Low Dietary Folate Interacts with MTHFD1 Synthetase Deficiency in Mice, a Model for the R653Q Variant, to Increase Incidence of Developmental Delays and Defects

Christensen, Karen E.; Bahous, Renata H.; Hou, Wenyang; Deng, Liyuan; Malysheva, Olga; Arning, Erland; Caudill, Marie A.; Jerome-Majewska, Loydie A.; Rozen, Rima

doi:10.1093/jn/nxy013

Cited by 9 publications

(11 citation statements)

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“…Total body weights of pregnant HET mice at sacrifice tended to be lower than WT ( p genotype = 0.0632, p diet = 0.69, p interaction = 0.26, 2-way ANOVA) ( Table S3 ). This is likely caused by the increased resorption rate that is usually observed in HET mice due to the lethality of the Mthfd1S −/− (null) genotype [ 28 , 29 ] ( Table S4 ). When the weight of the uterus was subtracted from body weight, to eliminate differences due to litter size, there was no significant difference in weights ( p genotype = 0.10, p diet = 0.63, p interaction = 0.27, 2-way ANOVA).…”

Section: Resultsmentioning

confidence: 99%

“…The mice were maintained on the same diet throughout mating and pregnancy. This sample size was selected to be able to observe significant effects of diet and genotype on embryonic development, based on previous experiments with this strain [ 27 , 28 , 29 ]. The morning a vaginal plug was discovered was designated E0.5.…”

Section: Methodsmentioning

confidence: 99%

“…Embryo loss per litter was calculated as the percentage of resorption sites per total implantation and resorption sites. Embryos were dissected and evaluated for developmental stage as described [ 27 , 28 , 29 ] using established morphological markers. Typical E10.5 embryos had complete or near-complete closure of the posterior neuropore (tail tip), distinct forelimb buds, visible hindlimb and tail buds, a lens plate, a closed otic vesicle with a round or pointed shape, and 25–33 somites.…”

Section: Methodsmentioning

confidence: 99%

“…In earlier work, we generated the MTHFD1-synthetase deficient mouse ( Mthfd1S) as a model for the 653QQ genotype. This mouse mimics the metabolic effects of the 653QQ genotype and is sensitive to both low and high folate diets with respect to negative reproductive outcomes at mid-gestation [ 4 , 27 , 28 , 29 ]. In this study, our objective was to assess the effects of choline deficiency on maternal choline metabolism and the incidence of embryonic delays and defects in the MTHFD1-synthetase deficient mouse.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

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“…En los humanos, la presencia del alelo 1958A no afecta las concentraciones de homocisteína ni de folato sérico y eritrocitario. Sin embargo, varios estudios indican que las mujeres portadoras tienen mayor riesgo de fetos con defectos del tubo neural y cardíacos congénitos, desprendimiento prematuro de placenta y aborto en el segundo trimestre (15,16) .…”

Section: Polimorfismos Relacionados Con El Metabo-lismo Del Folatounclassified

Programación fetal y modificaciones epigenéticas relacionadas al folato

Mejia-Montilla¹,

Reyna-Villasmil²

2020

Rev peru ginecol obstet.

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La vida fetal se caracteriza por su capacidad para responder a factores ambientales. La nutrición es el factor ambiental más importante que influye en los procesos de desarrollo a través de la regulación de los mecanismos epigenéticos. La identificación del papel de los factores dietéticos que modulan y remodelan el epigenoma fetal durante el desarrollo, incluidos donantes del grupo metilo, es de gran importancia. La epigenética estudia aquellos cambios heredados en la expresión genética que no están relacionados con las modificaciones en la secuencia de ADN. El metabolismo del folato regula el suministro de grupos metilo; por lo tanto, los trastornos alimentarios pueden influir en la regulación de los mecanismos epigenéticos. El papel crucial del folato en la división celular, así como en la conversión de homocisteína, ha sido demostrado en forma concluyente. Debido a que los procesos epigenéticos son una de las vías del proceso de programación fetal, el suministro anormal de folato puede producir anomalías fetales y mayor riesgo de enfermedades crónicas en la vida adulta. El objetivo de la revisión fue establecer la asociación entre la programación fetal y las modificaciones epigenéticas causadas por el folato.

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Folate Deficiency and/or the Genetic Variant Mthfr^{677C >T} Can Drive Hepatic Fibrosis or Steatosis in Mice, in a Sex‐Specific Manner

Leclerc,

Christensen,

Reagan

et al. 2024

Molecular Nutrition Food Res

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ScopeDisturbances in one‐carbon metabolism contribute to nonalcoholic fatty liver disease (NAFLD) which encompasses steatosis, steatohepatitis, fibrosis, and cirrhosis. The goal is to examine impact of folate deficiency and the Mthfr677C >T variant on NAFLD.Methods and resultsThis study uses the new Mthfr677C >T mouse model for the human MTHFR677C >T variant. Mthfr677CC and Mthfr677TT mice were fed control diet (CD) or folate‐deficient (FD) diets for 4 months. FD and Mthfr677TT alter choline/methyl metabolites in liver and/or plasma (decreased S‐adenosylmethionine (SAM):S‐adenosylhomocysteine (SAH) ratio, methyltetrahydrofolate, and betaine; increased homocysteine [Hcy]). FD, with contribution from Mthfr677TT, provokes fibrosis in males. Studies of normal livers reveal alterations in plasma markers and gene expression that suggest an underlying predisposition to fibrosis induced by FD and/or Mthfr677TT in males. These changes are absent or reverse in females, consistent with the sex disparity of fibrosis. Sex‐based differences in methylation potential, betaine, sphingomyelin, and trimethylamine‐N‐oxide (TMAO) levels may prevent fibrogenesis in females. In contrast, Mthfr677TT alters choline metabolism, dysregulates expression of lipid metabolism genes, and promotes steatosis in females.ConclusionThis study suggests that folate deficiency predisposes males to fibrosis, which is exacerbated by Mthfr677TT, whereas Mthfr677TT predisposes females to steatosis, and reveal novel contributory mechanisms for these NAFLD‐related disorders.

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Low Dietary Folate Interacts with MTHFD1 Synthetase Deficiency in Mice, a Model for the R653Q Variant, to Increase Incidence of Developmental Delays and Defects

Cited by 9 publications

References 50 publications

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

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

Programación fetal y modificaciones epigenéticas relacionadas al folato

Folate Deficiency and/or the Genetic Variant Mthfr^{677C >T} Can Drive Hepatic Fibrosis or Steatosis in Mice, in a Sex‐Specific Manner

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Low Dietary Folate Interacts with MTHFD1 Synthetase Deficiency in Mice, a Model for the R653Q Variant, to Increase Incidence of Developmental Delays and Defects

Cited by 9 publications

References 50 publications

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

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

Programación fetal y modificaciones epigenéticas relacionadas al folato

Folate Deficiency and/or the Genetic Variant Mthfr677C >T Can Drive Hepatic Fibrosis or Steatosis in Mice, in a Sex‐Specific Manner

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Folate Deficiency and/or the Genetic Variant Mthfr^{677C >T} Can Drive Hepatic Fibrosis or Steatosis in Mice, in a Sex‐Specific Manner