Introduction
Neural tube defects are the result of failed development of the brain and spinal cord during embryonic development. These defects include spina bifida (literally, open spine) and anencephaly (no head). A considerable number of human studies have demonstrated that folic acid supplementation during pregnancy of at least 0.4 mg/day reduces the incidence of neural tube defects by 30 percent to 70 percent. Folic acid supplementation affects a variety of cellular processes that influence neural tube closure; presumably, inhibition of these processes during folate (natural folic acid) deficiency leads to neural tube defects.
Biochemistry of Folate
Folic acid is a synthetic form of folate found in vitamins and fortified foods. Folic acid enters cells through a folate receptor, transporter or carrier. At this stage, folic supplementation has been proposed to increase entry of folate by cellular receptors that may otherwise bind another ligands (e.g. antibodies). Once inside the cell, folic acid is then metabolized and affects three major metabolic pathways: the folate cycle, remethylation and transsulfuration.
The Folate Cycle
The folate cycle contributes to several diverse reactions, all of which appear to be essential and influence neural tube development. These reactions are essential to deoxyribonucleic acid (DNA) synthesis. Low folate's influence on DNA synthesis is indicated in megaloblastic anemia, in which low folate impairs DNA synthesis. This interferes with cells undergoing rapid proliferation.
Methylation
The folate cycle passes methyl groups (-CH3) to the active methyl cycle to produce the universal methyl donor S-adenosylmethionine (SAM). This donor is essential in a variety of chemical processes, such that inhibition of the transfer of methyl groups to DNA has been shown to produce neural tube defects in animal models.
Transsulfuration
The third function of folate metabolism is the synthesis of an antioxidant. This pathway takes homocysteine from the methylation cycle to produce the essential cellular antioxidant glutathione. Though mutations in humans have indicated glutathione is not essential to embryonic development, glutathione provides important protection for cells against chemicals found in the environment that increase risk for spina bifida or anencephaly.
Summary
The addition of folic acid before and during pregnancy has decreased rates of neural tube defects. The reason for this reduction appears to be a combination of factors that are all dependent on folate uptake and metabolism. These reactions influenced include DNA synthesis, methylation and glutathione production. Although DNA synthesis and methylation reactions are considered essential for embryonic development, glutathione may indirectly reduce risk of spina bifida or anencephaly by reducing the availability of toxins such as arsenic to induce neural tube defects.
