National Key Discipline Laboratory, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, PR China.
National Key Discipline Laboratory, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, PR China.
Clin Nutr. 2022 Jan;41(1):21-32. doi: 10.1016/j.clnu.2021.11.004. Epub 2021 Nov 10.
BACKGROUND & AIMS: Folic acid supplementation is widely accepted during pregnancy, as it exerts a protective effect on neural tube defects. However, the long-term underlying effects of folic acid supplementation during pregnancy (FASDP) on offspring remain unclear.
Thirty pregnant female rats were randomly divided into normal control group, folic acid appropriate supplementation group (2.5 × FA group) and folic acid oversupplementation group (5 × FA group) and fed with corresponding folic acid concentration AIN93G diet. UPLC-Q-TOF-MS, UPLC-TQ-MS and GC-MS were performed to detect the serum metabolites profiles in adult male offspring and explore the effects of FASDP. Moreover, molecular biology technologies were used to clarify the underlying mechanism.
We demonstrate that 2.5-folds folic acid leads to dyslipidemic-diabetic slightly in male offspring, while 5-folds folic acid aggravates the disorder and prominent hepatic lipid accumulations. Using untargeted and targeted metabolomics, total 63 differential metabolites and 12 significantly differential KEGG pathways are identified. Of note, arginine biosynthesis, arginine and proline metabolism are the two most significant pathways. Mechanistic investigations reveal that the increased levels of arginase-1 (Arg1) causes the lipid metabolism disorder by regulating nitric oxide synthase-3 (NOS3)-adenosine monophosphate activated protein kinase-α (AMPKα) pathway, resulting in lipid accumulation in hepatocytes.
Our data suggest that maternal folic acid oversupplementation during pregnancy contributes to lipid metabolism disorder in male offspring by regulating Arg1-NOS3-AMPKα pathway.
叶酸补充剂在怀孕期间被广泛接受，因为它对神经管缺陷有保护作用。然而，怀孕期间叶酸补充（FASDP）对后代的长期潜在影响尚不清楚。
30 只怀孕雌性大鼠随机分为正常对照组、叶酸适当补充组（2.5×FA 组）和叶酸过度补充组（5×FA 组），并给予相应叶酸浓度 AIN93G 饮食。采用 UPLC-Q-TOF-MS、UPLC-TQ-MS 和 GC-MS 检测成年雄性后代的血清代谢物谱，探讨 FASDP 的影响。此外，还采用分子生物学技术阐明其潜在机制。
我们证明 2.5 倍叶酸导致雄性后代出现轻度血脂糖尿病，而 5 倍叶酸则加重了这种紊乱和明显的肝脂质堆积。通过非靶向和靶向代谢组学，共鉴定出 63 种差异代谢物和 12 种差异显著的 KEGG 通路。值得注意的是，精氨酸生物合成、精氨酸和脯氨酸代谢是两个最重要的通路。机制研究表明，增加的精氨酸酶-1（Arg1）水平通过调节一氧化氮合酶-3（NOS3）-腺苷单磷酸激活蛋白激酶-α（AMPKα）通路导致脂质代谢紊乱，导致肝细胞脂质堆积。
我们的数据表明，母亲在怀孕期间过度补充叶酸会通过调节 Arg1-NOS3-AMPKα 通路导致雄性后代脂质代谢紊乱。
