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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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Folate, homocysteine and polyamine pathways. Gray cells highlight molecules of special interest.
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Figure 3: Folate, homocysteine and polyamine pathways. Gray cells highlight molecules of special interest.

Mentions: FA affects many aspects of reproduction and fertility as well as imprinting and related parent-of-origin effects. Anomalies in FA metabolism can affect fertility, placental function and pregnancy in humans [12]–[17] and in mice [35]. FA acid metabolism is actively involved in DNA methylation, a major class of epigenetic modification (see Figure 3 for a schematic of the relevant pathways). The one-carbon (folate) pathway involves acquisition of a methyl group from diet or metabolic salvage, and then its transfer to S-adenosylmethionine (SAM) in the methylation (homocysteine) pathway. SAM is the one-carbon donor for methylation of nucleic acids, proteins, lipids and other molecules [9]–[11]. Methylation changes are the molecular basis for many imprinting [36] and some parent-of-origin effects [37]. FA deficiency affects expression of many genes in mouse sperm [16]. Some FA-induced epigenetic changes can also be transmitted through the germline to affect phenotypic variation in subsequent generations [38]–[41]. Recently, the egg receptor (Juno) for the sperm cell-surface protein (Izumo1) was identified [42], see also [43]. These two proteins mediate egg-sperm recognition and activate a block to polyspermy. Interestingly, Juno is a member of a folate receptor family, but does not bind folate. Whether FA affects interactions between Juno and Izumo1 has not been tested. Anomalies in FA metabolism could therefore bias allelic inheritance through imprinting and related parent-of-origin effects, but direct evidence for effects on gametes and fertilization is lacking.


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)

Folate, homocysteine and polyamine pathways. Gray cells highlight molecules of special interest.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Folate, homocysteine and polyamine pathways. Gray cells highlight molecules of special interest.
Mentions: FA affects many aspects of reproduction and fertility as well as imprinting and related parent-of-origin effects. Anomalies in FA metabolism can affect fertility, placental function and pregnancy in humans [12]–[17] and in mice [35]. FA acid metabolism is actively involved in DNA methylation, a major class of epigenetic modification (see Figure 3 for a schematic of the relevant pathways). The one-carbon (folate) pathway involves acquisition of a methyl group from diet or metabolic salvage, and then its transfer to S-adenosylmethionine (SAM) in the methylation (homocysteine) pathway. SAM is the one-carbon donor for methylation of nucleic acids, proteins, lipids and other molecules [9]–[11]. Methylation changes are the molecular basis for many imprinting [36] and some parent-of-origin effects [37]. FA deficiency affects expression of many genes in mouse sperm [16]. Some FA-induced epigenetic changes can also be transmitted through the germline to affect phenotypic variation in subsequent generations [38]–[41]. Recently, the egg receptor (Juno) for the sperm cell-surface protein (Izumo1) was identified [42], see also [43]. These two proteins mediate egg-sperm recognition and activate a block to polyspermy. Interestingly, Juno is a member of a folate receptor family, but does not bind folate. Whether FA affects interactions between Juno and Izumo1 has not been tested. Anomalies in FA metabolism could therefore bias allelic inheritance through imprinting and related parent-of-origin effects, but direct evidence for effects on gametes and fertilization is lacking.

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