Folate deficiency during pregnancy impacts on methyl metabolism without affecting global DNA methylation in the rat fetus

The methionine cycle and methyl group metabolism are implicated in the long-term programming of metabolism. Diets deficient in folic acid, methionine and choline have been fed to pregnant rats to examine the effects on amino acid metabolism, choline reserves and DNA methylation in dam and fetuses. Animals were fed folate-deficient, folate-deficient with low methionine, folate-deficient with low choline and folate-deficient, low-methionine, low-choline diets starting 2 weeks before mating. The dams and their fetuses were subsequently killed on day 21 of gestation for analysis. Diets low in methionine reduced fetal and maternal weight. Folate deficiency increased the concentrations of homocysteine, glycine, serine and threonine in the maternal plasma, and this was exacerbated by the low-methionine diets. The changes in the amino acid profile in the fetal serum were similar but less pronounced. This result suggests that fetal metabolism was less perturbed. Folate deficiency increased free choline in the maternal liver at the expense of phosphocholine stores. It has been suggested that a deficiency in methyl donors in the diet during pregnancy may impact on key methylation reactions, including the methylation of DNA. Despite widespread changes in the metabolism of choline and amino acids, there was no change in the global methylation of cytosine in DNA from either maternal or fetal livers. This suggests a more indirect mechanism in which gene-nutrient interactions modify the process of differential methylation during development.     

Disruption of lipid metabolism in the liver of the pregnant rat fed folate-deficient and methyl donor-deficient diets

The importance of folic acid and the methionine cycle in fetal development is well recognised even though the mechanism has not been established. Since the cycle is active in the maternal liver, poor folate status may modify hepatic metabolism. Pregnant rats were fed diets deficient in folic acid (-F) or in three key methyl donors, folic acid, choline and methionine (-FLMLC) and the maternal liver was analysed on day 21 of gestation. Two-dimensional gel electrophoresis of soluble proteins identified differentially abundant proteins, which could be allocated into nine functional groups. Five involved in metabolic processes, namely, folate/methionine cycle, tyrosine metabolism, protein metabolism, energy metabolism and lipid metabolism, and three in cellular processes, namely, endoplasmic reticulum function, bile production and antioxidant defence. The mRNA for sterol regulatory element-binding protein-1c and acetyl-CoA carboxylase-1 (fatty acid synthesis) were decreased by both -F and -FLMLC diets. The mRNA for PPARalpha and PPARgamma and carnitine palmitoyl transferase (fatty acid oxidation) were increased in the animals fed the -FLMLC diets. Changes in the abundance of proteins associated with intracellular lipid transport suggest that folate deficiency interferes with lipid export. Reduced fatty acid synthesis appeared to prevent steatosis in animals fed the -F diet. Even with increased oxidation, TAG concentrations were approximately three-fold higher in animals fed the -FLMLC diet and were associated with an increase in the relative abundance of proteins associated with oxidative stress. Fetal development may be indirectly affected by these changes in hepatic lipid metabolism.     

A methyl-deficient diet fed to rat dams during the peri-conception period programs glucose homeostasis in adult male but not female offspring

Methyl deficiencies have been implicated in metabolic programming during the periods of oocyte and embryo development. Semisynthetic methyl-deficient diets (MD) with no folic acid, 0.05% choline, and approximately one-half the recommended content of methionine were fed to female rats for 3 wk prior to mating and for the first 5 d of gestation. During the period of MD feeding, plasma homocysteine concentrations were approximately twice those of rats fed the complete (CON) diet. From d 5, both groups received a complete semipurified AIN diet until birth. On d 8, plasma homocysteine concentrations did not differ between the 2 groups. Thereafter, dams and offspring were fed a nonpurified diet for the remainder of the experiment. At 6 mo of age, the homeostatic model assessment (HOMA) index of the male MD offspring tended to be 32% higher (P = 0.053) and peak insulin during an oral glucose tolerance test (oGTT) was 39% higher (P < 0.05) compared with the male CON offspring. There was no difference in the response to an oGTT in the female offspring at 6 mo of age. The increased HOMA index of male MD offspring persisted to 12 mo of age. The peak glucose concentration during oGTT was 23% higher (P < 0.05) in MD compared with the CON males despite 39% greater (P < 0.05) peak insulin concentrations. This study shows that in rats, a physiologically relevant methyl-deficient diet fed during the period of oocyte maturation and preimplantation development programs gender-specific changes in glucose handling by the offspring.     

DNA stability and genomic methylation status in colonocyte isolated from methyl-donor-deficient rats

Summary Background: Epidemiological studies report an inverse relationship between intake of the B vitamine folic acid and colon cancer. Folate is important for DNA synthesis and repair. Moreover, the production of S-adenosylmethionine (SAM), essential for normal DNA methylation and gene expression, is dependent on folic acid. Folate deficiency may increase the risk of malignant transformation by perturbing these pathways. Aims of the study: The principal aim of this study was to determine the effects of folate deficiency on DNA stability and DNA methylation in rat colonocytes in vivo. As the metabolic pathways of folate and other dietary methyl donors are closely linked, the effects of methionine and choline deficiency were also evaluated. Methods: Male Hooded-Lister rats were fed a diet deficient in folic acid, or in methionine and choline, or in folate, methionne and choline for 10 weeks. DNA strand breakage and misincorporated uracil were determined in isolated colonocytes using alkaline single cell gel electrophoresis. Global DNA methylation was measured in colonic scrapings. Folate was measured in plasma, erythrocyte and liver samples. Results: Methyl donor deficiency induced DNA strand breakage in colonocytes isolated from all experimental groups. Uracil levels in colonocytes DNA remained unchanged compared with controls. DNA methylation was unaffected either by folate and/or methionine and choline depletion. Rats fed a folate-deficient diet had less folate in plasma, red blood cells and liver than controls. Conclusions: Folate and methyl deficiency in vivo primarily afects DNA stability in isolated colonocytes of rats, without affecting overall DNA methylation. Received: 16 February 2000, Accepted: 25 April 2000     

Excess Vitamins or Imbalance of Folic Acid and Choline in the Gestational Diet Alter the Gut Microbiota and Obesogenic Effects in Wistar Rat Offspring

Excess vitamin intake during pregnancy leads to obesogenic phenotypes, and folic acid accounts for many of these effects in male, but not in female, offspring. These outcomes may be modulated by another methyl nutrient choline and attributed to the gut microbiota. Pregnant Wistar rats were fed an AIN-93G diet with recommended vitamin (RV), high 10-fold multivitamin (HV), high 10-fold folic acid with recommended choline (HFol) or high 10-fold folic acid without choline (HFol-C) content. Male and female offspring were weaned to a high-fat RV diet for 12 weeks post-weaning. Removing choline from the HFol gestational diet resulted in obesogenic phenotypes that resembled more closely to HV in male and female offspring with higher body weight, food intake, glucose response to a glucose load and body fat percentage with altered activity, concentrations of short-chain fatty acids and gut microbiota composition. Gestational diet and sex of the offspring predicted the gut microbiota differences. Differentially abundant microbes may be important contributors to obesogenic outcomes across diet and sex. In conclusion, a gestational diet high in vitamins or imbalanced folic acid and choline content contributes to the gut microbiota alterations consistent with the obesogenic phenotypes of in male and female offspring.     

Folate deficiency results in alteration in intestinal brush border membrane composition and enzyme activities in weanling rats

Folic acid deficiency is the most prevalent vitamin deficiency throughout the world and its effect on brush border membrane composition has not been studied earlier. We investigated the effect of folate deficiency on the structure and function of the intestinal brush border membrane. Various brush border enzyme activities, membrane sugars and lipids were evaluated in two groups of weanling male albino rats after 3 mo of feeding control and folate deficient diets. Except sucrase, all the other three enzymes, viz., alkaline phosphatase, leucine amino peptidase and y-glutamyl transpeptidase showed decrease in activity in rats fed folate-deficient diets. Among sugars, hexoses and hexosamines showed significant decline in amount whereas sialic acid content showed great increase in brush border membrane of folate-deficient rats as compared to controls. Furthermore, there was a significant reduction in cholesterol, phospholipids, triglycerides, cerebrosides and fucolipids in the group fed the folate-deficient diet. Our study suggests that folate deficiency results in altered enzyme activities, lipid and sugar composition of intestinal brush border membrane. Such changes might reflect the underlying cause of the gastrointestinal disturbances observed in folate deficiency.     

Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load

BACKGROUND: Elevated concentrations of homocysteine in blood may be an independent risk factor for the development of atherosclerosis. Elevated homocysteine concentrations can be caused by decreased methylation of homocysteine to form methionine, as occurs in folate deficiency. A parallel pathway exists for methylation of homocysteine, in which choline, by way of betaine, is the methyl donor. OBJECTIVE: Our goal was to determine whether choline deficiency results in a decreased capacity to methylate homocysteine. DESIGN: C57BL/6J mice were fed diets containing 0, 10, or 35 mmol choline/kg diet for 3 wk. We then administered an oral methionine load to the animals and measured plasma homocysteine concentrations. Also, in a pilot study, we examined 8 men who were fed a diet providing 550 mg choline/d per 70 kg body weight for 10 d, followed by a diet providing almost no choline, until the subjects were clinically judged to be choline deficient or for 相似文献   

Gender-specific modulation of tumorigenesis by folic acid supply in the Apc mouse during early neonatal life

Epidemiological studies suggest an inverse association between folic acid intake and colorectal cancer risk. Conversely, conventional treatment of existing tumours includes the use of folate antagonists. This suggests that the level of exposure to folate and its timing in relation to stage of tumorigenesis may be critical in determining outcomes. We hypothesised that folic acid depletion in utero and during early neonatal life may affect tumorigenesis in offspring. To investigate this hypothesis, female C57Bl6/J mice were randomised to a folic acid adequate (2 mg folic acid/kg diet) or folic acid depleted diet (0.4 mg folic acid/kg) from mating with Apc+/Min sires and throughout pregnancy and lactation. At weaning the Apc+/Min offspring were randomised to a folic acid adequate (2 mg folic acid/kg diet) or depleted (0.26 mg folic acid/kg diet) diet, creating four in utero/post-weaning dietary regimens. At 10 weeks post-weaning, mice were killed and the intestinal tumour number and size were recorded. Folic acid depletion during pregnancy and post-weaning reduced erythrocyte folate concentrations in offspring significantly. Folic acid depletion during pregnancy and lactation did not affect tumour multiplicity or size. However, female mice fed normal folic acid diets post-weaning had more, and larger, tumours when compared with depleted females and both depleted and adequate folic acid fed males. These data suggest that folate depletion post-weaning was protective against neoplasia in female Apc+/Min mice and highlights the need for further investigation of the optimal timing and dose of folic acid supplementation with regard to colorectal cancer risk.     

Folate deficiency, methionine metabolism, and alcoholic liver disease.

Methionine metabolism is regulated by folate, and both folate deficiency and abnormal hepatic methionine metabolism are recognized features of alcoholic liver disease (ALD). Previously, histological features of ALD were induced in castrated male micropigs fed diets containing ethanol at 40% of kilocalories for 12 months, whereas in male micropigs fed the same diets for 12 months abnormal methionine metabolism and hepatocellular apoptosis developed. Folate deficiency may promote the development of ALD by accentuating abnormal methionine metabolism. Intact male micropigs received eucaloric diets that were folate sufficient, folate deficient, or each containing 40% of kilocalories as ethanol for 14 weeks. Folate deficiency alone reduced hepatic folates by one half, and ethanol feeding alone reduced methionine synthase, S-adenosylmethionine (SAM), and glutathione (GSH) levels and elevated plasma malondialdehyde (MDA) levels. The combined regimen elevated plasma homocysteine, hepatic S-adenosylhomocysteine (SAH), urinary 8-hydroxy-2-deoxyguanosine (oxy(8)dG), an index of DNA oxidation, and serum aspartate aminotransferase (AST) levels. Terminal hepatic histopathologic characteristics included typical features of steatonecrosis and focal inflammation in pigs fed the combined diet, with no changes in the other groups. Hepatic SAM levels correlated with those of GSH, whereas urinary oxy(8)dG and plasma MDA levels correlated with the SAM:SAH ratio and to hepatic GSH. The results demonstrate the linkage of abnormal methionine metabolism to products of DNA and lipid oxidation and to liver injury. The finding of steatonecrosis and focal inflammation only in the combined diet group supports the suggestion that folate deficiency promotes and folate sufficiency protects against the early onset of methionine cycle-mediated ALD.     

Incorporation of 3H-label from folic acid is tissue-dependent in folate-deficient rats.

To study the tissue-specificity of folate deficiency, male Sprague-Dawley rats were fed folate-replete or folate-deficient diets with and without sulfonamide for 16 wk, and then injected with [3H]folic acid (1.5 nmol/kg). Rats were killed after 24 h, and the blood, urine and various organs were prepared for analysis of endogenous and 3H-labeled folate. Endogenous folate levels decreased due to folate deficiency to the greatest extent in the urine and plasma, followed by liver, kidney and other tissues (spleen, testis, lung and intestine), but no decrease was noted in the brain. Of all tissues of folate-deficient rats, the brain showed the greatest increase in incorporation of 3H-label from folate relative to folate-replete rats, with the largest effect in rats that were most deficient in plasma folate. Incorporation of label was increased due to folate deficiency in a number of tissues, with an inverse correlation with the tissue folate concentration. In contrast, hepatic [3H]folate incorporation was lower in folate-deficient rats than in folate-replete rats, with a direct correlation between endogenous folate concentration and the incorporation of labeled folate. These results show that the brain and other organs adapt to the development of folate deficiency because of greater incorporation of folate from exogenous sources. The lower incorporation by the liver of folate-deficient rats may result from the greater incorporation by other tissues.     

Effect of dietary methyl group deficiency on folate metabolism in rats

The carcinogenic effects of methyl-deficient, amino acid-defined diets have been attributed to alterations in cellular methylation reactions. These diets contain no choline, and methionine is replaced by homocysteine. Hence, all methyl groups needed for methionine biosynthesis with subsequent formation of S-adenosylmethionine and polyamines must be formed de novo utilizing folate-dependent reduction of one-carbon units. In rats fed the methyl-deficient diet, there was a marked decrease in total liver folate levels. This decrease was apparent in the levels of the individual forms of folate: 10-HCO-H4folate, 5-HCO-H4folate, 5-CH3-H4folate and H4folate. The percent of the total folate pool made up by 5-CH3-H4folate did not change, however, until after the rats had been fed the methyl-deficient diet for 4 wk, and then an increase was seen. After the methyl-deficient rats were switched to a nutritionally adequate control diet containing methionine and choline, all values rapidly reversed. Increased use of folate for methyl group biosynthesis may be responsible for the loss of folates from the liver.     

A comparison of the response of woodchucks and rats to variations in dietary lipotrope and protein content

Juvenile woodchucks and weanling Fisher F344 rats were fed purified diets with or without supplemental lipotropic factors (choline, methionine, folic acid and vitamin B-12). The diets contained 10 or 20% protein. Lower weight gain due to low protein was observed in both species, while lipotrope depletion resulted in lower gain in male rats only. Urinary excretion of formimino-glutamic acid was higher due to low lipotrope in both species, as was relative liver weight. In rats, lipotrope depletion resulted in hepatic fatty metamorphosis at both levels of dietary protein with the low protein diet resulting in more severe lesions. No liver lesions were observed in woodchucks fed low lipotropes at the higher level of dietary protein, but fatty metamorphosis was observed in those fed the lower protein diets. The lesion was more severe in the low lipotrope group. The woodchuck appears to be less sensitive than the rat to induction of fatty liver by lipotrope deficiency, although the lesion was induced by lowering dietary protein.     

Interactions between protein and vegetable oils in the maternal diet determine the programming of the insulin axis in the rat

The available evidence suggests that metabolic control mechanisms are programmed early in life. Previous studies of pregnant rats fed low-protein diets have suggested that the vegetable oils used in the experimental diets influence the outcome. The present study investigated the offspring of female rats fed semi-synthetic diets containing either 180 or 90g casein/kg with 70 g/kg (w/w) of either corn oil or soya oil during gestation. During lactation, the dams received stock diet, and the offspring were subsequently weaned onto the stock diet. The offspring of dams fed the low-protein diets were smaller at birth. At 25 weeks of age, the offspring were subjected to an oral glucose tolerance test. In the offspring of dams fed the diet containing soya oil, the area under the insulin curve was affected by the protein content of the maternal diet. There was no effect of protein on the area under the insulin curve in the offspring of dams fed the diet prepared with corn oil. There were no differences in plasma glucose concentrations. The levels of mRNA for acetyl-CoA carboxylase- in the livers of female offspring were affected by the protein and oil content of the maternal diet. The level of carnitine palmitoyl transferase mRNA was affected by the protein content of the maternal diet. The present study suggests that PUFA in the maternal diet can interact with protein metabolism to influence the development of the offspring. This may involve the higher content of alpha-linolenic acid in soya oil compared with corn oil.     

Folate deficiency alters melatonin secretion in rats

The final step of melatonin (MLT) synthesis is methylation of N-acetyl-serotonin, with S-adenosylmethionine as a methyl donor provided by a metabolic pathway involving sulfur-containing amino acids (homocysteine and methionine). Remethylation of homocysteine to methionine requires folate. The present study was undertaken to test the influence of folate deficiency on MLT secretion. Severe folate deficiency was induced in rats by feeding them a synthetic diet containing (per kg diet) 0 mg folate and 10 g succinylsulfathiazole. Control rats were fed the same diet containing 8 mg folate/kg. After 4 wk, erythrocyte folate concentrations were significantly lower and plasma homocysteine levels were greater in folate-deficient rats than in controls. Pineal MLT concentration and urinary excretions of MLT, 6 sulfatoxymelatonin (the main hepatic MLT metabolite) and methoxylated catechol compounds were lower in the folate-deficient group than in the controls, whereas plasma catecholamine concentrations did not differ. Decreases generally were more marked at wk 2 than at wk 4 for the urinary metabolite excretions. These findings indicate that folate deficiency dramatically alters MLT secretion in rats.     

Folacin deficiency and requirement in the squirrel monkey (Saimiri sciuresus).

Acute folacin deficiency was studied in eight young squirrel monkeys (Saimiri sciureus). Half of the animals were fed a semipurified deficient diet (no added folic acid) and half were fed a control diet (0.84 mg of added folic acid per kilogram of dry diet). Monkeys fed the deficient diet lost weight and suffered from diarrhea and dehydration leading to the death of one of the animals after 6 weeks. Folacin deficiency also was studied in six older animals fed diets containing varying levels of added folic acid. Monkeys fed diets containing 0.14 or 0.27 mg of added folic acid per kilogram of dry diet slowly developed alopecia, a scaly dermatitis, and a mild macrocytic anemia. When these animals were fed the deficient diet, they lost weight rapidly, the alopecia and dermatitis worsened, excretion of formiminoglutamic acid in the urine increased, and a severe megaloblastic anemia with profound intramedullary hemolysis developed. Deficient monkeys had low plasma and red blood cell folacin values but maintained normal plasma vitamin B12 values. Repletion of the animals fed the deficient diet with injections of folic acid reversed both the hematological and physical deterioration. The folacin requirement for maintenance of body weight in these animals was 28 micrograms of total folacin per kilogram of body weight per day. More than 75 micrograms of total folacin per kilogram of body weight/day may be needed to assure growth and normal hematological parameters and bone marrow cytology.     

Purine synthesis and reutilization in folate-deficient rat hepatocytes

Although folic acid is known to be involved in the pathways of purine metabolism, the precise changes brought about in purine synthesis, reutilization, pool sizes, and ratios by experimental folate deficiency are not clear. Consequently, these aspects of purine metabolism were measured in hepatocytes from control and folate-deficient rats fed an amino acid diet with and without folic acid, respectively. Purine synthesis and reutilization were measured as the rates of incorporation of [U-14C]glycine and [G-3H]hypoxanthine, respectively, into the adenine and guanine pools of freshly isolated hepatocytes after a 3-hour incubation in folate-free, as well as folate- and/or thymidine-supplemented culture media. Hepatocytes from folate-deficient rats had the same rates of purine synthesis as those from control rats. Purine reutilization, purine pool sizes, and the adenine:guanine ratios were lower in hepatocytes from deficient compared with control rats. Purine synthesis was increased when folic acid or thymidine was added to the culture medium. Although hepatocytes from folate-deficient rats had a lower rate of purine reutilization compared with those from control rats, the reutilization rates did not respond to the addition of folic acid or thymidine to the culture medium. The data suggest that purine synthesis was not impaired but purine reutilization was diminished in folate deficiency. Thymidine was as effective as folic acid in stimulating purine synthesis in both control and folate-deficient hepatocytes.     

Effects of chronic ethanol and diet treatment on urinary folate excretion and development of folate deficiency in the rat

Because the folate deficiency of chronic alcoholism has been proposed to result from ethanol-induced effects on metabolism or urinary excretion of folate, the present study was designed to evaluate the role of chronic ethanol-induced urinary folate loss on folate homeostasis in the rat. Male Sprague-Dawley rats were fed nutritionally sufficient liquid diets for 12 wk with or without ethanol, folate and sulfonamide. Urinary folate excretion was increased in ethanol-fed rats consuming folate-containing diets, but not in rats fed folate deficient diets. Consumption of folate-deficient diets led to a rapid decrease in urinary folate excretion, suggesting renal adaptation to conserve folate. Tissue and plasma levels of folate were mostly unaffected by ethanol ingestion in rats fed folate-containing diets. Ethanol treatment did not consistently enhance tissue folate depletion in rats fed folate-deficient diets. The results suggest that in rats consuming diets containing high levels of folate, chronic ethanol ingestion increased urinary folate excretion, but not to a sufficient magnitude to consistently affect folate homeostasis.     

Supplemental dietary folic acid has no effect on chromosome damage in erythrocyte progenitor cells of mice

Folate deficiency can cause chromosome damage, which could result from reduced de novo thymidylate synthesis or DNA hypomethylation. High folic acid intake has been hypothesized to inhibit folate-dependent one-carbon metabolism, which could also lead to DNA damage. A large proportion of the general population may have high folic acid intakes. In this study, 2 experiments were conducted to examine the effects of folate on chromosome damage. First, male mice were fed folic acid-deficient (D) (0 mg folic acid/kg diet), control (C) (2 mg/kg), or folic acid-supplemented (S) (6 mg folic acid/kg diet) diets from weaning to maturity. Second, female mice were fed the D, C, or S diet throughout pregnancy, lactation, and breeding for 3 generations; male mice from the F3 generation were fed the same diet as their mothers from weaning, producing D, C, and S F3 male mice. RBC micronucleus frequencies, a measure of chromosome damage or aneuploidy, were determined for both experimental groups. In mice fed diets from weaning to maturity, erythrocyte micronucleus frequency was 24% greater in D compared with C mice. F3 mice fed diet D had 260% and 174% greater reticulocyte and erythrocyte micronucleus frequencies compared with F3 C mice, respectively. The S diets did not affect micronucleus frequency, suggesting that excess folic acid at this level does not promote or protect against chromosome damage. The results suggest that chronic exposure to folic acid at the levels similar to those achieved through fortification is unlikely to be clastogenic or aneugenic.     

Dietary folate and selenium affect dimethylhydrazine-induced aberrant crypt formation,global DNA methylation and one-carbon metabolism in rats

Several observations suggest a role for DNA methylation in cancer pathogenesis. Although both selenium and folate deficiency have been shown to cause global DNA hypomethylation and increased cancer susceptibility, the nutrients have different effects on one-carbon metabolism. Thus, the purpose of this study was to investigate the interactive effects of dietary selenium and folate. Weanling, Fischer-344 rats (n = 23/diet) were fed diets containing 0 or 2.0 mg selenium (as selenite)/kg and 0 or 2.0 mg folate/kg in a 2 x 2 factorial design. After 3 and 4 wk of a 12-wk experiment, 19 rats/diet were injected intraperitoneally with dimethylhydrazine (DMH, 25 mg/kg) and 4 rats/diet were administered saline. Selenium deficiency decreased (P < 0.05) colonic DNA methylation and the activities of liver DNA methyltransferase and betaine homocysteine methyltransferase and increased plasma glutathione concentrations. Folate deficiency increased (P < 0.05) the number of aberrant crypts per aberrant crypt foci, the concentration of colonic S-adenosylhomocysteine and the activity of liver cystathionine synthase. Selenium and folate interacted (P < 0.0001) to influence one-carbon metabolism and cancer susceptibility such that the number of aberrant crypts and the concentrations of plasma homocysteine and liver S-adenosylhomocysteine were the highest and the concentrations of plasma folate and liver S-adenosylmethionine and the activity of liver methionine synthase were the lowest in rats fed folate-deficient diets and supplemental selenium. These results suggest that selenium deprivation ameliorates some of the effects of folate deficiency, probably by shunting the buildup of homocysteine (as a result of folate deficiency) to glutathione.     

Short-term nutritional folate deficiency in rats has a greater effect on choline and acetylcholine metabolism in the peripheral nervous system than in the brain,and this effect escalates with age

The hypothesis of this study is that a folate-deficient diet (FD) has a greater effect on cholinergic system in the peripheral nervous system than in the brain, and that this effect escalates with age. It was tested by comparing choline and acetylcholine levels in male Sprague Dawley rats fed either control or folate-deficient diets for 10 weeks, starting at age 4 weeks (the young group) or 9 months (the adult group). Folate-deficient diet consumption resulted in depletion of plasma folate in both age groups. In young folate-deficient rats, liver and lung choline levels were significantly lower than those in the respective controls. No other significant effects of FD on choline and acetylcholine metabolism were found in young rats. In adult rats, FD consumption markedly decreased choline levels in the liver, kidneys, and heart; furthermore, choline levels in the cortex and striatum were moderately elevated, although hippocampal choline levels were not affected. Acetylcholine levels were higher in the heart, cortex, and striatum but lower in the hippocampus in adult folate-deficient rats, as compared to controls. Higher acetylcholine levels in the striatum in adult folate-deficient rats were also associated with higher dopamine release in the striatal slices. Thus, both age groups showed higher cholinergic metabolic sensitivity to FD in the peripheral nervous system than in the brain. However, compensatory abilities appeared to be better in the young group, implicating the adult group as a preferred model for further investigation of folate-choline-acetylcholine interactions and their role in brain plasticity and cognitive functions.