Folic Acid, B12, and Neurodevelopmental Risk

叶酸、维生素 B12 和神经发育风险

基本信息

批准号：
10346956
负责人：
RALPH GREEN
金额：
$ 41.4万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-10 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10346956
关键词：
Adolescent Animal Model Animals Anxiety Disorders Apoptosis Apoptotic Behavioral Biochemical Biological Assay Blood Blood specimen Brain Carbon Cereals Cerebral cortex Cerebrum Child Cognition Disorders Conceptions Consumption DNA Methylation Defect Development Diet Embryo Enzymes Exhibits Exposure to Folic Acid Food Generations Genetic Grain Guidelines Histologic Homocysteine Human In Situ Nick-End Labeling Incidence Intake Intellectual functioning disability Interneurons Investigation Label Learning Leucovorin Life Link Liver Malabsorption Syndromes Measures Memory Metabolism Methionine Methylation Methylmalonic Acid Micronutrients Morphology Mothers Mus Natural regeneration Neural Tube Defects Neurodevelopmental Disorder Neuronal Migration Disorder Neurons Newborn Infant Outcome Pathologic Pathway interactions Pattern Placenta Plasma Population Pre-Clinical Model Pregnancy Pregnant Women Prevention strategy Public Health Publishing Reaction Reporting Research Risk Risk Factors SLC19A1 gene Series Serum Folate Level Site Social Interaction Source Structural defect Supplementation Testing Tetrahydrofolates Tissues Umbilical Cord Blood United States Food and Drug Administration Variant Vegan Diet Vertebral column Vitamin B 12 Vitamin B 12 Deficiency Work anxiety-related behavior autism spectrum disorder behavior test bisulfite sequencing brain size childhood epilepsy density deprivation dietary dietary supplements embryo tissue epidemiology study fetal folic acid supplementation fortification metabolomics methylation pattern multidisciplinary neocortical nerve stem cell neurodevelopment neurogenesis novel object recognition offspring pregnant prenatal prevent progenitor programs pup social deficits trend whole genome young adult

项目摘要

The research objective of this multidisciplinary proposal is to examine the neurodevelopmental, behavioral, and biochemical consequences of excessive and deficient folic acid supplementation in a preclinical model. In this context vitamin B12 deficiency, a micronutrient required for the folate cycle, will also be tested. Central to our investigation are structural defects of the cerebral cortex, the predominant site of maldevelopment in a range of neurodevelopmental disorders, including neuronal migration disorders, childhood epilepsy, intellectual disability, and autism spectrum disorders (ASD). In these conditions, changes in prenatal neurogenesis can be the principal cause of structural abnormalities, such as pathological brain size variation, cortical lamination defects, or defective cytoarchitectural integrity. Consequently, further investigating the genetic and environmental causes and consequences of dysregulated early neurogenesis is of key importance towards a better understanding of neurodevelopmental disorders and the conception of preventive strategies. In 1998, the Food and Drug Administration mandated the fortification of grain products with folic acid to reduce the incidence of neural tube defects, which in combination with rising supplementation has led to a substantial increase in folic acid intake in the US. Intriguingly, our preliminary work has confirmed that excess maternal folic acid intake can alter cortical developmental neurogenesis. The question that arises from these observations is can too much of a good thing be a bad thing? Could excess folic acid intake during pregnancy result in altered cortical neurogenesis causing cerebral structural defects with life-long consequences. This concept has obtained further relevance by recent reports from epidemiological studies that found a higher incidence of ASD cases born to mothers with highest folate levels in their blood. To comprehensively explore this question, we will administer folic acid under three different conditions, a reduced folate in excess, and both in combination with B12 deficiency to pregnant dams to create test groups of offspring that we will analyze with respect to neurodevelopmental outcomes and behavioral abnormalities associated with social, cognitive, and anxiety disorders. These studies will be accompanied by detailed biochemical investigations on brain folate pathway dysregulations, including folate transport, processing, and consequences for DNA methylation.

这项多学科提案的研究目标是在临床前模型中检查叶酸补充过量和不足对神经发育、行为和生化的影响。在这种情况下，还将测试叶酸循环所需的微量营养素维生素 B12 缺乏症。我们研究的核心是大脑皮层的结构缺陷，这是一系列神经发育障碍中发育不良的主要部位，包括神经元迁移障碍、儿童癫痫、智力障碍和自闭症谱系障碍 (ASD)。在这些情况下，产前神经发生的变化可能是结构异常的主要原因，例如病理性大脑大小变化、皮质层压缺陷或细胞结构完整性缺陷。因此，进一步研究早期神经发生失调的遗传和环境原因和后果对于更好地理解神经发育障碍和预防策略的概念至关重要。 1998年，美国食品和药物管理局强制要求在谷物产品中添加叶酸，以减少神经管缺陷的发生率，这与补充量的增加相结合，导致美国叶酸摄入量大幅增加。有趣的是，我们的初步工作已经证实，母亲摄入过多的叶酸可以改变皮质发育神经发生。这些观察产生的问题是，好事太多会变成坏事吗？怀孕期间摄入过量的叶酸是否会导致皮质神经发生改变，从而导致大脑结构缺陷，并产生终生后果。最近的流行病学研究报告发现，血液中叶酸水平最高的母亲所生自闭症谱系障碍病例的发生率更高，这一概念得到了进一步的重视。为了全面探讨这个问题，我们将在三种不同的条件下给予叶酸，叶酸过量，并结合维生素 B12 缺乏，对怀孕母鼠创建后代测试组，我们将对其神经发育结果和行为异常进行分析与社交、认知和焦虑障碍有关。这些研究将伴随着对大脑叶酸途径失调的详细生化研究，包括叶酸运输、加工和 DNA 甲基化的后果。