scholarly journals Deficient or Excess Folic Acid Supply During Pregnancy Alter Cortical Neurodevelopment in Mouse Offspring

2020 ◽  
Vol 31 (1) ◽  
pp. 635-649
Author(s):  
Angelo Harlan De Crescenzo ◽  
Alexios A Panoutsopoulos ◽  
Lyvin Tat ◽  
Zachary Schaaf ◽  
Shailaja Racherla ◽  
...  
Keyword(s):  
Folic Acid ◽  
Cellular Proliferation ◽  
De Novo ◽  
Regulation Of Gene Expression ◽  
Folate Deficiency ◽  
Nucleotide Synthesis ◽  
Biochemical Alterations ◽  
Supplement Use ◽  
Behavioral Abnormalities ◽  
Folate Cycle

Abstract Folate is an essential micronutrient required for both cellular proliferation through de novo nucleotide synthesis and epigenetic regulation of gene expression through methylation. This dual requirement places a particular demand on folate availability during pregnancy when both rapid cell generation and programmed differentiation of maternal, extraembryonic, and embryonic/fetal tissues are required. Accordingly, prenatal neurodevelopment is particularly susceptible to folate deficiency, which can predispose to neural tube defects, or when effective transport into the brain is impaired, cerebral folate deficiency. Consequently, adequate folate consumption, in the form of folic acid (FA) fortification and supplement use, is widely recommended and has led to a substantial increase in the amount of FA intake during pregnancy in some populations. Here, we show that either maternal folate deficiency or FA excess in mice results in disruptions in folate metabolism of the offspring, suggesting diversion of the folate cycle from methylation to DNA synthesis. Paradoxically, either intervention causes comparable neurodevelopmental changes by delaying prenatal cerebral cortical neurogenesis in favor of late-born neurons. These cytoarchitectural and biochemical alterations are accompanied by behavioral abnormalities in FA test groups compared with controls. Our findings point to overlooked potential neurodevelopmental risks associated with excessively high levels of prenatal FA intake.

The Morphology of the Rat Kidney Following Folic Acid Administration

1970 ◽  
Vol 28 ◽  
pp. 200-201
Author(s):  
Aline Byrnes ◽  
Elsa E. Ramos ◽  
Minoru Suzuki ◽  
E.D. Mayfield
Keyword(s):  
Folic Acid ◽  
De Novo ◽  
Specific Activity ◽  
Rat Kidney ◽  
Present Report ◽  
Intracellular Localization ◽  
Male Rats ◽  
Renal Hypertrophy ◽  
Electron Microscopic ◽  
Biochemical Alterations

Renal hypertrophy was induced in 100 g male rats by the injection of 250 mg folic acid (FA) dissolved in 0.3 M NaHCO3/kg body weight (i.v.). Preliminary studies of the biochemical alterations in ribonucleic acid (RNA) metabolism of the renal tissue have been reported recently (1). They are: RNA content and concentration, orotic acid-c14 incorporation into RNA and acid soluble nucleotide pool, intracellular localization of the newly synthesized RNA, and the specific activity of enzymes of the de novo pyrimidine biosynthesis pathway. The present report describes the light and electron microscopic observations in these animals. For light microscopy, kidney slices were fixed in formalin, embedded, sectioned, and stained with H & E and PAS.

scholarly journals Epidemiology and (Patho)Physiology of Folic Acid Supplement Use in Obese Women before and during Pregnancy

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 331
Author(s):  
Melissa van der Windt ◽  
Sam Schoenmakers ◽  
Bas van Rijn ◽  
Sander Galjaard ◽  
Régine Steegers-Theunissen ◽  
...  
Keyword(s):  
Folic Acid ◽  
Scientific Evidence ◽  
Folate Deficiency ◽  
Folate Intake ◽  
Low Grade ◽  
Obese Women ◽  
Folic Acid Supplement ◽  
Physiological Uptake ◽  
Supplement Use ◽  
Acid Supplement

Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status, lifestyle, and medical conditions.

scholarly journals p53 Disruption Increases Uracil Accumulation in DNA of Murine Embryonic Fibroblasts and Leads to Folic Acid–Nonresponsive Neural Tube Defects in Mice

2020 ◽  
Vol 150 (7) ◽  
pp. 1705-1712
Author(s):  
Erica R Lachenauer ◽  
Sally P Stabler ◽  
Martha S Field ◽  
Patrick J Stover
Keyword(s):  
Folic Acid ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
De Novo ◽  
Embryonic Fibroblasts ◽  
Chi Square ◽  
Deficient Diet ◽  
Nucleotide Synthesis ◽  
Altered Expression ◽  
Chi Square Test

ABSTRACT Background Neural tube defects (NTDs) occur in nervous tissue during embryogenesis when the neural tube fails to close. Approximately 70% of all human NTDs can be prevented by folic acid (FA). Altered expression and/or function of the tumor suppressor protein p53 can lead to NTDs in mouse models. Objectives The aim of this study was to determine if dietary FA could rescue p53−/−-induced NTDs in mice, and to determine the effect loss of p53 has on pathways in folate 1-carbon metabolism. Methods p53+/− female mice were randomly allocated and weaned onto either an FA-sufficient diet (2 mg/kg folic acid; +FA), or an FA-deficient diet (−FA). After 8 wk, the females were time-mated to p53−/− males. Embryos were examined at E12.5 for NTDs. Folate enzyme concentrations, nucleotide synthesis, uracil accumulation in DNA, and proliferation were measured in primary murine embryonic fibroblasts (MEFs). The “n − 1” chi-square test was used to compare NTD percentages, whereas all other data were analyzed by Student t test, except where noted a multilevel-fit model was used. Results NTD rates of litters from dams consuming the +FA diet (20/46; 43%) did not differ from those of litters from dams consuming the −FA diet (14/35; 40%) (P > 0.05). p53−/− MEFs had 55% higher rates of folate-dependent de novo dTMP synthesis, a ∼2-fold higher accumulation of uracil in DNA, and a ∼30% higher rate of proliferation (P ≤ 0.05) than p53+/− MEFs independent of folate. Conclusions p53-related NTDs are not FA responsive. Increased dTMP synthesis in p53−/− MEFs might not have been sufficient to meet the demands for thymidine triphosphate (dTTP) synthesis as evidenced by the elevated amounts of uracil in DNA. This study provides additional evidence that elevated uracil in DNA is a risk factor for NTDs.

scholarly journals Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity

2021 ◽  
Author(s):  
Hans-Georg Sprenger ◽  
Thomas MacVicar ◽  
Amir Bahat ◽  
Kai Uwe Fiedler ◽  
Steffen Hermans ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Cultured Cells ◽  
De Novo ◽  
Metabolic Response ◽  
Interferon Response ◽  
Type I ◽  
Nucleotide Synthesis ◽  
Pyrimidine Synthesis ◽  
Pyrimidine Nucleotide ◽  
De Novo Pyrimidine Synthesis

AbstractCytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP–AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS–STING–TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS–STING–TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.

scholarly journals Folic acid food fortification prevents inadequate folate intake among preschoolers from Ontario

2009 ◽  
Vol 12 (9) ◽  
pp. 1548-1555 ◽  
Author(s):  
Kathleen Hennessy-Priest ◽  
Jill Mustard ◽  
Heather Keller ◽  
Lee Rysdale ◽  
Joanne Beyers ◽  
...  
Keyword(s):  
Folic Acid ◽  
Public Health Intervention ◽  
Folate Intake ◽  
Food Fortification ◽  
Folic Acid Intake ◽  
Cross Sectional ◽  
Dietary Folate ◽  
Supplement Use ◽  
Acid Intake ◽  
Fortified Food

AbstractObjectiveFolic acid food fortification has successfully reduced neural tube defect-affected pregnancies across Canada. The effect of this uncontrolled public health intervention on folate intake among Canadian children is, however, unknown. Our objectives were to determine folic acid intake from food fortification and whether fortification promoted adequate folate intakes, and to describe folic acid-fortified food usage among Ontario preschoolers.DesignCross-sectional data were used from the NutriSTEP™ validation project with preschoolers recruited using convenience sampling. Mean daily total folate and folic acid intakes were estimated from 3 d food records, which included multivitamin supplement use. Comparisons were made to Dietary Reference Intakes, accounting for and excluding fortificant folic acid, to determine the prevalence of inadequate and excessive intakes.SettingCanada.SubjectsTwo hundred and fifty-four preschoolers (aged 3–5 years).ResultsAll participants (130 girls, 124 boys) ate folic acid-fortified foods and 30 % (n76) used folic acid-containing supplements. Mean (se) fortificant folic acid intake was 83 (2) μg/d, which contributed 30 % and 50 % to total folate intake for supplement users and non-users, respectively. The prevalence of total folate intakes below the Estimated Average Requirement was <1 %; however, excluding fortificant folic acid, the prevalence was 32 %, 54 % and 47 % for 3-, 4- and 5-year-olds, respectively. The overall prevalence of folic acid (fortificant and supplemental) intakes above the Tolerable Upper Intake Level was 2 % (7 % among supplement users).ConclusionsFolic acid food fortification promotes dietary folate adequacy and did not appear to result in excessive folic acid intake unless folic acid-containing supplements were consumed.

scholarly journals Small-Molecule Screen Identifies De Novo Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3

Cell Reports ◽  
2018 ◽  
Vol 22 (8) ◽  
pp. 1945-1955 ◽  
Author(s):  
Karina N. Gonzalez Herrera ◽  
Elma Zaganjor ◽  
Yoshinori Ishikawa ◽  
Jessica B. Spinelli ◽  
Haejin Yoon ◽  
...  
Keyword(s):  
Small Molecule ◽  
De Novo ◽  
Nucleotide Synthesis ◽  
Small Molecule Screen
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