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Does dietary folic acid supplementation in mouse NTD models affect neural tube development or gamete preference at fertilization?

Nakouzi GA, Nadeau JH - BMC Genet. (2014)

Bottom Line: Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies.In addition, many cases remain resistant to the beneficial effects of folic acid supplementation.Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. jnadeau@pnri.org.

ABSTRACT

Background: Neural tube defects (NTDs) are the second most common birth defect in humans. Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies. FA plays an established role in folate and homocysteine metabolism, but the means by which it suppresses occurrence of NTDs is not understood. In addition, many cases remain resistant to the beneficial effects of folic acid supplementation. To better understand the molecular, biochemical and developmental mechanisms by which FA exerts its effect on NTDs, characterized mouse models are needed that have a defined genetic basis and known response to dietary supplementation.

Results: We examined the effect of FA supplementation, at 5-fold the level in the control diet, on the NTD and vertebral phenotypes in Apobtm1Unc and Vangl2Lp mice, hereafter referred to as Apob and Lp respectively. The FA supplemented diet did not reduce the incidence or severity of NTDs in Apob or Lp mutant homozygotes or the loop-tail phenotype in Lp mutant heterozygotes, suggesting that mice with these mutant alleles are resistant to FA supplementation. Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

Conclusion: Similar genotypic biases have been reported for several NTD models, but were interpreted as diet-induced increases in the incidence and severity of NTDs that led to increased embryonic lethality. Absence of differences in resorption rates and litter sizes argue against induced embryonic lethality. We suggest an alternative interpretation, namely that FA supplementation led to strongly skewed allelic inheritance, perhaps from disturbances in polyamine metabolism that biases fertilization in favor of wild-type gametes.

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Dietary supplementation protocol. Three-week old female and male heterozygous mice ( or Lp mutants) were weaned on either the 2 ppm or 10 ppm FA diet, mated at 6 weeks of age, and then maintained on these diets through the remainder of the study. Embryos examined at E12.5 – E14.5.
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Figure 4: Dietary supplementation protocol. Three-week old female and male heterozygous mice ( or Lp mutants) were weaned on either the 2 ppm or 10 ppm FA diet, mated at 6 weeks of age, and then maintained on these diets through the remainder of the study. Embryos examined at E12.5 – E14.5.

Mentions: Heterozygous males and females from both mutants were weaned at 3 weeks of age and thereafter maintained on either a control diet containing 2 ppm FA (D05072702, Research Diets) or a supplemented diet containing 10 ppm FA (D05072701, Research Diets) for at least 3 weeks prior to mating (Figure 4). Timed pregnancies were then generated by mating 6–10 week old females with males overnight. Upon discovery of a plug, females were kept on the same diet until they were sacrificed. Between E12.5-14.5 pregnant females were sacrificed and embryos examined (Figure 4). Tissues were obtained from all embryos for DNA extraction and genotyping. All mice shared the same animal room with controlled temperature, humidity, and 12 hour light–dark cycle. Mice were provided food and water ad libitum. The CWRU Institutional Animal Care and Use Committee approved all procedures.


Does dietary folic acid supplementation in mouse NTD models affect neural tube development or gamete preference at fertilization?

Nakouzi GA, Nadeau JH - BMC Genet. (2014)

Dietary supplementation protocol. Three-week old female and male heterozygous mice ( or Lp mutants) were weaned on either the 2 ppm or 10 ppm FA diet, mated at 6 weeks of age, and then maintained on these diets through the remainder of the study. Embryos examined at E12.5 – E14.5.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4151023&req=5

Figure 4: Dietary supplementation protocol. Three-week old female and male heterozygous mice ( or Lp mutants) were weaned on either the 2 ppm or 10 ppm FA diet, mated at 6 weeks of age, and then maintained on these diets through the remainder of the study. Embryos examined at E12.5 – E14.5.
Mentions: Heterozygous males and females from both mutants were weaned at 3 weeks of age and thereafter maintained on either a control diet containing 2 ppm FA (D05072702, Research Diets) or a supplemented diet containing 10 ppm FA (D05072701, Research Diets) for at least 3 weeks prior to mating (Figure 4). Timed pregnancies were then generated by mating 6–10 week old females with males overnight. Upon discovery of a plug, females were kept on the same diet until they were sacrificed. Between E12.5-14.5 pregnant females were sacrificed and embryos examined (Figure 4). Tissues were obtained from all embryos for DNA extraction and genotyping. All mice shared the same animal room with controlled temperature, humidity, and 12 hour light–dark cycle. Mice were provided food and water ad libitum. The CWRU Institutional Animal Care and Use Committee approved all procedures.

Bottom Line: Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies.In addition, many cases remain resistant to the beneficial effects of folic acid supplementation.Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. jnadeau@pnri.org.

ABSTRACT

Background: Neural tube defects (NTDs) are the second most common birth defect in humans. Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies. FA plays an established role in folate and homocysteine metabolism, but the means by which it suppresses occurrence of NTDs is not understood. In addition, many cases remain resistant to the beneficial effects of folic acid supplementation. To better understand the molecular, biochemical and developmental mechanisms by which FA exerts its effect on NTDs, characterized mouse models are needed that have a defined genetic basis and known response to dietary supplementation.

Results: We examined the effect of FA supplementation, at 5-fold the level in the control diet, on the NTD and vertebral phenotypes in Apobtm1Unc and Vangl2Lp mice, hereafter referred to as Apob and Lp respectively. The FA supplemented diet did not reduce the incidence or severity of NTDs in Apob or Lp mutant homozygotes or the loop-tail phenotype in Lp mutant heterozygotes, suggesting that mice with these mutant alleles are resistant to FA supplementation. Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

Conclusion: Similar genotypic biases have been reported for several NTD models, but were interpreted as diet-induced increases in the incidence and severity of NTDs that led to increased embryonic lethality. Absence of differences in resorption rates and litter sizes argue against induced embryonic lethality. We suggest an alternative interpretation, namely that FA supplementation led to strongly skewed allelic inheritance, perhaps from disturbances in polyamine metabolism that biases fertilization in favor of wild-type gametes.

Show MeSH
Related in: MedlinePlus