Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
Am J Clin Nutr. 2012 Apr;95(4):882-91. doi: 10.3945/ajcn.111.030783. Epub 2012 Feb 29.
MTHFD1 encodes C1-tetrahydrofolate synthase, which is a folate-dependent enzyme that catalyzes the formation and interconversion of folate-activated one-carbon groups for nucleotide biosynthesis and cellular methylation. A polymorphism in MTHFD1 (1958G→A) impairs enzymatic activity and is associated with increased risk of adverse pregnancy outcomes, but the mechanisms are unknown.
The objective of this study was to determine whether disruption of the embryonic or maternal Mthfd1 gene or both interacts with impaired folate and choline status to affect neural tube closure, fetal growth, and fertility in mice and to investigate the underlying metabolic disruptions.
Dams with a gene-trapped (gt) allele in Mthfd1 and wild-type dams were fed a control or folate- and choline-deficient AIN93G diet (Dyets Inc). Litters were examined for gross morphologic defects, crown-rump length, and resorptions. Folate status and amounts of folate-related metabolites were determined in pregnant dams.
Reduced folate and choline status resulted in severe fetal growth restriction (FGR) and impaired fertility in litters harvested from Mthfd1(gt/+) dams, but embryonic Mthfd1(gt/+) genotype did not affect fetal growth. Gestational supplementation of Mthfd1(gt/+) dams with hypoxanthine increased FGR frequency and caused occasional neural tube defects (NTDs) in Mthfd1(gt/+) embryos. Mthfd1(gt/+) dams exhibited lower red blood cell folate and plasma methionine concentrations than did wild-type dams.
Maternal Mthfd1(gt/+) genotype impairs fetal growth but does not cause NTDs when dams are maintained on a folate- and choline-deficient diet. Mthfd1(gt/+) mice exhibit a spectrum of adverse reproductive outcomes previously attributed to the human MTHFD1 1958G→A polymorphism. Mthfd1 heterozygosity impairs folate status in pregnant mice but does not significantly affect homocysteine metabolism.
MTHFD1 编码 C1-四氢叶酸合酶，该酶是一种依赖于叶酸的酶，可催化叶酸激活的一碳基团的形成和相互转化，用于核苷酸合成和细胞甲基化。MTHFD1 中的一个多态性（1958G→A）会损害酶的活性，并与不良妊娠结局的风险增加相关，但机制尚不清楚。
本研究旨在确定胚胎或母体 Mthfd1 基因的破坏或两者的相互作用是否会与叶酸和胆碱状态受损相互作用，从而影响小鼠的神经管闭合、胎儿生长和生育能力，并探讨潜在的代谢紊乱。
携带 Mthfd1 基因陷阱（gt）等位基因的母鼠和野生型母鼠分别喂食对照或叶酸和胆碱缺乏的 AIN93G 饮食（Dyets Inc）。检查胎鼠的大体形态缺陷、颅尾长度和吸收情况。测定妊娠母鼠的叶酸状态和叶酸相关代谢物的含量。
减少叶酸和胆碱状态会导致携带 Mthfd1(gt/+)基因型的母鼠的胎儿生长严重受限（FGR）和生育力受损，但胚胎 Mthfd1(gt/+)基因型不会影响胎儿生长。用次黄嘌呤对携带 Mthfd1(gt/+)基因型的母鼠进行妊娠期补充，增加了 FGR 的频率，并导致 Mthfd1(gt/+)胚胎偶尔出现神经管缺陷（NTD）。携带 Mthfd1(gt/+)基因型的母鼠的红细胞叶酸和血浆蛋氨酸浓度低于野生型母鼠。
当母鼠维持在叶酸和胆碱缺乏的饮食时，母体 Mthfd1(gt/+)基因型会损害胎儿生长，但不会导致 NTDs。Mthfd1(gt/+) 小鼠表现出一系列不良生殖结果，这些结果以前归因于人类 MTHFD1 1958G→A 多态性。Mthfd1 杂合性会损害妊娠小鼠的叶酸状态，但对同型半胱氨酸代谢没有显著影响。
