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

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.

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Formate metabolism in fetal and neonatal sheep

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00046.2015 ◽

2015 ◽

Vol 308 (10) ◽

pp. E921-E927 ◽

Cited By ~ 21

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.

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B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

Nutrients ◽

10.3390/nu12092867 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2867 ◽

Cited By ~ 1

Author(s):

Peter Lyon ◽

Victoria Strippoli ◽

Byron Fang ◽

Luisa Cimmino

Keyword(s):

Carbon Metabolism ◽

Water Soluble ◽

Nutritional Deficiencies ◽

High Dose ◽

Developmental Defects ◽

Cellular Processes ◽

Health And Disease ◽

Activity Of Enzymes ◽

One Carbon Metabolism

Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to cause developmental defects, impair cognitive function, or block normal blood production. Nutritional deficiencies have historically been treated with dietary supplementation or high-dose parenteral administration that can reverse symptoms in the majority of cases. Elevated levels of these vitamins have more recently been shown to correlate with immune dysfunction, cancer, and increased mortality. Therapies that specifically target one-carbon metabolism are therefore currently being explored for the treatment of immune disorders and cancer. In this review, we will highlight recent studies aimed at elucidating the role of folate, B12, and methionine in one-carbon metabolism during normal cellular processes and in the context of disease progression.

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

Journal of Nutrition ◽

10.1093/jn/nxz082 ◽

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.

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Genetic Variation: Impact on Folate (and Choline) Bioefficacy

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000040 ◽

2010 ◽

Vol 80 (45) ◽

pp. 319-329 ◽

Cited By ~ 9

Author(s):

Allyson A. West ◽

Marie A. Caudill

Keyword(s):

Carbon Metabolism ◽

Genetic Variants ◽

Plasma Homocysteine ◽

Water Soluble ◽

Gene Interactions ◽

Dietary Folate ◽

Methyl Donors ◽

Common Genetic Variants ◽

One Carbon Metabolism ◽

The Impact

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.

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