Folic Acid, B12, and Neurodevelopmental Risk

这项多学科建议的研究目的是在临床前模型中检查过量和缺乏叶酸补充的神经发育，行为和生化后果。在这种情况下，维生素B12缺乏症（叶酸循环所需的一种微量营养素）也将进行测试。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的主要发育不良部位，包括神经元迁移障碍、儿童癫痫、智力残疾和自闭症谱系障碍（ASD）。在这些情况下，产前神经发生的改变可能是结构异常的主要原因，如病理性脑大小变化、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（Food and Drug Administration）要求在谷物产品中添加叶酸，以减少神经管缺陷的发生率，这与叶酸补充剂的增加相结合，导致了美国叶酸摄入量的大幅增加。有趣的是，我们的初步工作已经证实，过量的母体叶酸摄入可以改变皮质发育性神经发生。从这些观察中产生的问题是，好事太多会是坏事吗？怀孕期间过量摄入叶酸是否会导致皮质神经发生改变，从而导致终身的大脑结构缺陷？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的ASD病例发病率更高，这一概念得到了进一步的证实。为了全面探索这个问题，我们将在三种不同的条件下给怀孕的水坝提供叶酸，叶酸过量减少，以及两者结合B12缺乏，以创建后代的测试组，我们将分析与神经发育结果和与社会，认知和焦虑障碍相关的行为异常。这些研究将伴随着对脑叶酸通路失调的详细生化调查，包括叶酸运输、加工和DNA甲基化的后果。

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.