Plasma Folate Research Articles

Studying the mechanism of sperm DNA damage caused by folate deficiency.

Sperm DNA injury is one of the common causes of male infertility. Folic acid deficiency would increase the methylation level of the important genes, including those involved in DNA double‐strand break (DSB) repair pathway. In the early stages, we analysed the correlation between seminal plasma folic acid concentration and semen parameters in 157 infertility patients and 91 sperm donor volunteers, and found that there was a significant negative correlation between seminal folic acid concentration and sperm DNA Fragmentation Index (DFI; r = −0.495, p < 0.01). Then through reduced representation bisulphite sequencing, global DNA methylation of sperm of patients in the low folic acid group and the high folic acid group was analysed, it was found that the methylation level in Rad54 promoter region increased in the folic acid deficiency group compared with the normal folic acid group. Meanwhile, the results of animal model and spermatocyte line (GC‐2) also found that folic acid deficiency can increase the methylation level in Rad54 promoter region, increased sperm DFI in mice, increased the expression of γ‐H2AX, that is, DNA injury marker protein, and increased sensitivity of GC‐2 to external damage and stimulation. The study indicates that the expression of Rad54 is downregulated by folic acid deficiency via DNA methylation. This may be one of the mechanisms of sperm DNA damage caused by folate deficiency.

Homocysteine, Folic Acid, Cyanocobalamin, and Frailty in Older People: Findings From the "Invece. Ab" Study.

Frailty is an important age-related syndrome associated with several adverse health outcomes. Its biological basis is undefined. Raised plasma homocysteine (HOcy) is an established risk factor for cardiovascular disease, dementia, cognitive impairment, and mortality, but little is known about the possible role of plasma HOcy, cyanocobalamin (B12), and folate (FO levels in the development of frailty. Our first aim was to explore the possible association between frailty and plasma concentrations of HOcy, FO, and B12 in a cohort of community-dwelling older people. The second was to assess the influence of these metabolic factors on six-year incidence of frailty in the 875 individuals eligible for inclusion in this study (those with a full follow-up dataset). This research is based on data from three waves – 2012 (herein taken as baseline), 2014, and 2018 – of a longitudinal study (InveCe.Ab) in which non-frail men and women born between 1935 and 1939 underwent multidimensional assessments. Frailty was estimated using a deficit accumulation-based frailty index (FI). HOcy concentration was significantly positively correlated with FI at all timepoints, while B12 and FO levels were not. Plasma concentration of HOcy emerged as a predictor of six-year cumulative incidence of frailty, independent of age, sex, and education, while B12 and FO levels showed no relationship with frailty incidence. Individuals with plasma HOcy in the top quintile showed five months less frailty-free survival (HR 1.487; 95% CI: 1.063–2.078), regardless of age, sex, and education. These results demonstrate that higher HOcy is a risk factor for frailty onset in older adults.

Evaluation of the Effectiveness of Personalized Treatment of Trace Element and Vitamin Status in Men with Initial Stages of Androgenic Alopecia Treated with Conservative Therapy

Background. Androgenic alopecia (AGA) is the most common form of pathological hair loss with multiple micronutrient disorders involvedin its occurrence and development.&#x0D; Aimto evaluatethe effectiveness of personalized treatment of micronutrient deficiencies in patients with early stages of AGA and conservative therapy using a vasodilator drug minoxidil based on evidence-based medicine.&#x0D; Methods. A total 48 patients with stages IIV of AGA (according to the NorwoodHamilton scale) were recruited to experimental prospective clinical study evaluating the effectiveness of pharmaceutical forms of trace elements and vitamins. The primary diagnosis of micronutrient deficiency was carried out by comparing laboratory parameters of patients with AGA and 25 healthy volunteers. After that, conservative treatment with 5% topical minoxidilin AGA patients was enriched with 2-month personalized systemic supplementation of pharmaceutical forms of trace elements and vitamins. At the end of the study, the correspondence between changes in trace elements and vitamins content in the plasma and the trichogram parameters before and after conservative therapy was assessed.&#x0D; Results. The majority (96%) of the examined patients with AGA were characterized by mono- or polynutrient deficiencies. Personalized correction made it possible to restore the content of Se, Mg, Fe and vitamin E to the baseline levels and to achieve a significant increase in Zn, vitamin D and folic acid plasma content. The relationship between changes in the level of micronutrients and trichogram parameters was recorded only for Se (decrease in anagen hairs: r = 0.43; p = 0.037; decrease in hair density: r = 0.45; p = 0.028) and folic acid (an increase in anagen hairs: r = 0.41; p = 0.024); the positive effect of vitamin E on hair density was also detected.&#x0D; Conclusion. The results of the study allow to recommend a personalized treatment of folic acid and vitamin E deficiencies, with possible refusal to use the Se-containing drugs in conservative therapy of patients with the early stages of AGA.

Low vitamin B12 but not folate is associated with incident depressive symptoms in community-dwelling older adults: a 4-year longitudinal study.

This was a longitudinal study utilising the Irish Longitudinal Study on Ageing (n 3849 aged ≥ 50 years) and investigated the relationship between blood plasma folate and B12 levels at baseline (wave 1) and incident depressive symptoms at 2 and 4 years (waves 2 and 3). A score ≥ 9 on the Center for Epidemiological Studies Depression Scale-8 at wave 2 or 3 was indicative of incident depressive symptoms. B12 status profiles (pmol/l) were defined as < 185, deficient low; 185 to < 258, low normal; > 258-601, normal and > 601 high. Folate status profiles (nmol/l) were defined as ≤ 10·0, deficient low; > 10-23·0, low normal; > 23·0-45·0, normal; >45·0, high. Logistic regression models were used to analyse the longitudinal associations. Both B12 and folate plasma concentrations were lower in the group with incident depressive symptoms v. non-depressed (folate: 21·4 v. 25·1 nmol/l; P = 0·0003; B12:315·7 v. 335·9 pmol/l; P = 0·0148). Regression models demonstrated that participants with deficient-low B12 status at baseline had a significantly higher likelihood of incident depression 4 years later (OR 1·51, 95 % CI 1·01, 2·27, P = 0·043). This finding remained robust after controlling for relevant covariates. No associations of folate status with incident depression were observed. Older adults with deficient-low B12 status had a 51 % increased likelihood of developing depressive symptoms over 4 years. The findings highlight the need to further explore the low-cost benefits of optimising vitamin B12 status for depression in older adults.

Impact of In Utero Folate Exposure on DNA Methylation and Its Potential Relevance for Later-Life Health-Evidence from Mouse Models Translated to Human Cohorts.

Persistent DNA methylation changes may mediate effects of early-life exposures on later-life health. Human lifespan is challenging for prospective studies, therefore data from longitudinal studies are limited. Projecting data from mouse models of early-life exposure to human studies offers a tool to address this challenge. C57BL/6J mice were fed low/normal folate diets before and during pregnancy and lactation. Genome-wide promoter methylation was measured in male offspring livers at 17.5 days gestation and 28 weeks. Eight promoters were concurrently hypermethylated by folate depletion in fetuses and adults (>1.10 fold-change; p < 0.05). Processes/pathways potentially influenced by global changes, and function of these eight genes, suggest neurocognitive effects. Human observational and randomized controlled trial data were interrogated for translation. Methylation at birth was inversely associated with maternal plasma folate in six genes (-1.15% to -0.16% per nmol L-1 ; p < 0.05), while maternal folic acid supplementation was associated with differential methylation of four genes in adulthood. Three CpGs were persistently hypermethylated with lower maternal folate (p = 0.04). Some persistent folate-induced methylation changes in mice are mirrored in humans. This demonstrates utility of mouse data in identifying human loci for interrogation as biomarkers of later-life health.

Inositol and folates in the restoration of reproductive function in women and prevention of congenital malformations

In recent years, Ukraine has seen a significant deterioration in the reproductive health of women in the face of declining birth rates. One of the main causes of comorbidity of infertility and background pathologies is the insufficient supply of a woman's body in the pre-pregnancy period with micronutrients – folate, vitamins, myo-inositol and others. This increases the risk of complications during pregnancy and childbirth and congenital malformations.Literature analysis showed that myo-inositol in combination with folate are an extremely important way to prevent fertility disorders, complications of pregnancy and childbirth, congenital malformations and support the reproductive health of the next generation. Myo-inositol in combination with folic acid promotes the effects of luteinizing and follicle-stimulating hormones, normalization of ovarian function, oocyte quality, trophoblast invasion during blastocyst attachment, prevention of congenital malformations by neutralizing the action of homocysteine with metafolin in the pregravid period and during pregnancy and assisted reproductive technologies, reducing the incidence of miscarriage, preeclampsia and other complications. The neuroprotective effect of myo-inositol indicates the importance of its use for fetal neuroprotection in late gestation, especially in hypoxia.Fertifolin, which contains an improved combination of natural nutrients as myo-inositol 1000 mg and folic acid 100 µg in the form of metafolin (calcium L-methylfolate), successfully copes with this goal. Metafolin has greater bioavailability and more actively helps to increase the level of folate in blood plasma, in contrast to folic acid. Metafolin is characterized by fewer drug interactions and less often masks the symptoms of B12-deficient anemia, reduces the risk of anemia, placental dysfunction, malformations of the neural tube. Fertifolin is also effectively used as an adjunct in polycystic ovary syndrome and in assisted reproductive technology protocols.

Plasma Vitamin B12 and Folate Alter the Association of Blood Lead and Cadmium and Total Urinary Arsenic Levels with Chronic Kidney Disease in a Taiwanese Population.

Heavy metals causing chronic nephrotoxicity may play a key role in the pathogenesis of chronic kidney disease (CKD). This study hypothesized that plasma folate and vitamin B12 would modify the association of CKD with total urinary arsenic and blood lead and cadmium levels. We recruited 220 patients with CKD who had an estimated glomerular filtration rate of <60 mL/min/1.73 m2 for ≥3 consecutive months and 438 sex- and age-matched controls. We performed inductively coupled plasma mass spectrometry to measure blood cadmium and lead levels. The urinary arsenic level was determined using a high-performance liquid chromatography–hydride generator–atomic absorption spectrometry. Plasma vitamin B12 and folate levels were measured through the SimulTRAC-SNB radioassay. Compared with patients with plasma vitamin B12 ≤ 6.27 pg/mL, the odds ratio (OR) and 95% confidence interval of CKD for patients with plasma vitamin B12 > 9.54 pg/mL was 2.02 (1.15–3.55). However, no association was observed between plasma folate concentration and CKD. A high level of plasma vitamin B12 combined with high levels of blood lead and cadmium level and total urinary arsenic tended to increase the OR of CKD in a dose-response manner, but the interactions were nonsignificant. This is the first study to demonstrate that patients with high plasma vitamin B12 level exhibit increased OR of CKD related to high levels of blood cadmium and lead and total urinary arsenic.

Provision of folic acid for reducing arsenic toxicity in arsenic-exposed children and adults.

Provision of folic acid for reducing arsenic toxicity in arsenic-exposed children and adults.

Maternal One-Carbon Metabolism during the Periconceptional Period and Human Foetal Brain Growth: A Systematic Review.

The maternal environment during the periconceptional period influences foetal growth and development, in part, via epigenetic mechanisms moderated by one-carbon metabolic pathways. During embryonic development, one-carbon metabolism is involved in brain development and neural programming. Derangements in one-carbon metabolism increase (i) the short-term risk of embryonic neural tube-related defects and (ii) long-term childhood behaviour, cognition, and autism spectrum disorders. Here we investigate the association between maternal one-carbon metabolism and foetal and neonatal brain growth and development. Database searching resulted in 26 articles eligible for inclusion. Maternal vitamin B6, vitamin B12, homocysteine, and choline were not associated with foetal and/or neonatal head growth. First-trimester maternal plasma folate within the normal range (>17 nmol/L) associated with increased foetal head size and head growth, and high erythrocyte folate (1538–1813 nmol/L) with increased cerebellar growth, whereas folate deficiency (<7 nmol/L) associated with a reduced foetal brain volume. Preconceptional folic acid supplement use and specific dietary patterns (associated with increased B vitamins and low homocysteine) increased foetal head size. Although early pregnancy maternal folate appears to be the most independent predictor of foetal brain growth, there is insufficient data to confirm the link between maternal folate and offspring risks for neurodevelopmental diseases.

Consumption of a Recommended Serving of Wheat Bran Cereals Significantly Increases Human Faecal Butyrate Levels in Healthy Volunteers and Reduces Markers of Inflammation Ex Vivo

Wheat bran cereals are an important source of dietary fibre. The aim of the study was to investigate if a high intake (120 g) of fibre rich breakfast cereal (which delivers the UK Government guidelines for fibre intake in one serving but is three-fold higher than the manufacturers recommended serving) has additional potential health benefits compared to the recommended serving (40 g, containing 11 g of dietary fibre). To assess this, the study determined the short chain fatty acid (SCFA) profiles in human faecal, urine and plasma samples after consumption of two different servings of fibre-rich cereal. Inhibition of prostanoid production was measured (ex vivo) in human colonic fibroblast cells after cytokine (IL-1β) inflammation stimulation. Eight healthy volunteers, 18-55 years old; BMI (18-30 kg/m2) consumed the wheat bran-rich “ready to eat cereal”, at both the high (120 g) serving and recommended (40 g) serving. Faecal, urine and plasma samples were collected at baseline, throughout the five-hour intervention period and approximately 24 hours following consumption. Faecal butyrate showed the largest increase (p&lt;0.05) of more than a two-fold change following the consumption of the recommended serving of wheat bran cereal (from 13.95 ± 9.17 to 31.63 ± 20.53 mM) and no significant change following the higher serving (from 21.96 ± 11.03 to 22.9 ± 12.69 mM). ANOVA analysis also found a weak serving effect (p = 0.046) of the portion size (high vs. recommended) only for butyrate in urine 24 hours after consumption of the bran cereal. The physiological nutritionally relevant concentrations of faecal SCFAs, as determined in the volunteers’ faecal samples showed significant anti-inflammatory activity or the individual faecal SCFAs; acetate (p&lt;0.001), propionate (p&lt;0.001) and butyrate (p&lt;0.01), as well as in combination. Plasma folate was also increased after consumption of both wheat bran servings and was significant (p = 0.037) at the three-hour time point following consumption of the high wheat bran serving. The consumption of the recommended serving (40 g) of wheat bran cereal increased the total microbial SCFAs levels (from 96.88 to 136.96 mM) compared to the higher serving (120 g) (from 110.5 to 117.64 mM) suggesting that the intake of the higher portion size is likely to promote a faecal bulking effect and thereby decrease colonic SCFA levels. These data indicate that consumption of the recommended serving of wheat bran cereal serving would therefore be sufficient to promote microbial butyrate formation, reduce colonic inflammation and increase plasma folate levels in humans.

287 Effects of a Novel Rumen-protected Folic Acid Supplement on Feedlot Performance and Carcass Characteristics of Beef Steers

Abstract To assess effects of a novel rumen-protected folic acid (RPFA) supplement, 180 Angus-cross steers (292 ± 18 kg) were blocked by body weight to pens and randomly assigned to dietary treatments (n = 6 pens/treatment): target intake of 0 (CON), 30 (RPFA-30), 60 (RPFA-60), 90 (RPFA-90), 120 (RPFA-120), or 150 (RPFA-150) mg RPFA·steer-1·d-1. Steers were weighed on d -1, 0, 55, 56 (end of growing), 86, 87, 181, and 182. Liver and blood were collected (two steers/pen) before trial initiation and at the end of growing and finishing. Data were analyzed as a randomized complete block design using ProcMixed of SAS (fixed effects of treatment and block; experimental unit of pen). Liver abscess scores were analyzed using ProcGenmod of SAS. Contrast statements evaluated polynomial effects of RPFA and compared CON vs. RPFA-30. At end of growing, RPFA linearly increased plasma folic acid (P &amp;lt; 0.01) and linearly decreased plasma glucose (P = 0.01). Liver folic acid concentrations at end of growing were greatest for CON, RPFA-90, and RPFA-120 (cubic P = 0.01), and growing period (d 0 to 56) average daily gain and gain:feed were greatest for CON and RPFA-120 (cubic P ≤ 0.03). At end of finishing, RPFA linearly increased plasma folic acid concentrations (P &amp;lt; 0.01), and liver folic acid concentrations were lesser for CON vs. RPFA-30 (P = 0.04). Severe liver abscess percentage tended to be greater for CON vs. RPFA-30 (P = 0.09), while dressing percent was lesser for CON vs. RPFA-30 (P = 0.04). Overall (d 0 to 182) carcass-adjusted gain:feed tended to be greater for CON vs. RPFA-30 (P = 0.09). Although RPFA increased plasma folic acid concentrations throughout the study, feedlot performance was not improved, possibly due to low vitamin B12 status (plasma &amp;lt; 200 pg/mL) of steers, regardless of treatment.

Interaction of maternal asthma history and plasma folate levels on child asthma risk in the Boston Birth Cohort.

Previous studies on maternal folate status during pregnancy and child asthma risk yielded mixed results, and few considered maternal asthma history, a known risk factor of childhood asthma. This study examined whether the role of maternal folate in childhood asthma differs by maternal asthma history and whether there is an interaction between the two factors. This study included 1948 mother-child dyads from the Boston Birth Cohort. Childhood asthma was defined based on physician diagnosis documented in electronic medical records, and maternal asthma was based on standard questionnaire interview. Maternal plasma folate level within a few days of delivery was measured by chemiluminescent immunoassay. Logistic regression models were applied to examine individual and joint associations of maternal asthma history and plasma folate level with childhood asthma, adjusting for other covariables. When stratified by maternal asthma history, an L-shaped relationship between maternal folate level and child asthma was observed in children born to mothers with asthma history (pinteraction = 0.03). The highest risk was found in children having maternal asthma history and low maternal folate level (odds ratio = 5.93; 95% confidence interval: 2.86-12.3) compared with children without maternal asthma history and with sufficient maternal folate levels. Sensitivity analyses using different definitions of asthma and stratified by major covariables yielded similar findings. In this US prospective high-risk birth cohort, maternal asthma history and low folate level interactively increased the risk of child asthma. If further confirmed, optimizing maternal folate levels during pregnancy may mitigate child asthma risk in the setting of maternal asthma history.

Interpretation of Folate Results in Hemolytic Plasma Samples: A Practical Approach.

Folate analysis in plasma is affected by hemolysis, which can lead to biased results. However, the degree of hemolysis that is considered acceptable is unclear. We explored the relationship between folate concentration and degree of hemolysis. Heparin plasma samples (N=77, hemolysis index ≤10 μmol/L) were spiked with increasing amounts of corresponding patient-specific hemolysate. Subsequently, the folate concentration and hemolysis index were measured using two Roche Cobas platforms, and their incremental relationship was investigated. The folate concentration ranged from 2.9 to 30.9 nmol/L with a median (interquartile range) of 11.4 (8.6-19.1) nmol/L. The linear relationship between the increments in folate concentration and hemolysis index was approximated by the function y=1.86x+1.56 (R2=0.996), where x represents the laboratory-specific critical difference in folate concentration, which can be calculated from the analytical variation of the employed folate assay(s), and y represents the hemolysis threshold. The hemolysis threshold did not significantly differ between the tertiles of plasma folate concentration (P=0.10). In conclusion, we have provided an evidence-based approach that can be used to reliably interpret folate concentrations in hemolytic samples, independent of the patient’s folate status.

Effects of Folate and Vitamin B12 Nutritional Status on Cognitive Function in Bangladeshi Adolescents

BACKGROUND AND AIM: Deficiencies in folate and vitamin B12 are widespread in Bangladesh. These micronutrients are essential for the synthesis of neurotransmitters and myelin, and for one-carbon metabolism, which supports synthesis of proteins and nucleotides during periods of rapid growth. Micronutrient deficiency has been associated with poorer cognitive function in adults and children, but this association has not been fully characterized in adolescents. This study aims to examine associations between the predictors of red blood cell (RBC) folate, plasma folate, and plasma B12, and the outcome of cognitive function in Bangladeshi adolescents. METHODS: The Metals, Arsenic, & Nutrition in Adolescents Study (MANAS) is a cross-sectional study of 572 Bangladeshi adolescents aged 14-16 years. Venous blood was collected for measurement of RBC folate, plasma folate, and plasma B12. Participants completed the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) and an abbreviated Cambridge Neuropsychological Test Automated Battery (CANTAB), with subtests assessing cognitive function. Linear models were employed to assess associations. RESULTS:For CANTAB outcome measures, positive associations were observed between plasma folate and Spatial Recognition Memory (SRM) (β=1.32, p0.05), and between B12 and Spatial Working Memory (SWM) (β=2.10, p0.05). No significant associations were observed between folate and B12 nutritional predictors and the WISC-IV outcome measures. CONCLUSIONS:The positive associations between folate and SRM and between B12 and SWM are consistent with previous findings linking folate and B12 deficiencies to memory deficits. Mild SRM impairments may include difficulty noticing that an object has been moved, whereas mild SWM impairments might include difficulty recalling where an object was placed. This research suggests that further investigation into the associations between folate and B12 nutritional status and measures of cognitive function in adolescents is needed. Additionally, these findings suggest that nutritional interventions involving B12 and folate supplementation may have a positive impact on overall adolescent health and cognition. KEYWORDS: Micronutrient deficiencies, Cognitive function, Neurotoxicology, Adolescent cognitive neurotoxicology, Folate and B12 deficiency, Nutritional status

Vitamin B12, folate and homocysteine concentrations during pregnancy and early signs of atherosclerosis at school-age

SummaryBackground & aimsSuboptimal circulating vitamin B12, folate and homocysteine concentrations during fetal life seem to be associated with cardiometabolic health at school-age. We examined whether fetal exposure to lower circulating vitamin B12 and folate concentrations and higher circulating homocysteine concentrations is also associated with early signs of atherosclerosis at school-age.MethodsThis study among 3826 school-age children and their mothers was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We examined the associations of early-pregnancy and cord blood serum total and active B12 and plasma folate and homocysteine concentrations with common carotid artery intima-media thickness and distensibility in the children aged ten years.ResultsAs compared to normal early-pregnancy serum total B12 concentrations (≥145 pmol/L), low serum total B12 concentrations (<145 pmol/L) were associated with higher carotid intima-media thickness in the children at school-age (difference 0.09 standard deviations score (SDS); 95% confidence interval (CI): 0.01, 0.16). As compared to normal early-pregnancy plasma folate concentrations (≥8 nmol/L), low plasma folate concentrations (<8 nmol/L) were associated with lower carotid disten-sibility in the children at school-age (difference −0.16 SDS; 95% CI: −0.28, −0.04). Early-pregnancy circulating total and active B12, folate and homocysteine concentrations measured continuously were not associated with carotid intima-media thickness or carotid distensibility in the children at school-age. One SDS higher plasma homocysteine concentrations measured in cord blood at birth was associated with a −0.05 SDS (95% CI: −0.09, −0.02) lower carotid distensibility at school-age. Cord blood total and active B12 and folate concentrations were not associated with carotid intima-media thickness or carotid distensibility at school-age.ConclusionsCirculating total B12, folate and homocysteine concentrations during fetal life seem to be associated with markers of subclinical atherosclerosis at school-age. Further studies need to examine the causality and mechanisms underlying these associations.

Predicted Effects and Cost-Effectiveness of Wheat Flour Fortification for Reducing Micronutrient Deficiencies, Maternal Anemia, and Neural Tube Defects in Yaoundé and Douala, Cameroon.

Policy makers aiming to reduce micronutrient deficiencies (MNDs) and their health effects must choose among alternative definitions of impact when evaluating cost-effectiveness. Estimate the cost-effectiveness of a mandatory wheat flour fortification program for reducing cases of MNDs (iron, zinc, folate, vitamin B12), anemia and neural tube defects (NTDs) averted, and disability-adjusted life years (DALYs) averted in urban Cameroon. A 13-year predictive model was developed, including a 3-year start-up period and 10 years of program activity. Costs were estimated using historical program budgets. Effects were calculated based on observed changes in prevalence of MND and anemia 1 year postfortification and predicted reductions in NTDs based on NTD burden and wheat flour intake. Total DALYs averted were estimated for anemia and NTDs. The program cost ∼$2.4 million over 13 years and averted an estimated ∼95 000 cases of maternal anemia and ∼83 500 cases of iron deficiency among children after 1 year. Cost/case-year averted for MNDs ranged from $0.50 for low plasma folate to $3.30 for iron deficiency and was $2.20 for maternal anemia. The program was predicted to avert 1600 cases of NTDs over 10 years at ∼$1500 per case averted. Estimated cost/DALY averted was $50 for NTDs and $115 for anemia. In Cameroon, cost-effectiveness of wheat flour fortification varied by the measure of impact employed, but was classified as "very cost-effective" for all outcomes using World Health Organization criteria. Policy makers and their advisors must determine how best to use information on program costs and benefits to inform their decisions.

Effect of dietary supplementation of 2 forms of a B vitamin and choline blend on the performance of Holstein calves during the transition and postweaning phase

The transition from a liquid- to a solid-based diet involves several adaptations in calves. Development of ruminal function is likely to alter B vitamin and choline supply, although little is known about the extent of these changes relative to the calf's requirements and consequences for the calf around weaning. Moreover, literature data are equivocal concerning the need to supplement B vitamins and choline through weaning and transition phase of the dairy calf. To evaluate the effect of increasing B vitamin and choline supply on performance, 61 Holstein calves were individually housed and raised from birth to 13 wk of age. Calves were fed milk replacer (28% crude protein, 15% fat) up to 1.6 kg of dry matter (DM)/d at 15% solids (3 times/d) from birth to 4 wk of age. At that time, calves were randomly assigned to one of 3 treatments: a rumen-protected blend of B vitamins and choline (RPBV); a 30:70 mix of a nonprotected blend of B vitamins and choline and fat (UPBV); or fat only, used as control (CTRL). Calves were maintained on milk replacer and offered ad libitum quantities of a starter grain (25.5% crude protein) specifically formulated to supply all essential amino acids with no added B vitamins or choline. The supplements were provided in gel capsules and administered once a day to each calf in quantities corresponding to 0.39 and 0.28% of the previous day's starter DM intake for the vitamin blends and control, respectively. Calves were weaned gradually from d 49 to 63. Body weight and stature were measured, and blood was collected and analyzed for hematocrit, plasma urea nitrogen, β-hydroxybutyrate, folates, and vitamin B12. Body weight and stature were similar among treatments. Overall gain (0.99 kg/d), DM intake (1.90 kg of DM/d), and feed efficiency (0.52) were not affected by vitamin supplementation. Plasma vitamin B12 concentrations were not different between RPBV and UPBV but tended to be higher at the end of weaning and were greater postweaning in RPBV and UPBV treatments compared with CTRL. Both forms of the vitamin blend effectively improved vitamin B12 status postweaning with no effect on folate status. No differences were observed in other blood measurements. Under conditions of this study, additional B vitamins and choline did not improve calf performance before, during, or after weaning.

Ischemia-Reperfusion Injury Reduces Kidney Folate Transporter Expression and Plasma Folate Levels.

Acute or chronic kidney disease can cause micronutrient deficiency. Patients with end-stage renal disease, kidney transplantation or on dialysis have reduced circulating levels of folate, an essential B vitamin. However, the molecular mechanism is not well understood. Reabsorption of folate in renal proximal tubules through folate transporters is an important process to prevent urinary loss of folate. The present study investigated the impact of acute kidney injury (AKI) on folate transporter expression and the underlying mechanism. AKI was induced in Sprague-Dawley rats that were subjected to kidney ischemia (45 min)-reperfusion (24 h). Both male and female rats displayed kidney injury and low plasma folate levels compared with sham-operated rats. The plasma folate levels were inversely correlated to plasma creatinine levels. There was a significant increase in neutrophil gelatinase-associated lipocalin (NGAL) and IL-6 mRNA expression in the kidneys of rats with ischemia-reperfusion, indicating kidney injury and increased inflammatory cytokine expression. Ischemia-reperfusion decreased mRNA and protein expression of folate transporters including folate receptor 1 (FOLR1) and reduced folate carrier (RFC); and inhibited transcription factor Sp1/DNA binding activity in the kidneys. Simulated ischemia-reperfusion through hypoxia-reoxygenation or Sp1 siRNA transfection in human proximal tubular cells inhibited folate transporter expression and reduced intracellular folate levels. These results suggest that ischemia-reperfusion injury downregulates renal folate transporter expression and decreases folate uptake by tubular cells, which may contribute to low folate status in AKI. In conclusion, ischemia-reperfusion injury can downregulate Sp1 mediated-folate transporter expression in tubular cells, which may reduce folate reabsorption and lead to low folate status.

Ancestry-Specific Interactions Between Circulatory Folate and One-Carbon Metabolism Genes’ Haplotypes for Higher-Grade Cervical Intraepithelial Neoplasia

Abstract Objectives Determine ancestry-specific interactions between circulatory folate concentrations, haplotypes of the one-carbon (1C) pathway genes and risk of higher-grade cervical intraepithelial neoplasia (CIN2+) in the US post-folic acid fortification era. Methods Study included self-reported African American and Caucasian American women positive for high-risk human papillomavirus (HPV) genotypes and diagnosed with ≤ CIN1 (non-cases, n = 340) or CIN2+ (cases, n = 337). Plasma and red blood cell (RBC) folate, vitamins B12 (B12) and C, and total carotene levels were measured. 660 single nucleotide polymorphisms of the 1C pathway genes and 104 ancestry informative markers (AIMs) were analyzed using buffy coat DNA and customizable Illumina GoldenGate arrays. Global African ancestry (GA) was estimated using the AIMs. Ancestry-based African American (AFR) had GA ≥ 0.8 and European Americans (EA) otherwise. Common haplotype blocks (n = 50) were tested for interactions with circulatory folate using logistic regression adjusting for age, education, body mass index (BMI), body fat %, smoking, parity, hormonal contraception use, plasma total carotene, B12 and C. False discovery rate &amp;lt; 0.1 was considered significant. Results Some of the main findings were, increasing plasma folate (1 SD) decreases the risk of CIN2 + when homozygous for haplotype CG at (rs575425, rs586199) of BHMT gene in EA (odds ratio/OR = 0.13, CI = 0.04,0.44), and for haplotype TA at (rs559062, rs515064) of CTH in AFR (OR = 0.23, CI = 0.1,0.52); increasing RBC folate (1 SD) decreases risk of CIN2 + when homozygous for haplotypes TA at (rs559062, rs515064) of CTH (OR = 0.27, CI = 0.12,0.61), AC at (rs7706298, rs10512934) of MTRR (OR = 0.21, CI = 0.08,0.57), and AGA at (rs11672909, rs759920, rs7253062) of DNMT1 (OR = 0.4, CI = 0.18,0.90) in AFR; and increasing RBC folate (1 SD) increases the risk of CIN2 + when homozygous for haplotypes GG at (rs3856027, rs4650051) of CTH gene (OR = 3.52, CI = 1.27,9.71), and CGG at (rs11672909, rs759920, rs7253062) of DNMT1 (OR = 5.70, CI = 1.86,17.49) in AFR. Conclusions Circulatory folate differentially modulates the risk for CIN2 + by interacting with haplotypes of the 1C pathway genes according to ancestry in reproductive-aged women exposed to US folic acid fortification program. Funding Sources National Cancer Institute

Folate Transporters Are Found Throughout the Colon of Humans and Their mRNA Expression Appears to Be Unaffected by Low Dose Folic Acid Supplementation

ObjectivesA large depot of folate resides in the colon and can exceed dietary intake. Little is known about the capacity of the colon to absorb folate. We aimed to determine the expression of key folate transporters, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT), throughout the colon of healthy adults and the impact of low dose folic acid (FA) supplementation. MethodsIn this 16 wk open-labelled randomized control trial, healthy adults (n = 25) from a colonoscopy waiting list were randomized to receive daily a multivitamin plus a 400 μg FA (400FA, n = 12) or no FA supplement (0FA, n = 13). Subjects were provided with low FA bread and pasta and instructions how to follow a low FA containing diet. Six 24-hr diet recalls were administered throughout the study and blood samples were collected at baseline, 8 and 16 wk. At colonoscopy (16 wk), 4 tissue biopsies were collected from the terminal ileum, cecum, ascending and descending colon. Blood folates were determined by microbial assay; mRNA levels of folate transporters were assessed using qPCR. ResultsOne subject was removed from analysis due to missing data (0FA). No group differences in age, sex, BMI, dietary intake, vitamin B12, red blood cell (RBC) and plasma folate levels at baseline were observed. Mean ± SD FA supplement adherence was 92 ± 12% and 96 ± 9% at 8 and 16 wk, respectively. Subjects in the 400FA group had higher total folate intake (P < 0.05) and higher RBC and plasma folate levels (P < 0.01) at 8 and 16 wk compared to 0FA subjects. RBC values at 16 wk were 1764 ± 636 and 865 ± 190 nmol/L in the 400FA and 0FA group, respectively. RFC and PCFT were detected in terminal ileum and colon biopsies (n = 96) and their mRNA levels in each section did not differ between groups. However, expression of RFC was markedly higher than PCFT across all biopsy sections (P < 0.05) and highest in the terminal ileum, compared to the cecum, ascending and descending colon in both groups (P < 0.05). ConclusionsWe demonstrated expression of folate transporters, RFC and PCFT, throughout the human colon suggesting their potential contribution to overall folate absorption. mRNA expressions were not affected by a low dose FA supplement. A deeper understanding of how FA and folate status affect colonic transporter regulation may inform future revisions of folate intake recommendations. Funding SourcesNatural Sciences and Engineering Research Council.