FOLATE ONE-CARBON METABOLISM IN MOUSE MODELS OF NEURAL TUBE DEFECTS

Abstract

Neural tube defects (NTDs) are common and severe birth defects. These abnormalities arise early in development, likely before the mother is aware she is pregnant. It has been well established that low maternal folate status before and during pregnancy is associated with NTD risk. However, the mechanism of how folic acid supplementation prevents NTDs is yet to be elucidated. It is known that NTDs have a multifactorial etiology, involving genetic and environmental contributions. To date, impaired de novo thymidylate (dTMP) biosynthesis and its associated accumulation of uracil in DNA is the only known metabolic risk for folate-responsive NTDs. The goals of these studies were to explore NTD risk in multiple mouse models of altered de novo dTMP synthesis including, p53-/-, Shmt1-/-, and Shmt2α-/-. We challenged the models with folate deficiency to determine if folic acid could prevent NTDs in these genetically-sensitized mouse models of NTDs. We also investigated the effects of dietary components on NTD prevalence. We exposed the mice to oral arsenic trioxide in the drinking water, because it is a known teratogen that can cause NTDs. In another study we compared a reduced folate supplementation to folic acid in its ability to rescue arsenic-induced NTDs. Our results revealed that p53-/--induced NTDs are not folic acid responsive and mouse embryonic fibroblasts (MEFs) still have increased uracil accumulation in DNA despite increased de novo dTMP synthesis. Another study determined that folic acid is not sufficient to rescue arsenic-induced NTDs although it does rescue genomic instability and uracil accumulation in DNA of MEFs. When comparing different types of folate supplementation, we found that a novel reduced form, 5-formyl, 10-formylTHF, is also unable to rescue arsenic-NTDs, but works as efficiently as folic acid supplementation in terms of rescuing other adverse reproductive outcomes. The last study found that loss of the isoform Shmt2α, does not cause NTDs even when presented with a folate deficient diet. In conclusion these studies shed light on gene-exposure interactions in the risk for NTDs.