New Mouse Model Could Explain Role of Folic Acid in Prevention of Birth Defects

Researchers Create World's First Model to Explain Folic Acid Journey;
Unlocks Further Understanding of Folic Acid in Prevention of Birth Defects

Researchers have created the world's first genetically-engineered mouse model to explain how folic acid protects against common human birth defects. The development of this tool will enable researchers to better understand how the transport of folic acid within the cell protects against birth defects such as neural tube defects and cleft lip and palate. They hope to learn which genes benefit from folic acid, and learn more about the underlying processes of how the neural tube closes.

The results come from a five-year study funded with support from a $700,000 grant from the National Institutes of Health and a grant from the March of Dimes Birth Defects Foundation and are published in the Oct. 1 issue of Nature Genetics, an international monthly journal about research in genetics.

"We know folic acid supplementation prevents birth defects, but we don't have any clue just how that comes about. It's a black box," said Richard Finnell, Ph.D., director of the Center for Human Molecular Genetics, University of Nebraska Medical Center and senior author. "Now we've created a tool which allows us to get into the black box."

About one in 1,000 babies born will have neural tube defects and as many as one in 600 are born with cleft lip and or cleft palate.

"If researchers can learn how folic acid works, the knowledge can help prevent a significant portion of the 4,000 pregnancies complicated each year in the U.S. with neural tube defects," Dr. Finnell said. "The health care cost nationwide for these children would probably approach a billion dollars. If you could also prevent even a portion of the children born with cleft lip palate, significant health care savings could be achieved in a single year."

In the study, Dr. Finnell and his colleagues genetically-engineered mice that lack the protein which brings folic acid into the cells.

The researchers discovered embryos lacking the protein died in utero with neural tube defects. However, when large amounts of supplemental folic acid were given to pregnant mice carrying abnormal embryos, the researchers were able to rescue the normal embryos and prevent the otherwise lethal birth defects.

"We are extremely gratified by these findings because they demonstrate the critical importance of folate uptake," said co-author Richard Anderson, Ph.D., professor of cell biology at the University of Texas Southwestern Medical Center at Dallas. "The results confirm our work on how folate, which is essential for cell growth, is taken up by cells."

It is recommended that pregnant women take 1,000 micrograms (1 milligram) of folic acid daily to prevent birth defects, Dr. Finnell said. The recommended daily allowance for the general population is 400 micrograms. Folic acid is found in multivitamins, fortified breakfast cereals and breads, dark green, leafy vegetables such as broccoli and spinach, egg yolks, and some fruits and fruit juices.

The study also will allow scientists to further research the benefits of folic acid, including what it does and what is the appropriate level to consume. It may also begin to answer questions such as why there is a high incidence of spina bifida in the Hispanic population.

"In some studies, Hispanic women don't seem to get the same benefits from taking folic acid as do other populations. "If it's validated that in fact Hispanics don't benefit, we want to know why they don't benefit. If there's an abnormal gene which prevents them from using the folic acid, let's find the gene," Dr. Finnell said.

He said it is imperative that women take folic acid supplements daily because they can never be sure when they are going to conceive, and the neural tube closes before anyone even knows they are pregnant.

"Folic acid is water soluble and is very inexpensive," he said. "It's the cheapest intervention imaginable. In terms of public health, it's a win-win situation for everyone, because we should be able to save billions of dollars in health care simply by raising everyone's level of folic acid."

Dr. Finnell said he is heartened by the study findings.

"I've been looking at neural tube defects and the genes involved for 18 years. Having a tool to dissect how an embryo gets folic acid is going to be useful to answering many clinical questions. There are practical applications to our findings. It is also gratifying when the collaborative efforts of an outstanding research team all comes together like it did in this study."

The research team consists of faculty from the University of Nebraska Medical Center in Omaha, Texas A&M University in College Station, and the University of Texas Southwestern Medical Center in Dallas. Dr. Finnell recently moved to UNMC from Texas A&M University, and maintains a faculty appointment with the Baylor College of Dentistry at Texas A&M University in Dallas.

UNMC is the only public academic health science center in the state. Through its commitment to research, education, outreach and patient care, UNMC has established itself as one of the country's leading centers for cancer research and treatment and solid organ transplantation. More than $32 million in research grants and contracts are awarded to UNMC scientists annually. In addition, UNMC's educational programs are responsible for training more health professionals practicing in Nebraska than any other institution.

-30-