Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC.
Department of Biology, The George Washington University, Washington, DC.
Birth Defects Res. 2017 Jan 20;109(1):16-26. doi: 10.1002/bdra.23589.
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.
We determined the effect of iron and/or folic acid supplementation on the penetrance of NTDs in the Lrp2 mouse model. The effects of supplementation on folate and iron status were measured in embryos and dams.
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, Lrp2 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 Lrp2 mutants.
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.
神经管缺陷（NTDs）是人类最常见的结构出生缺陷之一，是由遗传和环境因素的复杂相互作用引起的。在受孕前补充叶酸可以预防小鼠模型和人类群体中的 NTDs。更好地了解基因和环境因素如何相互作用，对于制定预防 NTDs 的合理策略至关重要。低密度脂蛋白相关蛋白 2（Lrp2）在摄取叶酸受体等多种营养物质和配体中起作用。
我们确定了铁和/或叶酸补充对 Lrp2 小鼠模型中 NTD 发生率的影响。补充对胚胎和母体中叶酸和铁状况的影响进行了测量。
受孕前补充叶酸并不能预防 Lrp2 突变胚胎中的 NTDs，而腹腔内注射高剂量的叶酸补充可降低 NTDs 的发生率。重要的是，Lrp2 母体的血液叶酸水平降低，而每日腹腔内注射叶酸可改善这种情况，但饮食补充则不行。相反，铁补充对 Lrp2 突变胚胎中 NTDs 的发生率没有影响，并否定了叶酸补充在 Lrp2 突变体中的预防作用。
Lrp2 是杂合子母体中叶酸平衡所必需的，高水平的补充可预防 NTDs。此外，高剂量的膳食铁补充会干扰叶酸补充，否定了这种模型中补充的积极作用。出生缺陷研究 109：16-26，2017。©2016 作者。出生缺陷由 Wiley 期刊出版公司出版。
