Grant Abstract: Folic Acid, B12, and Neurodevelopmental Risk

Grant Number: 5R01HD107489-03
PI Name: Zarbalis
Project Title: Folic Acid, B12, and Neurodevelopmental Risk

Abstract: 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. PUBLIC HEALTH RELEVANCE: The environmental causes of cerebral cortical defects that can be central to neurodevelopmental disorders remain poorly understood. Our research will uncover how different amounts of folic acid intake during pregnancy possibly in conjunction with vitamin B12 deficiency can alter brain development and potentially contribute to neurodevelopmental conditions.

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