressants in the management of depression and three examined effects of FA supplementation alone for prevention of depression. No benefit of FA was found compared to placebo (all, p > 0.05). The single L-MTHF trial that explored the interplay of genetic polymorphisms and methylation status found benefit in the Hamilton depression rating scale from adjunctive treatment with 15 mg/day of L-MTHF compared with placebo (−6.8 ± 7.2 vs. −3.7 ± 6.5; p = 0.017) and improvement with L-MTHF for most genetic markers. Currently, there is no evidence to support FA supplementation for the management or prevention of depression. More research is required to determine the efficacy of L-MTHF and folinic acid in certain clinical populations.

Is High Folic Acid Intake a Risk Factor for Autism?—A Review

Folate is required for metabolic processes and neural development. Insuring its adequate levels for pregnant women through supplementation of grain-based foods with synthetic folic acid (FA) in order to prevent neural tube defects has been an ongoing public health initiative. However, because women are advised to take multivitamins containing FA before and throughout pregnancy, the supplementation together with natural dietary folates has led to a demographic with high and rising serum levels of unmetabolized FA. This raises concerns about the detrimental effects of high serum synthetic FA, including a rise in risk for autism spectrum disorder (ASD). Some recent studies have reported a protective effect of FA fortification against ASD, but others have concluded there is an increased risk for ASD and other negative neurocognitive development outcomes. These issues are accompanied by further health questions concerning high, unmetabolized FA levels in serum. In this review, we outline the reasons excess FA supplementation is a concern and review the history and effects of supplementation. We then examine the effects of FA on neuronal development from tissue culture experiments, review recent advances in understanding of metabolic functional blocks in causing ASD and treatment for these with alternative forms such as folinic acid, and finally summarize the conflicting epidemiological findings regarding ASD. Based on the evidence evaluated, we conclude that caution regarding over supplementing is warranted.

Folic acid intake and folate status and colorectal cancer risk: A systematic review and meta-analysis

To evaluate the controversies among the studies assessing the association between folic acid intake or folate status and colorectal cancer risk. PubMed, Cochrane library and references of related articles were searched from January 2000 to September 2016. Studies on folic acid intake or folate status and colorectal cancer or adenoma risk were included. Full text review was conducted for potentially eligible studies. Quality assessment was performed. Random-effects meta-analysis was used to estimate risk ratio and 95% Confidence Intervals. Analysis was conducted by Comprehensive Meta-Analysis software. Folic acid supplement intake showed no significant effect on colorectal cancer risk in meta-analysis of randomized controlled trials, RR: 1.07(95% CI: 0.86-1.43). The effect on risk was not significant in cohort studies either; RR=0.96(95% CI: 0.76-1.21). However, there was significant reduced colorectal cancer risk in total folate intake in cohort studies; 0.71 (95% CI: 0.59-0.86). Odds Ratio was also significantly reduced in case control studies; 0.77 (95% CI: 0.62-0.95). Nevertheless once folate status was measured as Red Blood Cell folate content, no significant effect on colorectal cancer risk was observed; 1.05 (95% CI: 0.85-1.30). The differences in bioavailability and metabolism of synthetic folic acid and natural dietary folate as well as variation in the baseline characteristics of subjects and various methods of folate status assessment might be the main reasons for these controversies. Findings of present study highlightthe importance of individualized folic acid supplement intake given the fact that the beneficiary effects of long term folic acid supplementation is not confirmed.

Synthetic Folic Acid Supplementation during Pregnancy Increases the Risk of Neonatal Jaundice in Newborns

Synthetic Folic Acid Supplementation during Pregnancy Increases the Risk of Neonatal Jaundice in Newborns

A Cross-Sectional Study of Dietary and Genetic Predictors of Blood Folate Levels in Healthy Young Adults.

Since 1998, the U.S. has mandated folic acid (FA) fortification of certain grain products to reduce the risk of neural tube defects. Folate intake and red blood cell (RBC) folate concentrations increased substantially post-intervention, although recent studies raise concerns about the level of ongoing benefit. This study investigated blood folate level determinants in healthy young adults, including intake of naturally occurring food folate, synthetic FA, and the interaction of naturally occurring food folate with a common missense variant in the FOLH1 gene thought to affect absorption. Participants (n = 265) completed the Diet History Questionnaire II, RBC folate testing, and were genotyped for the 484T>C FOLH1 variant. Men reported significantly greater intake of all folate sources except for supplemental FA, but RBC folate levels did not significantly differ by sex. Synthetic FA was a stronger predictor of RBC folate than naturally occurring food folate. In the largest racial group, synthetic FA and the interaction of FOLH1 genotype with naturally occurring food folate significantly predicted RBC folate, with the overall model accounting for 13.8% of the variance in RBC folate levels. Blood folate levels rely on a complex interaction of natural and synthetic folate intake as well as FOLH1 genotype.

Folic Acid Impairs the Uptake of 5-Methyltetrahydrofolate in Human Umbilical Vascular Endothelial Cells.

Background:Adequate folate status supports endothelial structure and function. Folic acid (FA), an oxidized synthetic folate, which is present in the plasma of patients consuming fortified food or FA supplements, may impair cellular uptake of physiological, reduced folates. We studied the effect of FA on uptake of the dominant circulatory folate, 5-methyltetrahydrofolate (5MTHF) in endothelial cells.Methods and Results:For short-term effects of FA, primary human umbilical vein endothelial cells (HUVECs) were maintained in growth medium containing 200 nM 5MTHF and preincubated with 20 nM FA 10 minutes before the 5MTHF uptake assessment. For long-term effects, HUVECs were cultured for 3 passages in growth medium containing either 200 nM 5MTHF, or a combination of 100 nM 5MTHF and 100 nM FA. 5MTHF uptake was assessed after exposing cells to 200 nM [13C5]-5MTHF, after which intracellular [13C5]-5MTHF was quantified using liquid chromatography/tandem mass spectrometry. Acute FA exposure caused a 57% reduction in 5MTHF uptake compared with control conditions (51 ± 12 vs. 22 ± 7 fmol·min−1·mg−1 protein; P = 0.01). Long-term exposure to FA reduced 5MTHF uptake by 41% (51 ± 12 vs. 30 ± 11 fmol·min−1·mg−1 protein; P = 0.05) and reduced total cellular 5MTHF levels by 47 ± 21% in HUVEC (P = 0.02).Conclusion:Unmetabolized FA, which appears in the plasma after consumption of fortified food or FA supplements, may impair uptake of 5MTHF, the dominant bioactive form of folate, in HUVEC.

Abstract 5314: Long-term folate intake and prostate cancer risk in the health professionals follow-up study

Abstract Background: Randomized trials of supplemental folate and observational studies of circulating folate support a positive association with prostate cancer risk. However, epidemiological studies of dietary and synthetic folate intake are conflicting. Given mandatory folic acid fortification of grains in the US beginning in 1998, evaluation of long-term folate intake from natural and synthetic sources in relation to prostate cancer risk is warranted. Methods: We examined the association between folate intake and prostate cancer risk among 47,884 men in the Health Professionals Follow-up Study who were free from diagnosed cancer at baseline in 1986. Total, natural (from food sources), and synthetic (from supplements/fortification) folate intake was assessed every 4 years using a validated food frequency questionnaire, and categorized as the cumulative average and lagged (0-4, 4-8, 8-12, and 12-16 years in the past) intakes. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (CI). Results: We identified 6,186 incident prostate cancer cases from 1986-2012, including 1,078 with lethal disease (distant metastasis or death). Mean total folate intake was 481 µg/day in 1986 and increased to 671 µg/day by 2010. The proportion of men meeting the recommended intake of 400 µg/day increased from 47% in 1986 to 74% after fortification began in 1998. Folate intake was positively correlated with physical activity, multivitamin use, and PSA testing, and inversely correlated with smoking. Total folate intake averaged over time was not significantly associated with total prostate cancer risk: HR≥800 vs. 400-599=1.03 (95% CI: 0.95-1.13, p-trend=0.76). Neither natural nor synthetic folate intake was associated with risk of total prostate cancer. No associations were observed between total, natural, or synthetic folate intake and risk of lethal, advanced stage, or high-grade disease. Conclusions: Our findings do not support strong associations between intakes of total, natural, or synthetic folate and prostate cancer risk. We found no indication that folate intake of ≥800 µg/day (twice the recommended level) increases prostate cancer risk. Citation Format: Nadine M. Hamieh, Julie L. Batista, Sarah C. Markt, Mary K. Downer, Lorelei A. Mucci, Meir J. Stampfer, Edward L. Giovannucci, Kathryn M. Wilson. Long-term folate intake and prostate cancer risk in the health professionals follow-up study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5314. doi:10.1158/1538-7445.AM2017-5314