Dietary Folate Intake Research Articles

Prevalence of inadequate intake of folate in the post-fortification era: data from the Brazilian National Dietary Surveys 2008-2009 and 2017-2018.

The objectives were to compare the evolution of dietary folate intake, to estimate the prevalence of folate inadequacy (POFI) and the contribution of food groups to folate intake (dietary folate plus folic acid from fortified foods) in two post-fortification periods in the Brazilian population, according to life stages, geographic regions and per capita income. Population-based study including representative data from the National Dietary Survey - Brazilian Household Budget Surveys (NDS-HBS) 2008-2009 and 2017-2018, with a total of 32749 (2008-2009) and 44744 (2017-2018) individuals aged ≥ 10 years old, excluding pregnant and lactating women. The National Cancer Institute method was used to estimate the distributions of usual dietary folate intake. POFI was estimated according to estimated average requirement cut-off point method. After 10 years of the first NDS-HBS, POFI has increased in all sex-age groups, except for 10-13 years. POFI among women of reproductive age was around 30 and 40 % in 2008-2009 and 2017-2018. Higher POFI was observed in the North region. The top five food groups contributors to folate intake in Brazil were beans, breads, pasta and pizza, cakes and cookies and non-alcoholic beverages groups in both periods, differing in the rank order of the last two groups. Although being a country that has adopted mandatory folic acid flour fortification for almost two decades, increased POFI was observed in 2017-2018. This study brings significant scientific information, which can help understand folate dietary data in different contexts and consequently guide the approach for public health fortification strategies.

Influencing factors of insufficient and excessive folate intake in early pregnancy in Chengdu in 2017

To investigate the folate intake level of early pregnant women and its influencing factors in Chengdu. The healthy singleton pregnant women with 8-14 weeks of pregnancy in an obstetrical clinic of maternal-and-child health care institution in Chengdu in 2017 were selected as the object of the study. The basic information of pregnant women was collected by questionnaire survey, and the dietary intake of all kinds of food in early pregnancy was collected by 3-day 24-hour dietary recall method, and the average daily intake of folate was calculated according to China Food Composition(2018). A self-designed questionnaire was used to collect the use of folic acid supplements in pregnant women in the past one month, and the average daily intake of folic acid supplements was calculated. According to the Chinese Dietary Reference Intakes(2013), the folate intake <600 μg DFE/d was defined as insufficient, and folic acid supplements intake ≥1000 μg/d was defined as excessive. The influencing factors of folate intake were analyzed by binary Logistic regression model. A total of 1579 valid samples were included. The average folate intake of early pregnant women in Chengdu was 865.8(778.6, 1461.0) μg DFE/d, the average dietary folate intake was 145.4(101.9, 200.7) μg/d, and the average folic acid supplements intake was 400.0(400.0, 800.0) μg/d. The rate of insufficient intake of folate in early pregnancy was 12.1%, and the rate of excessive intake of folic acid supplements was 13.0%. Compared with the primiparous group, the risk of insufficient folate intake was higher in the multiparous group(OR=1.708, 95%CI 1.175-2.482). Compared with the low income group, risk of insufficient folate intake in the medium and high income group was lower(OR=0.660, 95%CI 0.477-0.913); taking folic acid supplements before pregnancy has a lower risk of overdose of folic acid than the non-taking group(OR=0.594, 95%CI 0.423-0.835). The phenomenon of insufficient intake of total folate and excessive intake of folic acid supplements coexists among women in early pregnancy in Chengdu, and the rational use of folic acid supplements is worthy of attention.

Dietary Intake of Folate and Assessment of the Folate Deficiency Prevalence in Slovenia Using Serum Biomarkers.

Folate deficiency is associated with various health issues, including anemia, cardiovascular disease, and birth defects. Low folate intake and suboptimal folate status were found in several countries; however, this topic has not yet been investigated in Slovenia. Dietary folate intake and serum folate status were investigated through the nationally representative food consumption study SI.Menu/Nutrihealth. Folate intake was estimated using a sample of N = 1248 subjects aged 10–74 years, stratified in three age groups (adolescents, adults, elderly population), through two 24 h-dietary recalls and food propensity questionnaire. Data on serum folate and homocysteine was available for 280 participants. Very low folate intake (<300 µg/day) was observed in 59% of adolescents, 58% of adults and 68% of elderlies, and only about 12% achieved the WHO recommended level of 400 µg/day. Major dietary contributors were vegetables and fruit, and cereal products. Living environment, education, employment status and BMI were linked with low folate intake in adults; BMI, and sex in adolescents; and sex in elderlies. Considering low serum folate (<7 nmol/L) and high serum homocysteine (>15 nmol/L), folate deficiency was found in 7.6 and 10.5% in adults and elderlies, respectively. Additional public health strategies should be employed to promote the consumption of folate-rich foods. With current folate intakes, supplementation with folic acid is relevant especially in specific vulnerable populations, particularly in women planning and during pregnancy.

Association of MTHFR C677T variant genotype with serum folate and Vit B12 in Iranian patients with colorectal cancer or adenomatous polyps

BackgroundThe incidence of colorectal cancer (CRC) has increased during recent years in Iran and other developing countries. Clinical studies suggest that essential folate dietary intake and moderate deficiency of methylenetetrahydrofolate reductase (MTHFR) may protect and reduce the risk of CRC. The present study aimed to investigate the clinical significance of C677T polymorphism within the MTHFR gene and its correlation with the serum folate and Vit B12 in the Iranian population suffering from CRC.MethodsBlood samples were taken from 1017 Iranian individuals (517 cases and 500 controls) who were referred for colonoscopy. TaqMan probe assay was performed for C677T MTHFR polymorphism. Sera were fractionated from the blood samples of 43 patients and controls and folate and Vit B12 concentrations were measured by a monobind kit. The correlation of MTHFR polymorphisms and folate/vitamin-B12 with CRC risk was analyzed.ResultsIn the current study, we found the frequency of three different genotypes of MTHFR polymorphism in the Iranian population i.e., CC, CT, and TT, to be 51.31, 26.73, 21.96 and 61, 32.2, 6.8 in case and control groups, respectively. The homozygote genotype of MTHFR rs1801133 polymorphism is associated with an increased risk of CRC by 3.68, 1.42, and 3.74-fold in codominant, dominant, and recessive models respectively (p value < 0.01). Our study revealed that there was no significant difference between the amount of folate and Vit B12 in the case and control groups (p value > 0.05).ConclusionsThis study revealed that there was no significant difference between the amount of folate and Vit B12 in the case and control groups. Furthermore, our results demonstrated a higher risk association for 677TT and 677TT + C677T genotypes of MTHFR compared with 677CC carriers among CRC patients.

Association of dietary intakes of vitamin B12, vitamin B6, folate, and methionine with the risk of esophageal cancer: the Japan Public Health Center-based (JPHC) prospective study

BackgroundB vitamins and methionine are essential substrates in the one-carbon metabolism pathway involved in DNA synthesis and methylation. They may have essential roles in cancer development. We aimed to evaluate the associations of dietary intakes of vitamin B12, vitamin B6, folate, and methionine with the risk of esophageal cancer (EC) using data from the Japan Public Health Center-based Prospective Study.MethodsWe included 87,053 Japanese individuals who completed a food frequency questionnaire and were followed up from 1995–1998 to 2013 and 2015. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by Cox proportional-hazard regression across quintiles of dietary intakes of B vitamins and methionine.ResultsAfter 1,456,678 person-years of follow-up, 427 EC cases were documented. The multivariable HR (95% CI) of incident EC in the highest versus lowest quintile of dietary intake of vitamin B12 was 1.75 (1.13–2.71; p-trend=0.01). Stratification analysis based on alcohol consumption showed that higher dietary intakes of vitamin B12 and methionine were associated with an increased risk of EC among never-drinkers; HRs (95% CIs) were 2.82 (1.18–6.74; p-trend=0.009; p-interaction=0.18) and 3.45 (1.32–9.06; p-trend=0.003; p-interaction 0.02) for vitamin B12 and methionine, respectively. Meanwhile, there was no association between vitamin B12 and methionine intake with the risk of EC among drinkers. There were no associations between dietary intake of folate or vitamin B6 and the risk of EC.ConclusionDietary intake of vitamin B12 was positively associated with the risk of EC in the Japanese population.

B vitamins and prevention of cognitive decline and incident dementia: a systematic review and meta-analysis.

Elevation of homocysteine (Hcy) levels is well-established as a risk factor for dementia, yet controversy exists regarding whether B-vitamin-mediated reduction of homocysteine levels can benefit cognitive function. To investigate whether B vitamin supplementation can reduce the risk of cognitive decline and incident dementia. The PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched for articles published from the inception dates to March 1, 2020. Randomized controlled trials (RCT) were included if B vitamins were supplied to investigate their effect on the rate of cognitive decline. Cohort studies investigating dietary intake of B vitamins and the risk of incident dementia were eligible. Cross-sectional studies comparing differences in levels of B vitamins and Hcy were included. Two reviewers independently performed data extraction and assessed the study quality. Random-effect or fixed-effect models, depending on the degree of heterogeneity, were performed to calculate mean differences (MDs), hazard ratios (HRs), and odds ratios (ORs). A total of 95 studies with 46175 participants (25 RCTs, 20 cohort studies, and 50 cross-sectional studies) were included in this meta-analysis. This meta-analysis supports that B vitamins can benefit cognitive function as measured by Mini-Mental State Examination score changes (6155 participants; MD, 0.14, 95%CI 0.04 to 0.23), and this result was also significant in studies where placebo groups developed cognitive decline (4211 participants; MD, 0.16, 95%CI 0.05 to 0.26), suggesting that B vitamins slow cognitive decline. For the > 12 months interventional period stratum, B vitamin supplementation decreased cognitive decline (3814 participants; MD, 0.15, 95%CI 0.05 to 0.26) compared to placebo; no such outcome was detected for the shorter interventional stratum (806 participants; MD, 0.18, 95%CI -0.25 to 0.61). In the non-dementia population, B vitamin supplementation slowed cognitive decline (3431 participants; MD, 0.15, 95%CI 0.04 to 0.25) compared to placebo; this outcome was not found for the dementia population (642 participants; MD, 0.20, 95%CI -0.35 to 0.75). Lower folate levels (but not B12 or B6 deficiency) and higher Hcy levels were significantly associated with higher risks of dementia (folate: 6654 participants; OR, 1.76, 95%CI 1.24 to 2.50; Hcy: 12665 participants; OR, 2.09, 95%CI 1.60 to 2.74) and cognitive decline (folate: 4336 participants; OR, 1.26, 95%CI 1.02 to 1.55; Hcy: 6149 participants; OR, 1.19, 95%CI 1.05 to 1.34). Among the population without dementia aged 50 years and above, the risk of incident dementia was significantly decreased among individuals with higher intake of folate (13529 participants; HR, 0.61, 95%CI 0.47 to 0.78), whereas higher intake of B12 or B6 was not associated with lower dementia risk. This meta-analysis suggests that B vitamin supplementation is associated with slowing of cognitive decline, especially in populations who received early intervention and intervention of long duration; the study also indicates that higher intake of dietary folate, but not B12 or B6, is associated with a reduced risk of incident dementia in non-dementia aged population. Given the prevalence of dementia cases in many countries with aging populations, public health policies should be introduced to ensure that subgroups of the population at risk have an adequate B vitamin status.

Dietary intake and blood concentrations of folate and folic acid in relation to serum per- and polyfluoroalkyl substances (PFAS) concentrations

BACKGROUND AND AIM: Folate may counteract the effects of environmental chemical exposures. This study aimed to explore the associations of dietary folate and folic acid intake with serum concentrations of per- and polyfluoroalkyl substances (PFAS). METHODS: We included 505 children (aged 3-11), 345 adolescents (aged 12-19), and 1,458 adults (aged 20-80) in the National Health and Nutrition Examination Study (NHANES), 2013 - 2014 cycle. Dietary intake of folate and folic acid in food and supplementation were evaluated by dietary recall in the last 24h and 30 days, respectively. Biomarker concentrations of folate and folic acid in serum and folate in red blood cells were also assessed. We examined serum perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS). Multivariable regression models were used to assess change in log2-transformed PFAS concentrations in relation to dietary intake and folate and folic acid biomarkers, adjusting for covariates. RESULTS:Children’s dietary supplement intake of folic acid was negatively associated with PFOA, PFOS and PFNA concentrations (for example, PFNA: -13%; 95%CI: -29%, 0.07%). In adolescents, significant negative associations were found for folate in red blood cells and all four PFAS concentrations (for example, PFNA: -25%; 95%CI: -43%, -1%); total serum folate concentration and PFNA; and dietary intake of folate in food and PFOA and PFHxS concentrations. In adults, significant negative associations were found for dietary supplement intake of folic acid and serum concentrations of PFOA, PFOS and PFNA (PFNA: -10%; 95%CI: -18%, -2%); folate concentrations in red blood cells and all four PFAS concentrations; as well as serum folic acid and total folate concentrations and PFOA, PFOS and PFNA. CONCLUSIONS:Dietary intake and biomarkers of folate and folic acid were negatively associated with select PFAS concentrations in the U.S. population. These findings may have important implications for reducing PFAS body burden. KEYWORDS: PFAS, folate, folic acid, exposure reduction

Maternal Folic Acid Intake and Methylation Status of Genes Associated with Ventricular Septal Defects in Children: Case-Control Study.

Background: DNA methylation is the best epigenetic mechanism for explaining the interactions between nutrients and genes involved in intrauterine growth and development programming. A possible contributor of methylation abnormalities to congenital heart disease is the folate methylation regulatory pathway; however, the mechanisms and methylation patterns of VSD-associated genes are not fully understood. Objective: To determine if maternal dietary intake of folic acid (FA) is related to the methylation status (MS) of VSD-associated genes (AXIN1, MTHFR, TBX1, and TBX20). Methods: Prospective case–control study; 48 mothers and their children were evaluated. The mothers’ dietary variables were collected through a food frequency questionnaire focusing on FA and the consumption of supplements with FA. The MS of promoters of genes was determined in the children. Results: The intake of FA supplements was significantly higher in the control mothers. In terms of maternal folic acid consumption, significant differences were found in the first trimester of pregnancy. Significant differences were observed in the MS of MTHFR and AXIN1 genes in VSD and control children. A correlation between maternal FA supplementation and MS of AXIN1 and TBX20 genes was found in control and VSD children, respectively. Conclusions: A lower MS of AXIN1 genes and a higher MS of TBX20 genes is associated with FA maternal supplementation.

The Role of Folate-supplementation in Depression: A Narrative Review

Background: There is a relationship between the etiology and management of clinical depression and vitamin deficiencies. Aim: To review the effect of dietary folic acid supplementation on cause, severity and treatment of depression. Methods: A narrative review of empirical and theoretical literature on the effect of folic acid supplementation on the se-verity and treatment outcomes of depression. Result: Many enzymes and neurotransmitters depend on folic acid for optimal functions. The monoamine hypothesis of depression confirms the depletion of serotonin, dopamine, and norepinephrine. The systemic level of methyl folate is dependent upon the enzyme methylenetetrahydrofolate reductase [MTHFR], which is encoded by a polymorphic gene [C677T-MTHFR], as well as being dependent on dietary folic acid intake. However, folate has procarcinogenic properties because its coenzymes are involved in de novo purine and thymine nucleotide biosynthesis. Besides, folate deficiency in normal tissues may also predispose to neoplastic transformation, while folate supplementation may suppress the development of tumors in normal tissues. Epidemiological studies revealed that low folate status is associated with depression; especially in terms of severity and the outcome of antidepressant use. Conclusion: The role of folic acid in the etiology and the management of depression cannot be overemphasized. Folate supplementation has been yielding positive results in the management of depression.

Preconception Dietary Folate Intake and Risk of Spontaneous Abortion

ObjectivesPrevious studies suggest a beneficial effect of supplemental folic acid use and dietary folate intake on fertility, while results for fetal loss are conflicting. Most previous research on fetal loss focused on folic acid supplement use. We therefore, investigated the association between dietary folate intake and spontaneous abortion (SAB) in a Danish preconception cohort of couples trying to conceive. MethodsWe recruited couples who were trying to conceive and did not receive fertility treatment. Pregnancies were ascertained through bimonthly follow-up questionnaires completed up to 12 months after study entry. SABs were identified by self-report on the follow-up questionnaires and through the Danish National Patient Registry. Dietary folate intake at study entry was estimated using a validated food frequency questionnaire (FFQ). Folate intake was adjusted for total energy intake using the residual method and categorized as < 250,250–399 and > = 400μg/day. We used Cox proportional hazards regression models with gestational weeks as time scale to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for SAB, adjusting for age, partner’s age, educational attainment, smoking status, anthropometry, physical activity, alcohol intake, folic acid supplement use, time-to-pregnancy, gravidity and parity. In sensitivity analyses, we stratified by folic acid supplement use, body mass index (BMI) and alcohol intake. ResultsOf the 2,957 women who became pregnant within 12 months of study entry and completed the FFQ, we identified 432 SABs. HRs for an SAB among women who consumed 250–399 and >= 400 μg/day of dietary folate compared with <250 μg/day were 0.83 (95% CI: 0.53; 1.29) and 0.87 (95% CI: 0.54; 1.39), respectively. Comparing intake > = 400 with <250 μg/day, the association was stronger when the analysis was restricted to folic acid supplement users, 0.74 (95% CI: 0.39; 1.40), to women with a BMI >= 25, 0.67 (95% CI: 0.31; 1.43), and to a reported alcohol intake >4 drinks/week, 0.66 (95% CI: 0.16; 2.66). ConclusionsOur study may suggest that high dietary folate intake among folic acid supplement users is associated with a lower risk of SAB, although our estimates are imprecise. Funding SourcesNational Institute of Child Health and Human Development.

Potential for elimination of folate and vitamin B12 deficiency in India using vitamin-fortified tea: a preliminary study

IntroductionThe majority of Indian women have a poor dietary folate and vitamin B12 intake resulting in their chronically low vitamin status, which contributes to anaemia and the high incidence of...

Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992–2000 and December 2013–December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.

Depression and Vegetarians: Association between Dietary Vitamin B6, B12 and Folate Intake and Global and Subcortical Brain Volumes.

Deficiency of vitamin B6 and vitamin B12, mostly in vegetarians, is found to be associated with depression and adverse neurological function. We investigated whether vitamin B6, B12, and folate have an effect on brain structure, especially among depressed people who follow a specific diet. The study sample comprised 9426 participants from the UK Biobank cohort with a mean age of 62.4 years. A generalized linear model controlling for age, sex, body mass index, ethnicity, town send deprivation index, educational qualification, smoking, and alcohol intake was used to test the association between study groups and structural brain volumes. Depression was more prevalent, and intake of vitamin B6 and B12 was lower among vegetarians, while non-vegetarians had a lower intake of folate. Overall, no significant association was observed between vitamin B6, B12, and folate intakes and both global and subcortical brain volumes among participants with depression. However, vitamin B12 intake was positively associated with right pallidum among non-depressed participants, and a significant interaction between vitamin B12 intake and depression status on the right pallidum was observed. Also, a significant interaction between folate intake and depression status on grey matter (GM) volume and left thalamus was observed. Upon diet stratification, folate intake is associated with total brain volume and GM volume among vegetarians with depression. Furthermore, no significant associations were observed for subcortical regions. Our findings suggest that dietary intake of vitamin B6 and B12 might have an effect on brain structure. Vegetarians, particularly those who suffer from depression may benefit from supplementing their diets with vitamins B6, B12, and folate to ensure brain health. Further studies, especially with a larger sample size and longitudinal design, are needed to confirm these findings.

Association Between Interpregnancy Interval and Risk of Preterm Birth and Its Modification by Folate Intake: The Japan Environment and Children's Study.

Both short and long interpregnancy intervals (IPIs) have been associated with risk of preterm birth, but the evidence is limited in Asians. It is also uncertain whether the association is modified by dietary folate intake or folic acid supplementation during pregnancy. Thus, we examined associations between IPI and risk of preterm birth and effect modification of those associations by dietary intake of folate and supplementation with folic acid on the basis of a nationwide birth cohort study. Among 103,062 pregnancies registered in the Japan Environment and Children's Study, 55,203 singleton live-birth pregnancies were included in the analysis. We calculated IPI using birth date, gestational age at birth of offspring, and birth data of the latest offspring. Odds ratios (ORs) and 95% confidence intervals (CIs) of the risk of preterm birth were estimated according to IPI categories. Both <6-month and ≥120-month IPIs were associated with an increased risk of preterm birth, compared with an 18-23-month IPI. The multivariable ORs were 1.63 (95% CI, 1.30-2.04) for <6-month and 1.41 (95% CI, 1.11-1.79) for ≥120-month IPIs. These associations were confined to women with inadequate intake of dietary folate and folic acid supplementation during pregnancy. Multivariable ORs were 1.76 (95% CI, 1.35-2.29) for <6-month IPI and 1.65 (95% CI, 1.24-2.19) for ≥120-month IPI. Both <6-month and ≥120-month IPIs were associated with an increased risk of preterm birth. These higher risks were confined to women with inadequate intake of dietary folate and folic acid supplementation during pregnancy.

Gestational Folate and Folic Acid Intake among Women in Canada at Higher Risk of Pre-Eclampsia.

Periconceptional folic acid (FA) supplementation is recommended to prevent neural tube defects; however, the extent to which recommendations are met through dietary sources and supplements is not clear. Our objective was to evaluate the dietary and supplemental intakes of FA in a Canadian pregnancy cohort and to determine the proportions of pregnant women exceeding the Estimated Average Requirement (EAR) and Tolerable Upper Intake Level (UL). FACT (the Folic Acid Clinical Trial) was an international multicenter, randomized, double-blinded, placebo-controlled, phase III trial investigating FA for the prevention of pre-eclampsia in high-risk pregnancies. Participants were enrolled from Canadian sites at 8-16 weeks of gestation. Dietary and supplemental FA intake data were collected through participant interviews and FFQs at the time of FACT enrollment. Categorical data were summarized as n (%) and continuous data as median (IQR). This study included 1198 participants. Participants consumed 485μg dietary folate equivalents (DFE)/d (IQR: 370-630 μg DFE/d) from dietary sources of folate and FA. Through diet alone, 43.4% of participants consumed ≥520μg DFE/d, the EAR for pregnant individuals. Of the 91.9% of participants who consumed daily FA supplements, 0.4% consumed <400μgFA/d and 96.0% consumed ≥1000μg/d, the UL for FA. Median (IQR) total folate intake was 2167μg DFE/d (2032-2325 μg DFE/d); 95.3% of participants met or exceeded the EAR from all sources, but 1069 (89.2%) participants exceeded the UL. The majority of participants in this Canadian pregnancy cohort did not consume the recommended amount of folate from dietary sources. However, most prenatal supplements contained 1000μg FA, resulting in the majority of women exceeding the UL. With no additional benefit associated with FA intakes beyond the UL for most women, modification of prenatal supplement formulations may be warranted to ensure women meet but do not exceed recommended FA intakes.FACT was registered at clinicaltrials.gov as NCT01355159 and at isrctn.com as ISRCTN23781770.

Folate Intake Alters Mutation Frequency and Profiles in a Tissue- and Dose-Specific Manner in MutaMouse Male Mice

While cancer is common, its incidence varies widely by tissue. These differences are attributable to variable risk factors, such as environmental exposure, genetic inheritance, and lifetime number of stem cell divisions in a tissue. Folate deficiency is generally associated with increased risk for colorectal cancer (CRC) and acute lymphocytic leukemia (ALL). Conversely, high folic acid (FA) intake has also been associated with higher CRC risk. Our objective was to compare the effect of folate intake on mutant frequency (MF) and types of mutations in the colon and bone marrow of mice. Five-week-old MutaMouse male mice were fed a deficient (0mg FA/kg), control (2mg FA/kg), or supplemented (8mg FA/kg) diet for 20 wk. Tissue MF was assessed using the lacZ mutant assay and comparisons made by 2-factor ANOVA. LacZ mutant plaques were sequenced using next-generation sequencing, and diet-specific mutation profiles within each tissue were compared by Fisher's exact test. In the colon, the MF was 1.5-fold and 1.3-fold higher in mice fed the supplemented diet compared with mice fed the control (P=0.001) and deficient (P=0.008) diets, respectively. This contrasted with the bone marrow MF in the same mice where the MF was 1.7-fold and 1.6-fold higher in mice fed the deficient diet compared with mice fed the control (P=0.02) and supplemented (P=0.03) diets, respectively. Mutation profiles and signatures (mutation context) were tissue-specific. Our data indicate that dietary folate intake affects mutagenesis in a tissue- and dose-specific manner in mice. Mutation profiles were generally tissue- but not dose-specific, suggesting that altered cellular folate status appears to interact with endogenous mutagenic mechanisms in each tissue to create a permissive context in which specific mutation types accumulate. These data illuminate potential mechanisms underpinning differences in observed associations between folate intake/status and cancer.

Homocysteine and Gliotoxicity.

Homocysteine is a sulfur amino acid that does not occur in the diet, but it is an essential intermediate in normal mammalian metabolism of methionine. Hyperhomocysteinemia results from dietary intakes of Met, folate, and vitamin B12 and lifestyle or from the deficiency of specific enzymes, leading to tissue accumulation of this amino acid and/or its metabolites. Severe hyperhomocysteinemic patients can present neurological symptoms and structural brain abnormalities, of which the pathogenesis is poorly understood. Moreover, a possible link between homocysteine (mild hyperhomocysteinemia) and neurodegenerative/neuropsychiatric disorders has been suggested. In recent years, increasing evidence has emerged suggesting that astrocyte dysfunction is involved in the neurotoxicity of homocysteine and possibly associated with the physiopathology of hyperhomocysteinemia. This review addresses some of the findings obtained from in vivo and in vitro experimental models, indicating high homocysteine levels as an important neurotoxin determinant of the neuropathophysiology of brain damage. Recent data show that this amino acid impairs glutamate uptake, redox/mitochondrial homeostasis, inflammatory response, and cell signaling pathways. Therefore, the discussion of this review focuses on homocysteine-induced gliotoxicity, and its impacts in the brain functions. Through understanding the Hcy-induced gliotoxicity, novel preventive/therapeutic strategies might emerge for these diseases.

Epidemiology and (Patho)Physiology of Folic Acid Supplement Use in Obese Women before and during Pregnancy.

Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status, lifestyle, and medical conditions.

The effect of folate intake on ovarian cancer risk: A meta-analysis of observational studies.

Background:Previous publications studied the correction about folate intake and ovarian cancer risk, with inconsistent results. This meta-analysis aimed to explore the association between folate intake and ovarian cancer risk using the existing published articles.Method:We searched for relevant studies in electronic databases of PubMed, Web of Science, Embase, Cochrane, and Wanfang databases from inception to May 31, 2020. The overall relative risk (RR) and its 95% confidence intervals (95% CI) were pooled using a random-effect model.Results:A total of 12 articles with 6304 ovarian cancer cases were suitable for the inclusion criteria. The evaluated of the ovarian cancer risk with total folate intake and dietary folate intake were reported in 6 articles and 10 articles, respectively. Overall, highest category of dietary folate intake compared with lowest category had nonsignificant association on the risk of ovarian cancer (RR = 0.90, 95% CI = 0.77–1.06). The association was not significant between total folate intake and ovarian cancer risk (RR = 1.06, 95% CI = 0.89–1.27). The results in subgroup analyses by study design and geographic location were not changed either in dietary folate intake analysis or in total folate intake analysis.Conclusion:Our meta-analysis demonstrates that folate intake had no significant association on the risk of ovarian cancer. Study design and geographic location were not associated with ovarian cancer while some other related factors were not investigated due to the limited information provided in each included study. Therefore, further studies are needed to verify our results.

Gestational Folate and Offspring Bone Health; The Vitamin D in Pregnancy Study.

Maternal nutritional intake, such as folate and folic acid supplementation, during pregnancy may affect offspring bone health during childhood. We aimed to determine the associations between maternal dietary and supplementary folate intake and offspring bone health measures, including fracture risk. Data were obtained from 160 of 475 mother-child pairs who had returned for the 11-year follow up of the Vitamin D in Pregnancy Study, an observational cohort study. Incident fractures were ascertained from radiological records and dual X-ray absorptiometry was used to measure bone mineral density and content at 11years of age. Maternal dietary folate intake during pregnancy was determined by Food Frequency Questionnaire and folate supplementation was determined through self-report. Both measures were undertaken at recruitment (before 16weeks gestation) and at 28-32weeks' gestation. Multivariable linear regression models and Cox regression models were used to examine associations. Results are presented as per 1000µg folate for dietary measures. There were significant associations between maternal folate supplementation in early pregnancy (< 16weeks gestation) and offspring spine bone mineral content (BMC) (β = 1.53, 95% CI 0.21, 2.86), spine area (β = 1.10, 95% CI 0.37, 1.82) and total body less head area (β = 329.30, 95% CI 3.50, 55.20) at the 11-year follow-up. The association between spine BMC was attenuated after adjustment for bone size (β = 0.13 95% CI - 0.85, 1.10). There was no association between maternal folate supplementation at 28-32weeks' or maternal dietary intake at either time point with any offspring bone outcome. These data suggest that folate supplementation in early pregnancy may be associated with offspring bone size, but not other bone measures.