Prevention of neural tube defects in Lrp2 mutant mouse embryos by folic acid supplementation.

BACKGROUND: Neural tube defects (NTDs) are among the most common structural birth defects in humans and are caused by the complex interaction of genetic and environmental factors. Periconceptional supplementation with folic acid can prevent NTDs in both mouse models and human populations. A better understanding of how genes and environmental factors interact is critical toward development of rational strategies to prevent NTDs. Low density lipoprotein-related protein 2 (Lrp2) is involved in endocytosis of the folic acid receptor among numerous other nutrients and ligands. METHODS: We determined the effect of iron and/or folic acid supplementation on the penetrance of NTDs in the Lrp2null mouse model. The effects of supplementation on folate and iron status were measured in embryos and dams. RESULTS: Periconceptional dietary supplementation with folic acid did not prevent NTDs in Lrp2 mutant embryos, whereas high levels of folic acid supplementation by intraperitoneal injection reduced incidence of NTDs. Importantly, Lrp2null/+ dams had reduced blood folate levels that improved with daily intraperitoneal injections of folate but not dietary supplementation. On the contrary, iron supplementation had no effect on the penetrance of NTDs in Lrp2 mutant embryos and negated the preventative effect of folic acid supplementation in Lrp2null/null mutants. CONCLUSION: Lrp2 is required for folate homeostasis in heterozygous dams and high levels of supplementation prevents NTDs. Furthermore, high levels of dietary iron supplementation interfered with folic acid supplementation negating the positive effects of supplementation in this model. Birth Defects Research 109:16-26, 2017. © 2016 The Authors Birth Defects Published by Wiley Periodicals, Inc.