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. 2012 Jan;95(1):109-14.
doi: 10.3945/ajcn.111.020305. Epub 2011 Nov 30.

Dietary folate, but not choline, modifies neural tube defect risk in Shmt1 knockout mice

Anna E Beaudin  1 , Elena V Abarinov, Olga Malysheva, Cheryll A Perry, Marie Caudill, Patrick J Stover
Affiliations

Dietary folate, but not choline, modifies neural tube defect risk in Shmt1 knockout mice

Anna E Beaudin et al. Am J Clin Nutr. 2012 Jan.

Abstract

Background: Low dietary choline intake has been proposed to increase the risk of neural tube defects (NTDs) in human populations. Mice with reduced Shmt1 expression exhibit a higher frequency of NTDs when placed on a folate- and choline-deficient diet and may represent a model of human NTDs. The individual contribution of dietary folate and choline deficiency to NTD incidence in this mouse model is not known.

Objective: To dissociate the effects of dietary folate and choline deficiency on Shmt1-related NTD sensitivity, we determined NTD incidence in embryos from Shmt1-null dams fed diets deficient in either folate or choline.

Design: Shmt1(+/+) and Shmt1(-/-) dams were maintained on a standard AIN93G diet (Dyets), an AIN93G diet lacking folate (FD), or an AIN93G diet lacking choline (CD). Virgin Shmt1(+/+) and Shmt1(-/-) dams were crossed with Shmt1(+/-) males, and embryos were examined for the presence of NTDs at embryonic day (E) 11.5 or E12.5.

Results: Exencephaly was observed only in Shmt1(-/-) embryos isolated from dams maintained on the FD diet (P = 0.004). Approximately 33% of Shmt1(-/-)embryos (n = 18) isolated from dams maintained on the FD diet exhibited exencephaly. NTDs were not observed in any embryos isolated from dams maintained on the CD (n = 100) or control (n = 152) diets or in any Shmt1(+/+) (n = 78) or Shmt1(+/-) embryos (n = 182).

Conclusion: Maternal folate deficiency alone is sufficient to induce NTDs in response to embryonic Shmt1 disruption.

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Figures

FIGURE 1.
FIGURE 1.
Nuclear and cytoplasmic folate-mediated one-carbon metabolism. The one-carbon unit and products of one-carbon metabolism are shown in bold. The remethylation of homocysteine to methionine can occur either through the folate-dependent pathway involving 5-methylTHF as the methyl donor or through a folate-independent pathway involving betaine as the methyl donor. The PEMT-catalyzed formation of phosphatidylcholine is an example of an AdoMet-dependent methylation reaction. The de novo thymidylate biosynthesis pathway translocates to the nucleus during the S phase. AdoHcy, S-adenosylhomocysteine; AdoMet, S-adenosylmethionine; BHMT, betaine:homocysteine methyltransferase; DHF, dihydrofolate; DHFR, dihydrofolate reductase; dUMP, deoxyuridine monophosphate; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; PEMT, phosphatidylethanolamine methyltransferase; SHMT1, serine hydroxymethyltransferase 1; THF, tetrahydrofolate; TYMS, thymidylate synthase.
FIGURE 2.
FIGURE 2.
A: Shmt1−/− embryos isolated from dams fed a folate-deficient diet exhibit exencephaly. B: No neural tube defects were observed in Shmt1+/− littermates.
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