Investigation of the effects of folate deficiency on embryonic development through the establishment of a folate deficient mouse model

Burgoon, Jennifer M.; Selhub, Jacob; Nadeau, Marie; Sadler, T. W.

doi:10.1002/tera.10040

Cited by 121 publications

(127 citation statements)

References 49 publications

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“…Maternal periconceptional supplementation with pteroylmonoglutamic acid (the synthetic form of folic acid) significantly decreases the risk of neural tube defects in offspring, and recent studies have suggested that it may also protect the embryo against the development of congenital heart defects (CHD) [1][2][3][4]. Risk for these defects may also be modified by polymorphisms in genes encoding enzymes in the folate metabolic pathway.…”

Section: Introductionmentioning

confidence: 99%

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

Deng

Elmore

Lawrance

et al. 2008

Molecular Genetics and Metabolism

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Low dietary folate and polymorphisms in genes of folate metabolism can influence risk for pregnancy complications and birth defects. Methionine synthase reductase (MTRR) is required for activation of methionine synthase, a folate-and vitamin B 12 -dependent enzyme. A polymorphism in MTRR (p.I22M), present in the homozygous state in 25% of many populations, may increase risk for neural tube defects. To examine the impact of MTRR deficiency on early development and congenital heart defects, we used mice harboring a gene-trapped (gt) allele in Mtrr. Female mice (Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt ) were mated with male Mtrr +/g mice. Reproductive outcomes and cardiac phenotype (presence of defects and myocardial thickness) were assessed at E14.5. Mtrrdeficient mothers had more resorptions and more delayed embryos per litter (resorptions per litter: 0.29 ± 0.13; 1.21 ± 0.41; 1.87 ± 0.38 and delayed embryos per litter: 0.07 ± 0.07; 0.14 ± 0.14; 0.60 ± 0.24 in Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt mothers respectively). Placentae of Mtrr gt/gt mothers were smaller and their embryos were smaller, with myocardial hypoplasia and a higher incidence of ventricular septal defects (VSD) per litter (0; 0.57 ± 0.30; 1.57 ± 0.67 in Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt groups respectively). Embryonic Mtrr gt/gt genotype was associated with reduced embryonic length, reduced embryonic and placental weight, and higher incidence of VSD, but did not affect myocardial thickness or embryonic delay. We conclude that Mtrr deficiency adversely impacts reproductive outcomes and cardiac development in mice. These findings may have implications for nutritional prevention of heart defects, particularly in women with the common MTRR polymorphism.

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Section: Introductionmentioning

confidence: 99%

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

Deng

Elmore

Lawrance

et al. 2008

Molecular Genetics and Metabolism

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“…The BA1 mesenchyme is populated with neural crest cells (NCCs) derived from the margins of the developing neural tube. Like the neural tube, NCCs appear to be particularly sensitive to maternal dietary and plasma folate concentrations during development (17,47,48) and methyl donor supplementation supports the role of folate in 1-carbon metabolism. This may partially explain how the NCC-populated BA1 mesenchyme could be a suitable target for methyl donor action.…”

Section: Discussionmentioning

confidence: 89%

Maternal Diet Supplementation with Methyl Donors and Increased Parity Affect the Incidence of Craniofacial Defects in the Offspring of Twisted gastrulation Mutant Mice

Billington

Schmidt

Zhang

et al. 2013

The Journal of Nutrition

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Diets rich in methyl-donating compounds, including folate, can provide protection against neural tube defects, but their role in preventing craniofacial defects is less clear. Mice deficient in Twisted gastrulation (TWSG1), an extracellular modulator of bone morphogenetic protein signaling, manifest both midline facial defects and jaw defects, allowing study of the effects of methyl donors on various craniofacial defects in an experimentally tractable animal model. The goal of this study was to examine the effects of maternal dietary supplementation with methyl donors on the incidence and type of craniofacial defects among Twsg1 2/2 offspring. Nulliparous and primiparous female mice were fed an NIH31 standard diet (control) or a methyl donor supplemented (MDS) diet (folate, vitamin B-12, betaine, and choline). Observed defects in the pups were divided into those derived mostly from the first branchial arch (BA1) (micrognathia, agnathia, cleft palate) and midline facial defects in the holoprosencephaly spectrum (cyclopia, proboscis, and anterior truncation). In the first pregnancy, offspring of mice fed the MDS diet had lower incidence of BA1-derived defects (12.8% in MDS vs. 32.5% in control; P = 0.02) but similar incidence of midline facial defects (6.4% in MDS vs. 5.2% in control; P = 1.0). Increased maternal parity was independently associated with increased incidence of craniofacial defects after adjusting for diet (from 37.7 to 59.5% in control, P = 0.04 and from 19.1 to 45.3% in MDS, P = 0.045). In conclusion, methyl donor supplementation shows protective effects against jaw defects, but not midline facial defects, and increased parity can be a risk factor for some craniofacial defects.

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“…Burgoon and co-authors on IRC mice for a duration of 4 weeks on 0% folic acid diet, revealed a reduction in male reproduction (less offspring per litter), in response to a folate deficient diet and therefore provided a further support to the human data (Burgoon et al, 2002). …”

Section: Folate Deficiency In Rodentsmentioning

confidence: 83%

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

Voutounou

Glen

Dubrova

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Investigation of the effects of folate deficiency on embryonic development through the establishment of a folate deficient mouse model

Cited by 121 publications

References 49 publications

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

Maternal Diet Supplementation with Methyl Donors and Increased Parity Affect the Incidence of Craniofacial Defects in the Offspring of Twisted gastrulation Mutant Mice

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

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