High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring.
High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring.
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DOI：
10.1093/hmg/ddx004
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发表时间：
2017-03-01
影响因子：
3.5
通讯作者：
Rozen R
中科院分区：
文献类型：
--
作者：
Bahous RH;Jadavji NM;Deng L;Cosín-Tomás M;Lu J;Malysheva O;Leung KY;Ho MK;Pallàs M;Kaliman P;Greene NDE;Bedell BJ;Caudill MA;Rozen R
亚甲基四氢叶酸还原酶（MTHFR）产生甲基四氢叶酸用于甲基化反应。严重的 MTHFR 缺乏会导致同型半胱氨酸尿症和神经功能障碍。轻度 MTHFR 缺乏（677C > T 多态性）会增加复杂性状的风险，包括神经精神疾病。尽管低膳食叶酸会影响大脑发育，但最近的担忧集中在食品强化和增加维生素使用后的高叶酸摄入量。我们的目标是确定怀孕期间高膳食叶酸是否会影响小鼠后代的大脑发育。雌性小鼠在交配、怀孕和哺乳期间均接受对照饮食（CD）或补充叶酸的饮食（FASD）。对三周大的雄性幼崽进行运动和认知功能评估。收集 E17.5 胚胎、幼崽和母鼠的组织用于胆碱/甲基代谢物测量、免疫印迹或相关酶的基因表达。检查大脑的海马体和皮质的形态。 FASD 母亲的幼崽表现出短期记忆障碍、海马尺寸减小和齿状回厚度减小。 FASD 幼犬肝脏中 MTHFR 蛋白水平降低，肝脏和海马中磷酸胆碱和甘油磷酸胆碱的浓度分别较低。 FASD 幼犬大脑显示出乙酰胆碱可用性改变的证据，并且皮层和海马中的 Dnmt3a mRNA 减少。 FASD 母鼠的 E17.5 胚胎和胎盘较小。胚胎肝脏中MTHFR蛋白和mRNA减少，胆碱、甜菜碱和磷酸胆碱浓度降低。胚胎大脑表现出皮质层发育的改变。总之，怀孕期间叶酸摄入过多会导致假性 MTHFR 缺乏、胆碱/甲基代谢紊乱、胚胎生长延迟和后代记忆障碍。这些发现凸显了补充叶酸带来的意想不到的负面后果。
Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C > T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or folic acid-supplemented diet (FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for choline/methyl metabolite measurements, immunoblotting or gene expression of relevant enzymes. Brains were examined for morphology of hippocampus and cortex. Pups of FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR protein levels were reduced in FASD pup livers, with lower concentrations of phosphocholine and glycerophosphocholine in liver and hippocampus, respectively. FASD pup brains showed evidence of altered acetylcholine availability and Dnmt3a mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from FASD dams were smaller. MTHFR protein and mRNA were reduced in embryonic liver, with lower concentrations of choline, betaine and phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high folate intake during pregnancy leads to pseudo-MTHFR deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid.