Dietary folic acid prevents peripheral neuropathy in mouse models of neural tube defects and type 2 diabetes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE275111 | GEO | 2025/12/17
REPOSITORIES: GEO
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Project description:Neural tube defects (NTDs) are serious birth defects with an estimated worldwide incidence of 1 per 1,000 live births. The multifactorial nature of NTDs in humans has made it difficult to elucidate pathogenesis mechanisms. However, a strong relationship has been established between folate-homocysteine metabolism and NTD risk. Prevention of a substantial proportion of fetal NTDs can be achieved through maternal folic acid (FA) supplementation. However the mechanism by which FA exerts its beneficial effect remains unclear. METHODS: To improve our understanding of the underlying mechanisms of NTD pathogenesis and the ways in which folate exerts its beneficial effect, we analyzed mRNA profiles as well as folate and vitamin B12 levels in five NTD mouse mutants whose response to dietary FA was previously established. RESULTS: Differentially expressed genes representing the effect of each NTD-causing mutation were identified and associated with biologic pathways. Interestingly, the panel of NTD mutants collectively revealed pathways related to two nuclear receptors, retinoid X receptor (RXR) and pregnane X receptor (PXR), suggesting that these pathways may be related to a shared mechanism of NTD development. Moreover, the NTD-causing mutations that were associated with FA responsiveness had expression profiles that were related to folate-homocysteine metabolic pathways. These pathways were not strongly associated with mutants that do not respond to FA supplementation, implying that FA may be beneficial when the NTD mutation affects pathways related to folate-homocysteine metabolism. 5 groups of NTD mutants were studied. From each mutant group Heterozygous (test) and wild-type (control) female pups were used for this study at 6-8 weeks of age. 4 biological replicates were used for each of the test and control groups of each mutant. All mice used for the experiments were fasted 4-5 hours before dissection. A total of 36 samples were analyzed.
2013-09-30 | E-GEOD-51285 | biostudies-arrayexpress
Project description:<p>Maternal folic acid intake is crucial for the development of the offspring's nervous system, and folic acid metabolism disorders during pregnancy lead to neural tube defects (NTDs) in the fetus. Folic acid and vitamins biosynthesis is a major biochemical feature of gut microbiota. The complex and diverse microbial ecosystem residing within maternal host contributes critically to these intergenerational impacts. However, the mechanisms still require further investigation. In this study, we found that the low folate diets combined MTX-induced changed the structure/composition of the gut microbiota and substantially altered the fecal metabolic phenotype of pregnant mice, including central carbon metabolism in cancer and vitamin digestion & absorption. We demonstrated that the correlation betweent gut microbiota of pregnant mice and the brain metabolic profiles of NTDs fetal mice. According to our data, the Lactobacillales and Bifidobacteriales abundances in pregnant mice gut were positively correlated with the abundances of lipid metabolites in fetal mice brain. The abundances of Enterobacterales and Clostridiales were negatively correlated with those lipid metabolites. Interestingly, the abundance of Inosine, Uridine, L-Carnitine and Glycerophosphocholine were down-regulated synchronously in pregnant feces and NTDs fetal mice brain. This was probably the intergenerational microbial-metabolism biomarkers of NTDs. Our study provides evidence for how perinatal microecological factors shape fetal neural tube development.</p><p><br></p><p><strong>Feces metabolomics</strong> is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS4893' rel='noopener noreferrer' target='_blank'><strong>MTBLS4893</strong></a>.</p><p><strong>Brain tissue metabolomics</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS4894' rel='noopener noreferrer' target='_blank'><strong>MTBLS4894</strong></a>.</p>
2022-12-05 | MTBLS4893 | MetaboLights
Project description:Defects in homocysteine and folate metabolism are associated with increased risks for neural tube and congenital heart defects, cardiovascular disease and stroke, cancers, and neurodegeneration. In many but not all cases, dietary supplementation with folate significantly reduces the severity and incidence of these conditions. Common polymorphisms modulate these metabolic pathways and disease risks, but do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test whether other pathways contribute to disease pathogenesis, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared to the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and translated to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting an interplay between homocysteine and folate metabolism and cholesterol metabolism. Absence of measurable changes in global methylation patterns or amelioration of effects with supplementation with an alternative methyl donor suggest that dietary folate perturbations do not act through large-scale or general changes in methylation. These results suggest that homeostatic responses in cholesterol metabolism contribute to the beneficial effects of dietary folate supplementation. Keywords: time course, stress response, diet, genetic, homeostasis Six-week old female A/J and C57BL/6J mice were purchased from the Jackson Laboratory. All mice were raised on a control diet containing four ppm folic acid (Basal Diet 5755, TestDiet) for one week before the start of studies. Selected mice were then placed on folic acid deficient diet (58C3, TestDiet) containing 1% succinylsulfathiazole, a non-absorbable antibiotic commonly used to suppress folate production by bacteria in the intestine. We had nine different treatment plans per strain with eight replicate mice per treatment. There were four folic acid depletion treatment in which mice were placed on folic acid deficient diet for 1, 2, 7, or 14 days. There were two folic acid repletion treatment in which mice were placed on folic acid deficient diet for 14 days followed by 1 day on control diet and another set of mice on 14 days of folic acid deficient diet followed by 7 days of control diet. There were three control time points in which mice were placed on the control diet for 0, 9, or 22 days. Eight biological replicate liver tissue from each treatment was pooled and total RNA from each pool and total RNA from Universal Mouse Reference RNA (Stratagene) were aminoallyl labeled with Cy3 and Cy5 in duplicate, with reversing of dyes.
2008-08-27 | E-GEOD-9242 | biostudies-arrayexpress
Project description:Background: In the early stage of embryonic development, the neural tube (NT) cannot be closed properly due to some complex factors such as, environmental factors, genetic factors and the relationship between various factors, leading to the occurrence of neural tube defects (NTDs). Methods: In this study, we induced the mouse model of NTDs by feeding mice a low-folate diet and injecting 1.5mg/kg methotrexate on E7.5. Fetal mice were achieved at E13.5, then we extracted proteins from brain tissue with trypsin digestion. After enzymatic digestion, peptides were labeled with TMT/iTRAQ and then separated in high-performance liquid chromatography (HPLC) for subsequent LC-MS/MS analysis. To analyze the functional enrichment of differentially expressed proteins(DEPs) in the NTDs mice tissues with low folate induction, we used Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway annotation to analyze proteomic changes. Results: Low folate induced mouse model was successfully constructed. Folate was used as a sensitizing agent, the teratogenicity rate of the NTDs fetal mice was increased to 36.5% when methotrexate was injected to maternal mice at E7.5. 6614 proteins were identified by mass spectrometry, among them, 5656 proteins were quantified. In the following proteomic analysis, GO classification and KEGG pathway enrichment analysis were conducted, and heatmaps were drawn for differentially expressed proteins(DEPs). Moreover, the main pathways associated with NTDs, such as Hedgehog, Wnt, p53, Hippo signaling pathways, and one carbon pool by folate, can be identified through the generation of a protein-protein interaction (PPI) network. It was also found that the regulation of ribosomal proteins has a certain impact on neural tube development, such as RPL13 and RPL14, which are upregulated in NTDs. Conclusions: Our results revealed proteomic changes in the tissues of low folate induced NTDs mice, as well as validation showed that ribosomal proteins play a regulatory role during the development of NTDs, it provides new ideas for the pathogenesis and preventive measures of NTDs.
2024-03-12 | PXD045752 | Pride
Project description:Neural tube defects (NTDs) are serious birth defects with an estimated worldwide incidence of 1 per 1,000 live births. The multifactorial nature of NTDs in humans has made it difficult to elucidate pathogenesis mechanisms. However, a strong relationship has been established between folate-homocysteine metabolism and NTD risk. Prevention of a substantial proportion of fetal NTDs can be achieved through maternal folic acid (FA) supplementation. However the mechanism by which FA exerts its beneficial effect remains unclear. METHODS: To improve our understanding of the underlying mechanisms of NTD pathogenesis and the ways in which folate exerts its beneficial effect, we analyzed mRNA profiles as well as folate and vitamin B12 levels in five NTD mouse mutants whose response to dietary FA was previously established. RESULTS: Differentially expressed genes representing the effect of each NTD-causing mutation were identified and associated with biologic pathways. Interestingly, the panel of NTD mutants collectively revealed pathways related to two nuclear receptors, retinoid X receptor (RXR) and pregnane X receptor (PXR), suggesting that these pathways may be related to a shared mechanism of NTD development. Moreover, the NTD-causing mutations that were associated with FA responsiveness had expression profiles that were related to folate-homocysteine metabolic pathways. These pathways were not strongly associated with mutants that do not respond to FA supplementation, implying that FA may be beneficial when the NTD mutation affects pathways related to folate-homocysteine metabolism.
2013-09-30 | GSE51285 | GEO
Project description:Folic acid is a nutrient essential for embryonic development. Folate deficiency can cause embryolethality or neural tube defects and orofacial anomalies. Folate receptor 1 (Folr1), is a folate binding protein that facilitates the cellular uptake of dietary folate. Animal studies highlighted critical roles of folate in embryogenesis including orofacial development. Orofacial clefts were observed in the offspring of experimental animals on folic acid-deficient diets. Mice lacking Folr1 (the gene encoding folate receptor 1) also demonstrated a variety of orofacial defects. In order to investigate potential roles of Folr1 during embryogenesis and to identify various genes functionally associated with this receptor, total RNA preparations from gestation day (GD)-9.5, Folr1+/+ and Folr1-/- mouse embryos were used to hybridize messenger RNA arrays, to identify genes expressed in wild type (Folr1+/+) and knockout (Folr1-/-) embryos.
2021-02-10 | GSE155428 | GEO
Project description:Folic acid is one of the B vitamins and is involved into neural function and brain development. Increasing evidence showed that folic acid can regulate neural gene function through DNA modification, while regulatory roles of folic acid in RNA modification remain largely unknown. In this study, we investigated the role of folic acid in regulating neural mRNA m6A epitranscriptome in Drosophila and mammals. We found that the folate treatment induced a significant increase in mRNA m6A levels compared to the control group in Drosophila and S2 cells. MeRIP-seq analysis indicated that carbon metabolism pathway and neural-related pathways were mainly affected. Subsequently, we migrated our validation experiments to human cells, our results showed that folate also affected mRNA m6A modification through one-carbon metabolic pathway in human cells, especially in neuronal cells. We also validated the effect of folic acid on mRNA methylation in mice, the results showed that folic acid treatment can significantly increase the expression of m6A-related proteins (Mettl3, Mettl14, FTO) and neural mRNA m6A methylation levels in mice brain. Moreover, we found that folic-acid producing Lactobacillus plantarum can significantly affects the m6A modification of mRNA in the host. In conclusion, we demonstrated that folic acid can participate in mRNA m6A modification through one-carbon metabolic pathway in Drosophila and mammals, and found that it has a significant effect on neural-related genes and pathways.
2025-08-01 | GSE275843 | GEO
Project description:Defects in homocysteine and folate metabolism are associated with increased risks for neural tube and congenital heart defects, cardiovascular disease and stroke, cancers, and neurodegeneration. In many but not all cases, dietary supplementation with folate significantly reduces the severity and incidence of these conditions. Common polymorphisms modulate these metabolic pathways and disease risks, but do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test whether other pathways contribute to disease pathogenesis, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared to the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and translated to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting an interplay between homocysteine and folate metabolism and cholesterol metabolism. Absence of measurable changes in global methylation patterns or amelioration of effects with supplementation with an alternative methyl donor suggest that dietary folate perturbations do not act through large-scale or general changes in methylation. These results suggest that homeostatic responses in cholesterol metabolism contribute to the beneficial effects of dietary folate supplementation. Keywords: time course, stress response, diet, genetic, homeostasis Six-week old female C57BL/6J and B6.129P2-Apoetm1Unc/J (Piedrahita et al. 1992) mice were purchased from the Jackson Laboratory. All mice were raised on a control diet containing four ppm folic acid (Basal Diet 5755, TestDiet) for one week before the start of studies. Mice were then placed on folic acid deficient diet (58C3, TestDiet) containing 1% succinylsulfathiazole, a non-absorbable antibiotic commonly used to suppress folate production by bacteria in the intestine, for 14 days. A subset of these mice were placed back on control diet for 7 days after 14 day depletion. There were three groups of mice that underwent folic acid depletion and repletion. ApoE knockout mice on C57BL/6J background, C57BL/6J mice supplemented with 25mM choline and 50mM saccharine in drinking water, and C57BL/6J mice supplemented with 50mM saccharine. Saccharine was used to reduce the bitter taste of choline in the drinking water. We also had C57BL/6J mice on the control diet for 14 days and 21 days. These mice served as controls for treated mice from each time point during hybridization. The folate level in the control diet for this study was significantly lower than the previous study (GSE9242) due to greater loss of folic acid by irradiation of the diet. There were eight replicate mice per treatment group per folic acid perturbation protocol. An equal amount (by weight) of liver tissue from eight replicate mice was separated into two pools of four replicate tissues each. Pooled RNA from treated mice and pooled RNA from control mice for each time point were aminoallyl labeled with Cy3 and Cy5 in duplicate with reversing of dyes.
2008-08-27 | E-GEOD-9243 | biostudies-arrayexpress
Project description:The incidence of neural tube defects (NTDs) declined by about 40% in Canada with the introduction of national folic acid (FA) fortification programs. However, NTDs persist despite the fact that few Canadians currently exhibit folate deficiency. FA fortification may have aided in reducing NTDs by overcoming abnormal one carbon metabolism cycling, the process which provides one carbon units for methylation of DNA. We considered that NTDs persisting in a folate replete population may also occur in the context of compromised one carbon metabolism, and that this might manifest as abnormal DNA methylation (DNAm). Second trimester human placental chorionic villi, kidney, spinal cord, brain and muscle were collected from 19 control, 22 spina bifida and 15 anencephaly fetuses in British Columbia, Canada. DNA was extracted, assessed for methylenetetrahydrofolate reductase (MTHFR) genotype and for genome-wide DNAm using repetitive elements, in addition to the Illumina Infinium HumanMethylation450 (450k) array. No difference in repetitive element DNAm was noted. Using a false discovery rate <0.05 and average group difference in DNAm >0.05, differentially methylated array sites were only identified in (i) the comparison of anencephaly to controls in chorionic villi (n=4 sites) and (ii) the comparison of spina bifida to controls in kidney (n=3,342 sites). We suggest that the distinctive DNAm of spina bifida kidneys may be consequent to the neural tube defect. Although other studies have provided data to support altered DNAm in NTDs, this was not a major feature of British Columbian cases on a genome-wide or site specific level.
2016-01-23 | GSE69502 | GEO
Project description:Folic acid is present in pre-natal vitamins, fortified cereal grains and multi-vitamin supplements. High intake of folic acid through these sources has resulted in populations with increased levels of serum folate and unmetabolized folic acid. Although the benefits of folic acid in the prevention of neural tube defects are undeniable, the impact of long-term consumption of folic acid on the prostate is not fully understood. In this study, we used a rodent model to test whether dietary folic acid (FA) supplementation changes prostate homeostasis and response to androgen deprivation. Although intact prostate weights do not differ between diet groups, we made the surprising observation that dietary folic acid supplementation confers partial resistance to castration-mediated prostate involution. More specifically, male mice that were fed a folic acid supplemented diet and then castrated had greater prostate wet weights, greater prostatic luminal epithelial cell heights, and more abundant RNAs encoding prostate secretory proteins compared to mice that were fed a control diet and castrated. We used RNA-seq to identify signaling pathways enriched in the castrated prostates from folic acid supplemented diet fed mice compared to control mice. We observed differential expression of genes involved in several metabolic pathways in the FA supplemented mice. Together, our results show that dietary FA supplementation can impact metabolism in the prostate and attenuate the prostate’s response to androgen deprivation. This has important implications for androgen deprivation therapies used in the treatment of prostate disease, as consumption of high levels of folic acid could reduce the efficacy of these treatments.
2018-08-22 | GSE116299 | GEO