Background Folic acid (FA) supplementation during pregnancy aims to protect foetal development. However, maternal over-supplementation of FA has been demonstrated to cause metabolic dysfunction and increase the risk of autism, retinoblastoma, and respiratory illness in the offspring. Moreover, FA supplementation reduces the risk of congenital heart disease. However, little is known about its possible adverse effects on cardiac health resulting from maternal over-supplementation. In this study, we assessed the detrimental effects of maternal FA over-supplementation on the cardiac health of the offspring. Methods and Results Eight-week-old C57BL/6J pregnant mice were randomly divided into control and over-supplemented groups. The offspring cardiac function was assessed using echocardiography. Cardiac fibrosis was assessed in the left ventricular myocardium by histological analysis. Proteomic, protein, RNA, and DNA methylation analyses were performed by liquid chromatography–tandem mass spectrometry, western blotting, real-time quantitative PCR, and bisulfite sequencing, respectively. We found that maternal periconceptional FA over-supplementation impaired cardiac function with the decreased left ventricular ejection fraction in the offspring. Biochemical indices and tissue staining further confirmed impaired cardiac function in offspring caused by maternal FA over-supplementation. The combined proteomic, RNA expression, and DNA methylation analyses suggested that key genes involved in cardiac function were inhibited at the transcriptional level possibly due to increased DNA methylation. Among these, superoxide dismutase 1 was downregulated, and reactive oxygen species (ROS) levels increased in the mouse heart. Inhibition of ROS generation using the antioxidant N-acetylcysteine rescued the impaired cardiac function resulting from maternal FA over-supplementation. Conclusions Our study revealed that over-supplementation with FA during mouse pregnancy is detrimental to cardiac function with the decreased left ventricular ejection fraction in the offspring and provides insights into the mechanisms underlying the association between maternal FA status and health outcomes in the offspring.

中文翻译：

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母体过量补充叶酸通过抑制 SOD1 表达损害小鼠后代的心功能


背景 怀孕期间补充叶酸（FA）旨在保护胎儿发育。然而，母亲过量补充 FA 已被证明会导致代谢功能障碍，并增加后代患自闭症、视网膜母细胞瘤和呼吸道疾病的风险。此外，补充FA可降低先天性心脏病的风险。然而，人们对母亲过度补充可能对心脏健康产生的不利影响知之甚少。在这项研究中，我们评估了母亲过量补充 FA 对后代心脏健康的不利影响。方法和结果将8周龄的C57BL/6J妊娠小鼠随机分为对照组和过量补充组。使用超声心动图评估后代的心脏功能。通过组织学分析评估左心室心肌的心脏纤维化。分别通过液相色谱-串联质谱、蛋白质印迹、实时定量PCR和亚硫酸氢盐测序进行蛋白质组、蛋白质、RNA和DNA甲基化分析。我们发现，母亲围孕期过量补充 FA 会损害心脏功能，导致后代左心室射血分数降低。生化指标和组织染色进一步证实母体 FA 过量补充导致子代心脏功能受损。蛋白质组学、RNA 表达和 DNA 甲基化综合分析表明，与心脏功能相关的关键基因在转录水平受到抑制，可能是由于 DNA 甲基化增加所致。其中，小鼠心脏中的超氧化物歧化酶 1 下调，活性氧 (ROS) 水平升高。 使用抗氧化剂 N-乙酰半胱氨酸抑制 ROS 生成，可挽救因母体 FA 过量补充而导致的心脏功能受损。结论 我们的研究表明，小鼠妊娠期间过量补充 FA 不利于心脏功能，导致后代左心室射血分数降低，并为了解母体 FA 状态与后代健康结果之间的关联机制提供了见解。