scholarly journals Formate metabolism in fetal and neonatal sheep

2015 ◽  
Vol 308 (10) ◽  
pp. E921-E927 ◽  
Author(s):  
Shannon E. Washburn ◽  
Marie A. Caudill ◽  
Olga Malysheva ◽  
Amanda J. MacFarlane ◽  
Nathalie A. Behan ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
Carbon Metabolism ◽  
Maternal Plasma ◽  
Nucleotide Synthesis ◽  
Fetal Sheep ◽  
Vitamin Deficiencies ◽  
Cellular Events ◽  
High Concentrations ◽  
One Carbon Metabolism ◽  
Formate Metabolism

By virtue of its role in nucleotide synthesis, as well as the provision of methyl groups for vital methylation reactions, one-carbon metabolism plays a crucial role in growth and development. Formate, a critical albeit neglected component of one-carbon metabolism, occurs extracellularly and may provide insights into cellular events. We examined formate metabolism in chronically cannulated fetal sheep (gestation days 119–121, equivalent to mid-third trimester in humans) and in their mothers as well as in normal full-term lambs. Plasma formate levels were much higher in fetal lamb plasma and in amniotic fluid (191 ± 62 and 296 ± 154 μM, respectively) than in maternal plasma (33 ± 13 μM). Measurements of folate, vitamin B12, and homocysteine showed that these high formate levels could not be due to vitamin deficiencies. Elevated formate levels were also found in newborn lambs and persisted to about 8 wk of age. Formate was also found in sheep milk. Potential precursors of one-carbon groups were also measured in fetal and maternal plasma and in amniotic fluid. There were very high concentrations of serine in the fetus (∼1.6 mM in plasma and 3.5 mM in the amniotic fluid) compared with maternal plasma (0.19 mM), suggesting increased production of formate; however, we cannot rule out decreased formate utilization. Dimethylglycine, a choline metabolite, was also 30 times higher in the fetus than in the mother.

scholarly journals A candidate gene study of one-carbon metabolism pathway genes and colorectal cancer risk

2012 ◽  
Vol 109 (6) ◽  
pp. 984-989 ◽  
Author(s):  
Marcella Martinelli ◽  
Luca Scapoli ◽  
Gabriella Mattei ◽  
Giampaolo Ugolini ◽  
Isacco Montroni ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Carbon Metabolism ◽  
Protein Function ◽  
Restriction Analysis ◽  
Likelihood Ratio Statistic ◽  
Folate Intake ◽  
Nucleotide Synthesis ◽  
Preliminary Results ◽  
Increased Risk ◽  
One Carbon Metabolism

The risk of colorectal cancer (CRC) may be influenced by aberrant DNA methylation and altered nucleotide synthesis and repair, possibly caused by impaired dietary folate intake as well as by polymorphic variants in one-carbon metabolism genes. A case–control study using seventy-one CRC patients and eighty unrelated healthy controls was carried out to assess the genetic association of fifteen SNP and one insertion in nine genes belonging to the folate pathway. Polymorphism selection was based on literature data, and included those which have a known or suspected functional impact on cancer and missense polymorphisms that are most likely to alter protein function. Genotyping was performed by real-time PCR and PCR followed by restriction analysis. The likelihood ratio statistic indicated that most of the polymorphisms were not associated with the risk of CRC. However, an increased risk of CRC was observed for two variant alleles of SNP mapping on the transcobalamin 2 gene (TCN2): C776G (rs1801198) and c.1026-394T>G (rs7286680). Considering the crucial biological function played by one-carbon metabolism genes, further investigations with larger cohorts of CRC patients are needed in order to confirm our preliminary results. These preliminary results indicate that TCN2 polymorphisms can be a susceptibility factor for CRC.

scholarly journals Mild Choline Deficiency and MTHFD1 Synthetase Deficiency Interact to Increase Incidence of Developmental Delays and Defects in Mice

Nutrients ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 127
Author(s):  
Karen E. Christensen ◽  
Olga V. Malysheva ◽  
Stephanie Carlin ◽  
Fernando Matias ◽  
Amanda J. MacFarlane ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Developmental Delays ◽  
Maternal Plasma ◽  
Choline Deficiency ◽  
Adequate Intake ◽  
Developmental Defects ◽  
Synthetase Deficiency ◽  
Maternal Liver ◽  
One Carbon Metabolism ◽  
Phosphatidylcholine Metabolism

Folate and choline are interconnected metabolically. The MTHFD1 R653Q SNP is a risk factor for birth defects and there are concerns that choline deficiency may interact with this SNP and exacerbate health risks. 80–90% of women do not meet the Adequate Intake (AI) for choline. The objective of this study was to assess the effects of choline deficiency on maternal one-carbon metabolism and reproductive outcomes in the MTHFD1-synthetase deficient mouse (Mthfd1S), a model for MTHFD1 R653Q. Mthfd1S+/+ and Mthfd1S+/− females were fed control (CD) or choline-deficient diets (ChDD; 1/3 the amount of choline) before mating and during pregnancy. Embryos were evaluated for delays and defects at 10.5 days gestation. Choline metabolites were measured in the maternal liver, and total folate measured in maternal plasma and liver. ChDD significantly decreased choline, betaine, phosphocholine, and dimethylglycine in maternal liver (p < 0.05, ANOVA), and altered phosphatidylcholine metabolism. Maternal and embryonic genotype, and diet-genotype interactions had significant effects on defect incidence. Mild choline deficiency and Mthfd1S+/− genotype alter maternal one-carbon metabolism and increase incidence of developmental defects. Further study is required to determine if low choline intakes contribute to developmental defects in humans, particularly in 653QQ women.

scholarly journals Effects of chronic hyperinsulinemia on metabolic pathways and insulin signaling in the fetal liver

2020 ◽  
Vol 319 (4) ◽  
pp. E721-E733
Author(s):  
Paul J. Rozance ◽  
Amanda K. Jones ◽  
Stephanie L. Bourque ◽  
Angelo D’Alessandro ◽  
William. W. Hay ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Amino Acid ◽  
Insulin Signaling ◽  
Carbon Metabolism ◽  
Fetal Liver ◽  
Whole Body ◽  
Ampk Activation ◽  
Fetal Sheep ◽  
Glucose And Lipid Metabolism ◽  
One Carbon Metabolism

The effect of chronic of hyperinsulinemia in the fetal liver is poorly understood. Here, we produced hyperinsulinemia with euglycemia for ∼8 days in fetal sheep [hyperinsulinemic (INS)] at 0.9 gestation. INS fetuses had increased insulin and decreased oxygen and amino acid (AA) concentrations compared with saline-infused fetuses [control (CON)]. Glucose (whole body) utilization rates were increased, as expected, in INS fetuses. In the liver, however, there were few differences in genes and metabolites related to glucose and lipid metabolism and no activation of insulin signaling proteins (Akt and mTOR). There was increased p-AMPK activation and decreased mitochondrial mass ( PGC1A expression, mitochondrial DNA content) in INS livers. Using an unbiased multivariate analysis with 162 metabolites, we identified effects on AA and one-carbon metabolism in the INS liver. Expression of the transaminase BCAT2 and glutaminase genes GLS1 and GLS2 was decreased, supporting decreased AA utilization. We further evaluated the roles of hyperinsulinemia and hypoxemia, both present in INS fetuses, on outcomes in the liver. Expression of PGC1A correlated only with hyperinsulinemia, p-AMPK correlated only with hypoxemia, and other genes and metabolites correlated with both hyperinsulinemia and hypoxemia. In fetal hepatocytes, acute treatment with insulin activated p-Akt and decreased PGC1A, whereas hypoxia activated p-AMPK. Overall, chronic hyperinsulinemia produced greater effects on amino acid metabolism compared with glucose and lipid metabolism and a novel effect on one-carbon metabolism in the fetal liver. These hepatic metabolic responses may result from the downregulation of insulin signaling and antagonistic effects of hypoxemia-induced AMPK activation that develop with chronic hyperinsulinemia.

Interactions between folate and aging for carcinogenesis

2005 ◽  
Vol 43 (10) ◽  
Author(s):  
Sang-Woon Choi ◽  
Simonetta Friso
Keyword(s):  
Carbon Metabolism ◽  
Genomic Dna ◽  
Folate Intake ◽  
Dna Hypomethylation ◽  
Folate Supplementation ◽  
Nucleotide Synthesis ◽  
Dietary Folate ◽  
One Carbon Metabolism ◽  
Molecular Aberrations ◽  
Folate Depletion

AbstractInadequate folate intake and aging are each strongly implicated as important risk factors for certain cancers. Since both folate depletion and aging are strongly associated with hyperhomocysteinemia, genomic DNA hypomethylation, and increased uracil misincorporation into DNA, it appears that each of them enhances carcinogenesis by inducing a derangement of one-carbon metabolism that supplies one-carbons to biological methylation reactions and nucleotide synthesis. Recent studies have demonstrated that inadequate dietary folate and aging may interact and synergistically disturb the normal homeostasis of one-carbon metabolism, thereby provoking subsequent biochemical and molecular aberrations, including alterations in critical gene expression related to carcinogenesis. These studies have further indicated that modest folate supplementation may reverse or partially ameliorate those adverse effects induced by folate depletion and aging.

scholarly journals 390 Micronutrients, One-Carbon Metabolism, and Epigenetics: Potential Developmental and Production Outcomes

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 170-170
Author(s):  
Matthew S Crouse ◽  
Joel Caton ◽  
Alison K Ward
Keyword(s):  
Carbon Metabolism ◽  
Management Practices ◽  
Nutrient Sensing ◽  
The Body ◽  
Late Gestation ◽  
Offspring Performance ◽  
Nucleotide Synthesis ◽  
Methyl Donors ◽  
One Carbon Metabolism

Abstract One-carbon metabolism is the network of biochemical pathways in which methyl groups are transferred from one compound to another for methylation processes. Expansion of the core pathway connects one-carbon metabolism to polyamine synthesis, nucleotide synthesis, redox metabolism, and the citric acid cycle. One-carbon metabolites (OCM) are methyl donors and cofactors which play key roles in the one-carbon metabolism pathway and include B-vitamins (choline, vitamin B12, vitamin B6, riboflavin, and folate), minerals (cobalt and sulfur) and amino acids (methionine, serine, and glycine). One-carbon metabolites are fundamental methyl donors for epigenetic modifications. Immediately post-fertilization, the embryonic genome undergoes epigenetic remodeling, and is the time when cell division is greatest (cell divisions/total cell number). At this time OCM supplementation may have its greatest impact on programming of offspring development, growth and postnatal performance, due to established metabolic roles in epigenetics (methyl transfer), growth (polyamine and nucleotide synthesis), and energetics. Limited data are available, however, which directly investigates the developmental effects of OCM supplementation in ruminants. In dairy cows, OCM supplementation in late gestation increased calf birth weight, nutrient sensing pathway activation, and offspring performance through the pre-weaning period. Methyl deficient diets during the pre-conception period in ewes altered the offspring hepatic methylome at 90 days of gestation, as well as the body composition and insulin tolerance of ram lambs at 22-mo of age. Bovine embryonic fibroblasts cultured in vitro with increasing OCM had greater growth rates and mitochondrial respiration parameters. Additional research into the area of one-carbon metabolism and the roles that OCM supplementation may play on postnatal function will provide new knowledge that could lead to altered management practices and increased efficiency of beef cattle. USDA is an equal opportunity provider and employer.

scholarly journals Metabolic Regulation of Longevity by One-Carbon Metabolism and Flavin-Containing Monooxygenase

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 126-126
Author(s):  
Christopher Choi ◽  
Scott Leiser ◽  
Charles Evans ◽  
Daniel Beard
Keyword(s):  
Carbon Metabolism ◽  
Metabolic Regulation ◽  
Metabolic Flux ◽  
Rna Seq ◽  
Stress Perception ◽  
Nucleotide Synthesis ◽  
Expression Of Genes ◽  
One Carbon Metabolism ◽  
Future Work ◽  
And Oxidative Stress

Abstract Nematode flavin-containing monooxygenase-2 (fmo-2) is induced by dietary restriction and hypoxia, and is required for the longevity and health benefits of these pathways. It is also sufficient to confer these benefits when overexpressed. As FMOs are well-conserved across taxa, the fmo-2 mechanism has high translational potential. To determine the changes that occur following fmo-2 induction, we performed RNA-seq and untargeted metabolomics analyses. Our data reveal that one-carbon metabolism (OCM) is significantly altered by fmo-2 overexpression. OCM is a nexus for essential metabolic pathways, including transmethylation, transsulfuration, nucleotide synthesis, and amino acid metabolism. We hypothesized that fmo-2 confers longevity benefits by altering key metabolic processes within or downstream of OCM. To test this, we asked whether fmo-2 and OCM interact to regulate longevity by knocking down expression of genes involved with OCM and measuring lifespan and oxidative stress resistance. To understand the biological implications of these interactions, we generated a computational model using qPCR data of key OCM-related genes to predict changes in OCM metabolic flux. Our model predicts significant changes in OCM flux that are regulated by fmo-2 expression levels and are consistent with our RNAi and multi-omics results. We are now testing this model by knocking down genes downstream of OCM to determine their role in fmo-2-mediated benefits. Preliminary results support our hypothesis that changes in metabolic flux through OCM are involved downstream of fmo-2 expression, and may also implicate the UPRER in this pathway. Our future work will elucidate this mechanism and link stress perception and fmo-2-mediated longevity.

scholarly journals One-carbon metabolism during the menstrual cycle and pregnancy

2021 ◽  
Vol 17 (12) ◽  
pp. e1009708
Author(s):  
Ruby Kim ◽  
H. Frederik Nijhout ◽  
Michael C. Reed
Keyword(s):  
Mathematical Model ◽  
Menstrual Cycle ◽  
Carbon Metabolism ◽  
Direct Effects ◽  
Homocysteine Concentration ◽  
Vitamin Deficiencies ◽  
Adenosyl Methionine ◽  
One Carbon Metabolism ◽  
The Mathematical Model ◽  
Estradiol Concentration

Many enzymes in one-carbon metabolism (OCM) are up- or down-regulated by the sex hormones which vary diurnally and throughout the menstrual cycle. During pregnancy, estradiol and progesterone levels increase tremendously to modulate physiological changes in the reproductive system. In this work, we extend and improve an existing mathematical model of hepatic OCM to understand the dynamic metabolic changes that happen during the menstrual cycle and pregnancy due to estradiol variation. In particular, we add the polyamine drain on S-adenosyl methionine and the direct effects of estradiol on the enzymes cystathionine β-synthase (CBS), thymidylate synthase (TS), and dihydrofolate reductase (DHFR). We show that the homocysteine concentration varies inversely with estradiol concentration, discuss the fluctuations in 14 other one-carbon metabolites and velocities throughout the menstrual cycle, and draw comparisons with the literature. We then use the model to study the effects of vitamin B12, vitamin B6, and folate deficiencies and explain why homocysteine is not a good biomarker for vitamin deficiencies. Additionally, we compute homocysteine throughout pregnancy, and compare the results with experimental data. Our mathematical model explains how numerous homeostatic mechanisms in OCM function and provides new insights into how homocysteine and its deleterious effects are influenced by estradiol. The mathematical model can be used by others for further in silico experiments on changes in one-carbon metabolism during the menstrual cycle and pregnancy.

scholarly journals Maternal Plasma Pyridoxal 5′-Phosphate Concentration Is Inversely Associated with Plasma Cystathionine Concentration across All Trimesters in Healthy Pregnant Women

2019 ◽  
Vol 149 (8) ◽  
pp. 1354-1362
Author(s):  
Maria F Mujica-Coopman ◽  
Dayana R Farias ◽  
Ana B Franco-Sena ◽  
Juliana S Vaz ◽  
Gilberto Kac ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Carbon Metabolism ◽  
Plasma Concentrations ◽  
First Trimester ◽  
Maternal Blood ◽  
Maternal Plasma ◽  
Third Trimester ◽  
Metabolite Concentrations ◽  
Mixed Regression ◽  
One Carbon Metabolism

ABSTRACTBackgroundVitamin B-6 (B-6), in the form of pyridoxal 5′phosphate (PLP), is critical for one-carbon metabolism reactions and cellular function. Plasma PLP concentration decreases throughout pregnancy, but the functional consequences of this have not been studied. Plasma cystathionine is a sensitive indicator of suboptimal B-6 status in healthy adults.ObjectivesThe aim of this study was to determine the relation between plasma PLP and cystathionine concentrations, and to assess longitudinal changes in plasma concentrations of metabolites of one-carbon metabolism, including total homocysteine (tHcy), cysteine, methionine, glycine, serine, and glutathione, over the course of pregnancy.DesignThis was a prospective cohort study of 186 healthy Brazilian pregnant women (20–40 y). Plasma PLP and metabolite concentrations were quantified in fasting maternal blood samples collected between 5–13, 20–26, and 30–36 weeks of gestation. Linear mixed regression models were used to determine the association of 1) first-trimester PLP tertiles, and 2) the variation of PLP concentration throughout pregnancy, with related metabolite concentrations across weeks of gestation.ResultsMedian (IQR) PLP concentration decreased from 36.2 (29.2–44.5) to 21.0 (15.9–26.0) to 16.8 (12.9–21.4) nmol/L in the first, second, and third trimester, respectively, whereas cystathionine concentration increased from 63.2 (49.7–78.9) to 122 (98.0–167) to 143 (114–193) nmol/L, respectively (both P < 0.001). The variation of PLP throughout pregnancy was inversely associated with cystathionine concentration across weeks of gestation, after adjusting for confounding factors; β (95% CI) = −0.387 (−0.752, −0.219), P = 0.04. This association significantly differed by trimester and was strongest in the third trimester. Plasma concentrations of glycine, serine, methionine, cysteine, and tHcy decreased, and that of glutathione increased, between the first and second trimesters (all P < 0.05).ConclusionsThe variation of PLP concentration predicted cystathionine concentration throughout pregnancy. Increases in plasma cystathionine across trimesters may reflect maternal intracellular B-6 deficiency.

Fetal organ growth in response to oesophageal infusion of amniotic fluid, colostrum, milk or gastrin-releasing peptide: a study in fetal sheep

2000 ◽  
Vol 12 (2) ◽  
pp. 87 ◽  
Author(s):  
Jeff F. Trahair ◽  
Per T. Sangild
Keyword(s):  
Amniotic Fluid ◽  
Biological Fluids ◽  
Premature Delivery ◽  
Mesenteric Lymph Nodes ◽  
Fetal Sheep ◽  
Crown Rump Length ◽  
Milk Whey ◽  
Gastrin Releasing Peptide ◽  
Fetal Organ ◽  
High Concentrations

The hypothesis of the present study was that the infusion of the biological fluids to which the develop-ing gut is normally exposed (i.e. amniotic fluid, colostrum, milk) and a single growth factor (gastrin-releasing peptide), which is found in high concentrations in fetal fluids and milk, could ameliorate the altered growth induced by the elimination of swallowed input secondary to ligation of the oesophagus. At 108–110 days of gestation the fetal oesophagus was ligated and a catheter inserted towards the stomach (32 fetuses). At 117–119 days of gestation saline (n = 5), amniotic fluid (n = 5), colostral whey (n = 5), milk whey (n= 5) or gastrin-releasing peptide (3.6 nmol day –1 , n = 6), was infused for 7 days (4 &yen; 20mL day –1 ), or no infusion was given (ligated group, n = 6). A further 15 fetuses ere not ligated (normal group, n = 15). All fetuses had carotid artery and/or jugular vein catheters implanted. At 124–126 days of gestation the fetus was delivered and fetal body and organ weights recorded. Analysing the results by ANOVA, there were no effects of either ligation alone or infusion after ligation on fetal weight, crown–rump length, or weight relative to bodyweight of heart, adrenal, pancreas, large intestine and cecum. There were significant differences between the infusion groups for lungs, kidney, pancreas, total gut, abomasum, small intestine, spleen, chest and neck thymus, and mesenteric lymph nodes. Ligation alone significantly reduced small intestinal growth and increased kidney and spleen growth. Colostrum infusion enhanced growth of most organs. Gastrin-releasing peptide significantly increased growth of all the immune organs studied. It was concluded that at an age when premature delivery could be encountered, the fetal gut is capable of significant adaptive growth, to varying degrees, depending on the enteral diet. Growth effects in organs distant to the gut suggest that either gastrointestinal uptake and transport of growth factors or altered nutrient uptake and/or availability can affect the growth of other major fetal organs.

scholarly journals Adrenomedullin production is increased in normal human pregnancy

1999 ◽  
pp. 201-206 ◽  
Author(s):  
R Di Iorio ◽  
E Marinoni ◽  
C Letizia ◽  
B Villaccio ◽  
A Alberini ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
Pregnant Women ◽  
Gestational Age ◽  
Umbilical Vein ◽  
Maternal Plasma ◽  
Human Reproduction ◽  
Human Pregnancy ◽  
Significant Difference ◽  
High Concentrations ◽  
And Function

OBJECTIVE: Adrenomedullin, a recently discovered vasoactive peptide originally identified in pheochromocytoma, has been found to be increased in the plasma of pregnant women at term. This study was designed to elucidate whether adrenomedullin secretion is dependent on gestational age and the possible source and function of this peptide in human pregnancy. STUDY DESIGN: Adrenomedullin concentrations were determined by RIA in amniotic fluid and maternal plasma obtained from 110 pregnant women between 8 and 40 weeks of gestation. Subjects were stratified into five groups according to gestational age. In term patients (n = 15), adrenomedullin was also measured in the umbilical artery and vein separately. RESULTS: High concentrations of adrenomedullin were present in plasma and amniotic fluid samples from patients in the first, second and third trimester. There was no significant difference in mean maternal plasma concentration of adrenomedullin between the five patient groupings. Amniotic fluid adrenomedullin concentrations decreased from 81.2 +/- 11.7 pg/ml at 8-12 weeks of gestation to 63.7 +/- 6.0 pg/ml at 13-20 weeks of gestation and then increased at 21-28 weeks of gestation to 99.1 +/- 10.4 pg/ml. A further increase was found in samples collected after 37 weeks of gestation (132.6 +/- 10.1 pg/ml). In the umbilical vein, adrenomedullin concentration was higher (P < 0.05) than in the artery (65.7 +/- 6.1 pg/ml and 48.5 +/- 5.2 pg/ml respectively), suggesting that adrenomedullin in the fetal circulation derives from the placenta. CONCLUSIONS: Our results demonstrate the presence of adrenomedullin in maternal plasma and amniotic fluid throughout gestation, and show that its production starts very early in gestation, suggesting that this hormone may have an important role in human reproduction, from implantation to delivery.

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