An NIEHS-led study has identified key genes, related to folate levels in mothers, that are modified in newborns. These genes may be important for early stages of fetal development. The results were published Feb. 10 in the journal Nature Communications.
Strong scientific evidence that folate helps to prevent certain birth defects of the brain and spinal cord, called neural tube defects, prompted the U.S. to begin fortifying breads and flours with folic acid, the synthetic form of folate, in 1998. Yet how folate works is still not clear, the authors wrote, and some research studies have suggested harmful effects from excessive folate intake.
“It is notable that many of the implicated genes have functional relevance to various developmental pathways,” the authors wrote. However, what role those genes may play in prevention of birth defects, or development of harmful effects, is not yet known and may be a fruitful direction for further study.
“Having a better understanding of what the folate is doing, and how much you need to do the good things but not the potentially bad things, could enable better public health recommendations,” explained senior author Stephanie London, M.D., Dr.P.H., deputy chief of the NIEHS Epidemiology Branch and head of the Genetics, Environment, and Respiratory Disease Group.
Folate may alter gene expression through methylation
The study found that higher maternal folate levels during early pregnancy were linked to DNA methylation on 320 genes in the newborns under study. DNA methylation can affect how genes are expressed and may provide a clue to how folate works. The authors cautioned, however, that DNA methylation on these genes may be just a marker for maternal folate intake.
“We’ve seen that some genes are differentially methylated in relation to the maternal folate levels, but that doesn’t mean that is the mechanism,” said London. “Even so, having great biomarkers that reflect the total folate exposure over the pregnancy could be very useful.”
The authors established a collaboration to increase the strength of the study, combining results from two separate population-based projects, the Norwegian Mother and Child Cohort Study and the Generation R Study, in the Netherlands. The Office of Dietary Supplements at the National Institutes of Health provided supplementary funding so additional samples could be analyzed.
“This study emphasizes the value of collaborative research,” said lead author Bonnie Joubert, Ph.D., health scientist administrator at NIEHS. “By combining data from birth cohorts in Norway and the Netherlands, we gained a larger sample size and saw consistent results between the two populations among the top methylation markers, a helpful confirmation.”
High folate intake may have both positive and negative effects
The National Toxicology Program (NTP) convened an expert panel in May 2015 to identify research needs related to high folate intake. The report, titled Identifying Research Needs for Assessing Safe Use of High Intakes of Folic Acid, was issued in August 2015. It recommended further study regarding cancer and immune system effects, such as allergy and asthma.
Abee Boyles, Ph.D., project lead for the NTP report, emphasized that the current findings are an important piece of the puzzle regarding how folate functions in the body. “The mechanisms for both benefit and possible harm aren’t well known so this sheds some light on that,” she said.
Citation: Joubert BR, den Dekker HT, Felix JF, Bohlin J, Ligthart S, Beckett E, Tiemeier H, van Meurs JB, Uitterlinden AG, Hofman A, Haberg SE, Reese SE, Peters MJ, Kulle Andreassen B, Steegers EA, Nilsen RM, Vollset SE, Midttun O, Ueland PM, Franco OH, Dehghan A, de Jongste JC, Wu MC, Wang T, Peddada SD, Jaddoe VW, Nystad W, Duijts L, London SJ. 2016. Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns. Nat Commun; doi: 10.1038/ncomms10577 [Online 10 February 2016].
(Virginia Guidry, Ph.D., is a technical writer and public information specialist in the NIEHS Office of Communications and Public Liaison.)