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Excessive Folic Acid Supplementation: A Cause for Autism Spectrum Disorders?

Autism spectrum disorders (ASDs) are a group of phenotypically heterogeneous neurodevelopmental disabilities characterized by impairments in three core functional domains: reciprocal social interactions, verbal communication and stereotyped, repetitive patterns of behaviors. The ASDs are phenotypically heterogeneous, in that affected individuals have varying degrees of deficits. Recent prevalence data indicate a marked increase in ASDs throughout the United States and the world, the causative factors of which remain largely unknown. ASDs are complex disorders, with the probable involvement of both dysregulation of multiple genes and environmental factors. Although ASD are labeled as highly heritable, extensive genome-wide analyses of linkages, copy-number variations, and single nucleotide polymorphism approaches have identified genetic causative factors in only less than 10% of the total cases. Therefore, there is a need for greater emphasis on studies of environmental factors that contribute to the etiology of ASDs. The primary targets for such studies would be factors to which pregnant women and their developing fetuses are exposed and that have the ability to modify gene expression. The New York State Institute for Basic Research in Developmental Disabilities (IBR), located in Staten Island, NY, is studying such factors that contribute to modification of the genome, affecting normal gene expression. These factors that do not change the primary DNA sequence but instead cause dysregulation of gene expression due to covalent modification of the building blocks of the DNA are termed epigenetic factors.

Folic acid (FA) is an essential vitamin that is prescribed to every woman who is pregnant or is planning to achieve pregnancy, and hence can be considered an environmental factor. There are mandatory recommendations for FA supplementation of foods to prevent the occurrence of neural tube defects (NTDs) in newborns. In addition, the guidelines recommend that all women planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400 to 800 mg) of folic acid per day, which is increased to 4 mg/day for women with a history of a prior child with NTDs. Because neural tube closure in human fetuses occurs within the first trimester, the question is raised of the rationale for FA supplementation for the entire duration of the pregnancy. A primary function of FA is to act as a co-factor in enzymes that synthesize nucleic acid and facilitate transfer of 1-carbon methyl groups to DNA and proteins. Methyl groups added on cytosine residues in promoter regions’ CpG dinucleotides in the genomic DNA are responsible for the regulation of gene expression. The IBR research team led by Mohammed Junaid, PhD, head of the Structural Neurobiology Laboratory, hypothesizes that excessive FA supplementation during pregnancy will lead to altered gene expression during the crucial development of the fetus and may be responsible for the behavioral changes evident in the ASDs. Epigenetics plays a crucial role in gene expression during gestational development. The development of a fetus is controlled by precise regulation of gene expression. Certain genes are turned on and off at particular time intervals, and any disruption of such highly orchestrated gene expression will likely have persistent deleterious effects. In a fertilized egg, global DNA demethylation, followed by remethylation, occurs to reprogram the maternal and paternal genomes for efficient regulation of gene expression. A number of imprinted genes with the potential to undergo hypermethylation at CpG islands are expressed in human brain in addition to large regions of partially methylated genomic DNA within neuronally expressed genes that can undergo methylation in response to epigenetic agents such as FA.

Our preliminary results with human lymphoblastoid cells in culture have revealed that FA supplementation causes widespread changes in gene expression, as measured by expression microarrays and further confirmed by Western blot analyses [M.A. Junaid, S. Kuizon, J. Cardona, T. Azher, N. Murakami, R.K. Pullarkat and W.T. Brown. (2011). Folic acid supplementation dysregulates gene expression in lymphoblastoid cells─implications in nutrition. Biochem. Biophys. Res. Comm. 412(4): 688-692]. A prominent gene whose expression is inhibited by FA is FMR1, which encodes the protein FMRP.  In humans, reduced protein levels of FMRP cause Fragile X syndrome, the most common known cause of inherited intellectual or developmental disability as well as the most common known single-gene cause of autism. These results provide evidence of abnormal gene expression in response to excessive FA supplementation due to cytosine residue hypermethylation. Studies of dietary FA supplementation in female C57BL/6J mice are underway to determine whether such supplementation modifies the behavior of the progeny.

 

About the Laboratory of Structural Neurobiology

 

The major research focus of the Laboratory of Structural Neurobiology is to identify the causative factors responsible for children’s neurodevelopmental disorders, understand the molecular mechanisms involved, and ultimately develop blood-based biomarkers for early identification and prevention. Currently, we are working on three different disorders: autism, late-infantile neuronal ceroid lipofuscinosis (LINCL), and ataxia telangiectasia (A-T).

 

Mohammed Junaid, PhD, is the Head of the Laboratory of Structural Neurobiology at the New York State Institute for Basic Research in Developmental Disabilities in Staten Island, NY.

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