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Toxicity of di(2-ethylhexyl)phthalate (DEHP) and di(2-ethylhexyl)adipate (DEHA) under conditions of renal dysfunction induced with folic acid in rats: enhancement of male reproductive toxicity of DEHP is associated with an increase of the mono-derivative.

F344 male rats were given five consecutive weekly subcutaneous injections of folic acid for induction of chronic renal dysfunction and then di(2-ethylhexyl)phthalate (DEHP) or di(2-ethylhexyl)adipate (DEHA) in the diet at a concentration of 0, 6000 or 25,000 ppm for 4 weeks in order to investigate whether male reproductive toxicity of the two chemicals might be enhanced under conditions of renal disease. Control animals also received DEHP or DEHA in the same manner but without folic acid pretreatment. Decreased testicular weights, seminiferous atrophy with vacuolization of sertoli cells and diminished sperm counts were more prominent in rats given folic acid and then 25,000 ppm DEHP as compared to those exposed to DEHP alone. No such reproductive toxicity was evident in rats given 6000 ppm DEHP or either dose of DEHA. An increased concentration of the mono-derivative of DEHP (mono(2-ethylhexyl)phthalate, MEHP) in the blood, testis and urine was considered relevant to the enhanced reproductive toxicity observed with DEHP.

Adipates↗

Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring.

Environmental constraints during early life result in phenotypic changes that can be associated with increased disease risk in later life. This suggests persistent alteration of gene transcription. DNA methylation, which is largely established in utero, provides a causal mechanism by which unbalanced prenatal nutrition results in such altered gene expression. We investigated the effect of unbalanced maternal nutrition on the methylation status and expression of the glucocorticoid receptor (GR) and peroxisomal proliferator-activated receptor (PPAR) genes in rat offspring after weaning. Dams were fed a control protein (C; 180 g/kg protein plus 1 mg/kg folic acid), restricted protein (R; 90 g/kg casein plus 1 mg/kg folic acid), or restricted protein plus 5 mg/kg folic acid (RF) diet throughout pregnancy. Pups were killed 6 d after weaning (n = 10 per group). Gene methylation was determined by methylation-sensitive PCR and mRNA expression by semiquantitative RT-PCR. PPARalpha gene methylation was 20.6% lower (P < 0.001) and expression 10.5-fold higher in R compared with C pups. GR gene methylation was 22.8% lower (P < 0.05) and expression 200% higher (P < 0.01) in R pups than in C pups. The RF diet prevented these changes. PPARgamma methylation status and expression did not differ among the groups. Acyl-CoA oxidase expression followed that of PPARalpha. These results show that unbalanced prenatal nutrition induces persistent, gene-specific epigenetic changes that alter mRNA expression. Epigenetic regulation of gene transcription provides a strong candidate mechanism for fetal programming.

Acyl-CoA Oxidase↗

Folic acid and phenytoin induced gingival overgrowth--is there a preventive effect.

The role of folic acid (5mg/day) in combination with oral hygiene measures (group II) vis-a-vis oral hygiene measures alone (group I) in prevention of phenytoin-induced gingival overgrowth was investigated in a one-year follow-up study on sixty, 8-13-year-old epileptic children receiving phenytoin. The allocation of the children to the two groups was done alternately. In these children, at baseline, plaque (Silness & Löe), gingivitis (Löe & Silness) and probing depths of gingival sulcus were recorded. These parameters were re-evaluated at 3-monthly intervals when gingival overgrowth was also recorded (Modified Harris & Ewalt Index). It was seen that, after a period of one year, gingival overgrowth occurred in 60 and 50 percent children of groups I & II respectively and its development, too, was delayed in group II. More cases (93 percent) in group II exhibited minimal overgrowth as against 78 percent in group I. The study concluded that systemic folic acid prescribed along with phenytoin delays the onset and reduces the incidence and severity of gingival overgrowth induced by phenytoin.

Adolescent↗

Effects of folic acid on phenytoin kinetics in healthy subjects.

Phenytoin (DPH) disposition was studied in normal subjects before and after treatment with folic acid for 14 days. Our results suggest that folic acid lowers (DPH) serum levels without significantly modifying its bound fraction and increases the rate of DPH and meta-hydroxydiphenylhydantoin excretion in urine.

Adult↗

Folic acid for prevention of neural tube defects: pediatric anticipatory guidance.

The incidence of neural tube defects including myelomeningocele, which is one of the most common causes of infant and childhood disability, can be substantially reduced by folic acid supplementation to the diet of women before and during the early stages of pregnancy. All females of childbearing age should be taking folic acid supplements of 0.4 mg/day (400 micrograms/day) and consuming a diet rich in folate. Because many pregnancies are unplanned, supplementation should not await plans for pregnancy. Because pediatric nurse practitioners are in frequent contact with both adolescent patients and patients whose mothers are of childbearing age, and because pediatric nurse practitioners have an interest in preventing neural tube defects in future pediatric patients, they are in a good position to provide the necessary anticipatory guidance regarding the critical need for adequate folic acid intake by females of childbearing age. This article discusses and includes guidelines for providing this anticipatory guidance.

Adult↗

Mineral water fortified with folic acid, vitamins B6, B12, D and calcium improves folate status and decreases plasma homocysteine concentration in men and women.

OBJECTIVE: We investigated the effects of mineral water fortified with folic acid, vitamins B(6), B(12), D and calcium on folate concentrations in serum and erythrocytes, serum vitamin B(12) and plasma homocysteine concentrations in free-living subjects. In addition, we investigated the bioavailability of calcium added to mineral water by measuring urinary calcium excretion and serum alkaline phosphatase activity. DESIGN: Randomized, controlled, double-blinded, parallel design. SETTING: Outpatient dietary intervention with free-living subjects in Eastern Finland. SUBJECTS: Altogether, 66 subjects were recruited for the study. In all, 60 subjects completed the study. INTERVENTIONS: The study began with a 2-week run-in period followed by an 8-week intervention period. During the intervention study, subjects consumed mineral water fortified with folic acid (563 microg/day), vitamins B(6) (1 mg/day), B(12) (7.5 microg/day), cholecalciferol (0.6 microg/day) and calcium (563 mg/day) or placebo mineral water. RESULTS: The fortified mineral water increased serum and erythrocyte folate concentrations by 16.1+/-5.6 nmol/l (P<0.001) and 199+/-76 nmol/l (P<0.001), respectively, and decreased plasma homocysteine concentration by 1.6 micromol/l (P<0.001). Urinary calcium excretion and serum alkaline phosphatase activity for 24 h increased significantly (P<0.001 and P=0.01 respectively) in the intervention group. CONCLUSIONS: Mineral water fortified with folic acid, vitamins B(6), B(12) and D and calcium enhanced folate status and reduced plasma homocysteine concentration in normohomocysteinemic subjects without folate deficiency. Indirect measures of calcium and bone metabolism indicated that the calcium used in the fortification of the mineral water was bioavailable.

Adult↗

Preliminary data on changes in neural tube defect prevalence rates after folic acid fortification in South America.

Several South American countries are fortifying wheat flour with folic acid. However, only Chile started in 2000 to add 2.2 mg/kg, providing 360 microg daily per capita, an acceptable dosage for preventing the occurrence of some neural tube defect (NTD) cases. ECLAMC (Spanish acronym for the Latin American Collaborative Study of Congenital Malformations) routinely monitoring birth defects in South America since 1976, surveyed the impact of this fortification. Data from 361,374 births occurred in 43 South American hospitals, distributed in five different countries, active throughout the 1999-2001 triennium, were selected from the ECLAMC network. Birth prevalence rates for three different congenital anomalies with similar expected prevalence rates, were surveyed by the Cumulative Sum Method (CUSUM) method. They were NTD, oral clefts (OC), and Down syndrome (DS). Expected values were derived from observations made in 1999, and CUSUM was applied to the consecutive series of 24 months covering years 2000 and 2001. Only one of three congenital anomaly types, NTDs, in only one of five sampled out countries, Chile, showed a significant decrease, of 31%, during the 2000-2001 biennium, corresponding to the birth of the periconceptionally fortified infants. The level of significance (P < 0.001) was reached in the 20th month after fortification started, corresponding to August 2001. This is the first observation of a significant decrease in the occurrence of NTD after folic acid food fortification in a population little influenced by confounders common in the developed world as pre-existing secular decreasing trends, and partially unregistered induced abortions.

Cleft Palate↗

Hyperhomocysteinemia can be ameliorated by dimethylsulfoniopropionate in place of folic acid in mice.

Acute homocysteinemia mice were prepared by forcibly oral administration of homocysteine (4 mM, 2 mL). The amounts of plasma homocysteine were estimated by a fluorescence method with HPLC. Folic acid (0.6 mM, 2 mL), DMSP, or betaine (20 mM, 2 mL each) was intraperitoneally administrated into the mice suffered from the acute homocysteinemia on the 20th, 40th or 60th min after the oral supplementation of homocysteine, then amounts of plasma homocysteine were determined by the HPLC method 40 min after each addition, respectively. The results indicated that the intraperitoneal addition of folic acid or DMSP in this order of the 40th, 60th and 20th min after the oral supplementation of homocysteine significantly reduce the quantities of plasma homocysteine, but betaine exerted the fairly lesser effects. The amounts of homocysteine without any additive linearly and rapidly appeared to increase up to 60 min, at which those were about 8-12 fold the normal levels of homocysteine, and thereafter decreased in these experiments. Accordingly, folic acid which is known to effectively improve homocysteinemia was proven to be completely replaced by DMSP under the experimental conditions.

Animals↗

Folic acid in folate-deficient patients with epilepsy.

A double-blind trial using folic acid 15 mg. daily and identical placebo was carried out in 51 epileptic patients having a serum folate level below 3.6 ng./ml. Treatment was for a minimum of six months and in 41 patients was for more than one year. There were no significant changes in the frequency of seizures, behaviour, and personality, or in a number of cognitive functions.

Adolescent↗

Trypanosoma lewisi, Trypanosoma rhodesiense: mitotic activity in normal and folic acid deficient rats.

Ten experiments were performed to compare mitotic activity in livers of rats infected with Trypanosoma rhodesiense and Trypanosoma lewisi. The host dietary groups were: (1) complete of full complement; (2) folic acid deficient, and (3) pair-fed or calorically restricted. Liver mitotic counts of T. lewisi-infected rats fed complete and pair-fed control diets showed a high degree of significance over that of control rats. From days 35 to 55, liver mitotic counts of T. lewisi-infected rats deficient in folic acid showed an average of 16 +/- 2 mitotic phases as compared to 9 +/- 2 for livers of uninfected animals. Liver mitotic counts of T. rhodesiense-infected and non-infected rats fed complete and pair-fed control diets showed that there were essentially no differences in the mitotic counts from that seen in liver from control, uninfected animals. On day 25 (day 5 of infection), folic acid-deficient infected rats showed a significantly higher number of dividing cells than the controls. Folate was measured in isolated, washed T. lewisi and T. rhodesiense cells. T. lewisi and T. rhodesiense contained 9.6 ng folate per 10(8) cells and 6.2 ng of folate per 10(8) cells respectively. Metabolic products of T. lewisi contained an average of 0.51 ng of folate per 10(8) trypanosomes. T. rhodesiense metabolic products contained 0.3 ng of folate per 10(8) trypanosomes.

Animals↗

Content of polyunsaturated fatty acids (PUFAs) in serum and liver of rats fed restricted diets supplemented with vitamins B2, B6 and folic acid.

The aim of study was to investigate an influence of nutritional deficiency and dietary addition of vit. B(2), B(6) and folic acid on PUFAs content in rats' serum and liver. Limitation of consumption full value diet to 50% of its previously determined daily consumption, enriched with m/a vitamins, significant decreased of linoleic (LA) and alpha-linolenic (ALA) acids as well as distinctly increased arachidonic (AA) and docosahexaenoic (DHA) acids content in serum in 30th day. In 60th day lower content of AA and DHA fatty acids was found. Nutrition with such diet, lasting 90 days caused decrease of LA content and increase of AA. Diet limitation to its 30% of daily consumption decreased of eicosapentaenoic acid (EPA) and DHA in the 30th day, while AA and DHA content was increased in the 60th day. Distinct decrease of AA content and increase of EPA content were found in the 90th day of experiment. Use of diets, with limited consumption to 50% caused increase of LA and ALA acids content while AA and DHA acids content were significantly decreased in the liver, in 90th day. Limited consumption supplemented diet to 30% caused in liver significant decrease of LA and increase of EPA acids content.

Animals↗

[Correlations between folic acid, human papilloma virus (HPV) and cervix neoplasms].

The study aimed to verify the probable correlation between the incidence of cervical cancer and the presence of human papilloma virus (HPV) in relation to a state of folic acid hypovitaminosis. In this context, however, it is important not to overlook the important protective role played by vitamins A and C in cancer prevention, as mentioned in the paper. Numerous authors agree that this is a real finding in cervical pathology, as shown in our research, even if folic acid therapy does not alter the course and prognosis of disease. On the contrary, low blood levels of folic acid appear to increase the risk of contracting the disease. Extensive and radical surgery therefore appears to be even more justified in order to increase the probability of recovery on the operating table in view of the irrational and inexorable progress of this pathology, especially if metastases are already present.

Adult↗

Chloroquine prophylaxis, iron-folic acid supplementation or case management of malaria attacks in primigravidae in western Uganda: effects on maternal parasitaemia and haemoglobin levels and on birthweight.

The effects of weekly chloroquine prophylaxis, daily iron-weekly folic acid supplementation or passive case management on maternal haemoglobin and parasitaemia and on birthweight were examined in primigravidae in a randomized, double-blind placebo-controlled intervention trial in 1996-98 in Hoima District, western Uganda. Iron-folic acid supplementation significantly increased mean birthweight as compared to case management (P = 0.03). Low birthweight (< 2.5 kg) occurred in 2% of babies of women receiving chloroquine prophylaxis for > or = 8 weeks and in 9% in the case management group (RR = 0.36, 95% CI 0.13-1.00, P = 0.009). Parasitaemia at enrolment significantly correlated with low birthweight in the case management group as compared to the intervention groups (P = 0.02). Women in the case management group who were parasitaemia and had haemoglobin levels < 100 g/L at delivery had babies with lower mean birthweight as compared to babies in the other groups (P = 0.04). Low haemoglobin level at enrolment, irrespective of parasitaemia status, was a predictor of low birthweight in the case management group only (P = 0.04). Chloroquine prophylaxis and iron-folic acid supplementation significantly increased maternal haemoglobin levels during pregnancy as compared to case management (P = 0.01 and 0.007, respectively) and the increase correlated to the duration of the intervention.

Adolescent↗

Controlled comparison of L-5-methyltetrahydrofolate versus folic acid for the treatment of hyperhomocysteinemia in hemodialysis patients.

BACKGROUND: The hyperhomocysteinemia regularly found in hemodialysis patients is largely refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid. We evaluated whether a high-dose L-5-methyltetrahydrofolate-based regimen provided improved total homocysteine (tHcy)-lowering efficacy in chronic hemodialysis patients. METHODS AND RESULTS: We block-randomized 50 chronic, stable hemodialysis patients on the basis of their screening predialysis tHcy levels, sex, and dialysis center into 2 groups of 25 subjects treated for 12 weeks with oral folic acid at 15 mg/d (FA group) or an equimolar amount (17 mg/d) of oral L-5-methyltetrahydrofolate (MTHF group). All 50 subjects also received 50 mg/d of oral vitamin B(6) and 1.0 mg/d of oral vitamin B(12). The mean percent reductions (+/-95% CIs) in predialysis tHcy were not significantly different: MTHF, 17.0% (12.0% to 22.0%); FA, 14.8% (9.6% to 20.1%); P=0.444 by matched ANCOVA adjusted for pretreatment tHcy. Final on-treatment values (mean with 95% CI) were MTHF, 20.0 micromol/L (18.8 to 21.2 micromol/L); FA, 19.5 micromol/L (18.3 to 20.7 micromol/L). Moreover, neither treatment resulted in "normalization" of tHcy levels (ie, final on-treatment values <12 micromol/L) among a significantly different or clinically meaningful number of patients: MTHF, 2 of 25 (8%); FA, 0 of 25 (0%); Fisher's exact test of between-groups difference, P=0.490. CONCLUSIONS: Relative to high-dose folic acid, high-dose oral L-5-methyltetrahydrofolate-based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients. The preponderance of hemodialysis patients (ie, >90%) exhibit mild hyperhomocysteinemia refractory to treatment with either regimen. This treatment refractoriness is not related to defects in folate absorption or circulating plasma and tissue distribution.

Administration, Oral↗

Lactobacillus casei microbiological assay of folic acid derivatives in 96-well microtiter plates.

Microbiological assay is still widely used for estimating folic acid derivatives in serum and other biological samples. We describe here a modification of this procedure involving use of 96-well microtiter plates. This procedure, used with modern, computer-interfaced microtiter-plate readers and data-reduction software, greatly shortens the time and minimizes reagent costs for this assay. Under the conditions of our assay procedures, all folic acid derivatives tested gave equal growth response for Lactobacillus casei. Results for assays of rat liver extracts showed excellent agreement between the standard bioassay and the 96-well procedure.

Animals↗

Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function in healthy adults, irrespective of the methylenetetrahydrofolate reductase (C677T) genotype.

OBJECTIVES: We sought to study the effect of low-dose folic acid supplementation or optimization of dietary folate intake on plasma homocysteine and endothelial function in healthy adults. BACKGROUND: Elevated homocysteine is associated with cardiovascular disease, but it is not known whether this relationship is causal. Individuals homozygous (TT) for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene ( approximately 12% of the population) have increased homocysteine levels, particularly in association with suboptimal folate intake. METHODS: Healthy subjects (n = 126; 42 of each MTHFR genotype) were included in this cross-over study of three interventions of four months each: 1) placebo plus natural diet; 2) daily 400-microg folic acid supplement plus natural diet; and 3) increased dietary folate intake to 400 microg/day. RESULTS: At baseline, homocysteine was inversely related to plasma folate and was higher in TT homozygotes. For the whole group, plasma folate increased by 46% after dietary folate and by 79% after supplementation, with reductions of homocysteine of 14% and 16%, respectively. Within the genotype, TT homozygotes exhibited the most marked changes in these variables. Brachial artery endothelial function, as determined by a change in end-diastolic diameter in response to increased flow, was not changed by increased folate intake (98 +/- 73 microm at baseline, 110 +/- 69 microm after a high-folate diet, 114 +/- 59 microm after supplementation and 118 +/- 68 microm after placebo). Plasma von Willebrand factor antigen was unaltered. CONCLUSIONS: Optimization of dietary folate or low-dose folic acid supplementation reduces plasma homocysteine but does not enhance endothelial function, irrespective of the MTHFR (C667T) genotype.

Adolescent↗

A pregnant woman with severe epistaxis--a rare manifestation of folic acid deficiency.

The case-history of a pregnant woman with a life-threatening thrombocytopenia, due to folic acid deficiency, caused by an extremely low dietary intake is described. As folic acid deficiency manifests itself in a variety of ways, its clinical features are not always easily recognized. Timely recognition is important because of the rapid progressive nature of the disorder, especially in pregnancy, and because rapid improvement is achieved by simple treatment: supplementation of the deficiency. This is well illustrated in the patient described in this case report. A short review of the literature is presented.

Adult↗