Departments of Human Genetics and Pediatrics, McGill University Health Center (MUHC), McGill University, Montreal, Canada.
Division of Nutritional Sciences and Genomics, Cornell University, Ithaca, NY, USA.
Mol Nutr Food Res. 2021 Jul;65(14):e2100197. doi: 10.1002/mnfr.202100197. Epub 2021 Jun 10.
Many pregnant women have higher folic acid (FA) intake due to food fortification and increased vitamin use. It is reported that diets containing five-fold higher FA than recommended for mice (5xFASD) during pregnancy resulted in methylenetetrahydrofolate reductase (MTHFR) deficiency and altered choline/methyl metabolism, with neurobehavioral abnormalities in newborns. The goal is to determine whether these changes have their origins in the placenta during embryonic development.
Female mice are fed control diet or 5xFASD for a month before mating and maintained on these diets until embryonic day 17.5. 5xFASD led to pseudo-MTHFR deficiency in maternal liver and altered choline/methyl metabolites in maternal plasma (increased methyltetrahydrofolate and decreased betaine). Methylation potential (S-adenosylmethionine:S-adenosylhomocysteine ratio) and glycerophosphocholine are decreased in placenta and embryonic liver. Folic acid supplemented diet results in sex-specific transcriptome profiles in placenta, with validation of dietary expression changes of 29 genes involved in angiogenesis, receptor biology or neurodevelopment, and altered methylation of the serotonin receptor 2A gene.
Moderate increases in folate intake during pregnancy result in placental metabolic and gene expression changes, particularly in angiogenesis, which may contribute to abnormal behavior in pups. These results are relevant for determining a safe upper limit for folate intake during pregnancy.
由于食物强化和维生素使用的增加，许多孕妇的叶酸（FA）摄入量较高。据报道，怀孕期间饮食中 FA 的含量比推荐给老鼠的含量高五倍（5xFASD），导致亚甲基四氢叶酸还原酶（MTHFR）缺乏和胆碱/甲基代谢改变，新生儿出现神经行为异常。目的是确定这些变化是否在胚胎发育过程中起源于胎盘。
雌性小鼠在交配前一个月接受对照饮食或 5xFASD 喂养，并在这些饮食中维持到胚胎第 17.5 天。5xFASD 导致母鼠肝脏出现假性 MTHFR 缺乏，并改变母鼠血浆中的胆碱/甲基代谢物（甲基四氢叶酸增加，甜菜碱减少）。胎盘和胚胎肝脏中的甲基化潜力（S-腺苷甲硫氨酸：S-腺苷同型半胱氨酸比）和甘油磷酸胆碱减少。叶酸补充饮食导致胎盘出现性别特异性转录组谱，验证了涉及血管生成、受体生物学或神经发育的 29 个基因的饮食表达变化，以及 5-羟色胺受体 2A 基因的甲基化改变。
怀孕期间叶酸摄入量适度增加会导致胎盘代谢和基因表达改变，特别是在血管生成方面，这可能导致幼崽出现异常行为。这些结果对于确定怀孕期间叶酸摄入的安全上限具有重要意义。
