A new study assessed the link between folic acid supplementation during pregnancy and levels of DNA methylation in the offspring. The researchers discussed the potential effects of continuing folic acid intake throughout pregnancy.
Folate is an important nutrient for normal metabolism and development. It is a B-vitamin found in fruits and vegetables. Folic acid is the oxidized and most active form of folate, but it is rarely found in food. Folic acid is a synthetic version that is used to fortify cereals, bread, and other foods. It is also in vitamin supplements.
It is a well-known fact that folic acid is especially important if a woman is pregnant or trying to get pregnant. Folic acid protects unborn babies from serious birth defects. A folate deficiency in mothers is linked to developmental disabilities in the babies.
Folate and congenital malformations
Over 50 years ago, scientists found a relationship between folate and neural tube defects. A neural tube defect is a type of malformation that occurs when the neural tube fails to close during the embryo’s early development in the womb. Genetics and environmental factors can influence neural tube defects. Among the environment influences, folic acid intake plays an important role.
Births with neural tube defects have steadily declined over the past four decades as a result of public health campaigns focused on increasing folic acid intake by women of reproductive age. The US Public Health Service and Centers for Disease Control and Prevention recommend 400 micrograms of folic acid per day by women of childbearing age. However, recent studies point to the possible harmful effects that of an excess of folic acid intake. It is therefore important to aim for an optimal level of folic acid intake.
A recent editorial published in the American Journal of Clinical Nutrition reflects on the important role of folate and discusses the possible effects of increased folic acid intake. The authors from the Duke University School of Medicine in the US briefly presented the work of Caffrey and colleagues on the effects of maternal folate during pregnancy and brain development in the offspring.
Role of folate in biological pathways
Folate is critical for the molecular mechanisms of child development. These molecular mechanisms include nucleotide synthesis and DNA-methylation reactions.
DNA methylation is a mechanism that cells use to control gene expression. DNA methylation changes the way genes are expressed, but it does not alter the original DNA code. It changes the way genes are expressed by adding a methyl group (one carbon and three hydrogen molecules) to the DNA. The methyl group acts as a mask on top of the original DNA. This methylation is programmed during the early development of the embryo.
Studies have shown that impaired DNA methylation is associated with neural tube defects. However, folic acid can improve methylation by donating methyl groups, thereby preventing neural tube defects.
Vitamin B-12 and the type of delivery (vaginal or Cesarean) can also influence DNA methylation. Vitamin B-12, like folate, is a methyl donor and contributes to DNA methylation of certain genes. The study showed that infants born by Cesarean have different DNA methylation levels compared with infants born vaginally.
Folic acid supplementation through second and third trimesters
Neural tube development takes place mainly during the first trimester of pregnancy. Folic acid intake is, therefore, more critical during this time. Researchers found significantly lower levels of DNA methylation of some genes in the cord blood of infants born to women who continued folic acid supplementation in the second and third trimesters, compared with the women who did not.
The scientists concluded that the changes in DNA methylation were directly associated with folic acid intake. It is important to note that based on this study’s results, the researchers concluded that the prolonged use of folic acid leads to an overall decrease in DNA methylation of the genes investigated in this study.
Consequences of loss of DNA methylation
As shown by this study, an excess of folic acid leads to reduced DNA methylation. Many studies have shown that the loss of methylation is associated with disordered epigenetic gene regulation that is associated with a number of human diseases including cancer.
There is some evidence that suggests a link between increased folic acid supplementation and risk of colon cancer. These findings, although with conflicting evidence, appear as warning lights for excessive intake of folic acid.
In conclusion, folic acid fortification and supplementation is critical to human health because of its role in DNA methylation and nucleotide synthesis. Although the benefits of folic acid in the prevention of neural tube defects is well established, an emerging body of evidence raises concern regarding possible adverse health effects of excessive folic acid intake.
These health concerns warrant the need to aim for optimal doses of folic acid and perhaps question if there is a need for continuing folic acid supplementation into the second and third trimester of pregnancy. Future studies should investigate the health hazards associated with long-term excessive intake of folic acid by mothers and its effects on the cognitive and social development of children.
Written by Preeti Paul, MS Biochemistry
Reference: Rose Schrott and Susan K Murphy. Folic acid throughout pregnancy: too much? Editorial, Am J Clin Nutr 2018;107:497-498.