Formate metabolism in fetal and neonatal sheep

Washburn, Shannon E.; Caudill, Marie A.; Malysheva, Olga; MacFarlane, Amanda J.; Behan, Nathalie A.; Harnett, Brian; MacMillan, Luke; Pongnopparat, Theerawat; Brosnan, John T.; Brosnan, Margaret E.

doi:10.1152/ajpendo.00046.2015

Cited by 34 publications

(27 citation statements)

References 41 publications

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“…Formate, involved in glyoxylate/dicarboxylate metabolism, was significantly diminished in early pregnancy in women that developed GDM compared to controls. Formate is involved in one-carbon metabolism and is believed to be important in fetal development [ 58 ]. While formate has not been previously linked to GDM, decreased urinary formate has been associated with fetal growth restriction, suggesting that depletions may cause poor outcomes at birth [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

et al. 2020

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Women with diabetes during pregnancy are at increased risk of poor maternal and neonatal outcomes. Despite this, the effects of pre-gestational (PGDM) or gestational diabetes (GDM) on metabolism during pregnancy are not well understood. In this study, we utilized metabolomics to identify serum metabolic changes in women with and without diabetes during pregnancy and the cord blood at birth. We observed elevations in tricarboxylic acid (TCA) cycle intermediates, carbohydrates, ketones, and lipids, and a decrease in amino acids across gestation in all individuals. In early gestation, PGDM had elevations in branched-chain amino acids and sugars compared to controls, whereas GDM had increased lipids and decreased amino acids during pregnancy. In both GDM and PGDM, carbohydrate and amino acid pathways were altered, but in PGDM, hemoglobin A1c and isoleucine were significantly increased compared to GDM. Cord blood from GDM and PGDM newborns had similar increases in carbohydrates and choline metabolism compared to controls, and these alterations were not maternal in origin. Our results revealed that PGDM and GDM have distinct metabolic changes during pregnancy. A better understanding of diabetic metabolism during pregnancy can assist in improved management and development of therapeutics and help mitigate poor outcomes in both the mother and newborn.

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Section: Discussionmentioning

confidence: 99%

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

et al. 2020

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“…Nevertheless, rodents may be less prone to formate accumulation than humans owing to a greater capacity to remove formate by oxidation [36] . Moreover, studies in sheep show higher concentrations of formate in the foetal circulation and amniotic fluid compared to maternal plasma [40] . In adult female humans, use of calcium formate at a significantly higher dosage than present in a typical supplement, led to plasma formate concentrations of around 0.5 mM and this was cleared rapidly from the circulation within 4 h [41] .…”

Section: Discussionmentioning

confidence: 99%

Formate supplementation enhances folate-dependent nucleotide biosynthesis and prevents spina bifida in a mouse model of folic acid-resistant neural tube defects

et al. 2016

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The curly tail mouse provides a model for neural tube defects (spina bifida and exencephaly) that are resistant to prevention by folic acid. The major ct gene, responsible for spina bifida, corresponds to a hypomorphic allele of grainyhead-like 3 (Grhl3) but the frequency of NTDs is strongly influenced by modifiers in the genetic background. Moreover, exencephaly in the curly tail strain is not prevented by reinstatement of Grhl3 expression. In the current study we found that expression of Mthfd1L, encoding a key component of mitochondrial folate one-carbon metabolism (FOCM), is significantly reduced in ct/ct embryos compared to a partially congenic wild-type strain. This expression change is not attributable to regulation by Grhl3 or the genetic background at the Mthfd1L locus. Mitochondrial FOCM provides one-carbon units as formate for FOCM reactions in the cytosol. We found that maternal supplementation with formate prevented NTDs in curly tail embryos and also resulted in increased litter size. Analysis of the folate profile of neurulation-stage embryos showed that formate supplementation resulted in an increased proportion of formyl-THF and THF but a reduction in proportion of 5-methyl THF. In contrast, THF decreased and 5-methyl THF was relatively more abundant in the liver of supplemented dams than in controls. In embryos cultured through the period of spinal neurulation, incorporation of labelled thymidine and adenine into genomic DNA was suppressed by supplemental formate, suggesting that de novo folate-dependent biosynthesis of nucleotides (thymidylate and purines) was enhanced. We hypothesise that reduced Mthfd1L expression may contribute to susceptibility to NTDs in the curly tail strain and that formate acts as a one-carbon donor to prevent NTDs.

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“…Washburn and colleagues (Washburn et al, 2015) examined the concentration of formate in the mother, fetus and the neonate in the sheep. The animals were chronically cannulated and were studied at days 119–121 of gestation (full term ~147 days).…”

Section: One Carbon Metabolism In Pregnancymentioning

confidence: 99%

One carbon metabolism in pregnancy: Impact on maternal, fetal and neonatal health

Kalhan

2016

Molecular and Cellular Endocrinology

103

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One carbon metabolism or methyl transfer, a crucial component of metabolism in all cells and tissues, supports the critical function of synthesis of purines, thymidylate and methylation via multiple methyl transferases driven by the ubiquitous methyl donor s-adenosylmethionine. Serine is the primary methyl donor to the one carbon pool. Intracellular folates and methionine metabolism are the critical components of one carbon transfer. Methionine metabolism requires vitamin B12, B6 as cofactors and is modulated by endocrine signals and is responsive to nutrient intake. Perturbations in one carbon transfer can have profound effects on cell proliferation, growth and function. Epidemiological studies in humans and experimental model have established a strong relationship between impaired fetal growth and the immediate and long term consequences to the health of the offspring. It is speculated that during development, maternal environmental and nutrient influences by their effects on one carbon transfer can impact the health of the mother, impair growth and reprogram metabolism of the fetus, and cause long term morbidity in the offspring. The potential for such effects is underscored by the unique responses in methionine metabolism in the human mother during pregnancy, the absence of transsulfuration activity in the fetus, ontogeny of methionine metabolism in the placenta and the unique metabolism of serine and glycine in the fetus. Dietary protein restriction in animals and marginal protein intake in humans causes characteristic changes in one carbon metabolism. The impact of perturbations in one carbon metabolism on the health of the mother during pregnancy, on fetal growth and the neonate are discussed and their possible mechanism explored.

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Formate metabolism in fetal and neonatal sheep

Cited by 34 publications

References 41 publications

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

Formate supplementation enhances folate-dependent nucleotide biosynthesis and prevents spina bifida in a mouse model of folic acid-resistant neural tube defects

One carbon metabolism in pregnancy: Impact on maternal, fetal and neonatal health

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