High folic acid and low vitamin B12 may affect fetal brain development in mice

Folate is a B vitamin and a nutrient necessary to prevent neural tube defects, such as spina bifida. Folic acid, a synthetic form of folate, has been added to vitamins, breakfast cereals and other products in the United States and more than 80 other countries to ensure that pregnant women receive adequate amounts. adequate. However, new research suggests that there may be excess folic acid.

In a study published in Communication biologyResearchers from the UC Davis School of Medicine and the UC Davis MIND Institute have shown that imbalances in folic acid and vitamin B12 can impair brain development in mice.

“There is no doubt that the introduction of a diet enriched with folic acid has been beneficial, significantly reducing the incidence of neural tube defects,” said Ralph Green, distinguished professor in the Department of Pathology and Medicine at laboratory and co-senior author of the study. “However, too much folic acid can have detrimental effects on brain development, and this is a problem we need to address.”

Concerns about folate deficiencies and neural tube defects, which can lead to stillbirths, paralysis, cognitive impairment and other problems, peaked in the 1990s. At the time, Food and Drug Administration and the Centers for Disease Control and Prevention had revised their guidelines to ensure pregnant people received the necessary amounts. Green played an important role in developing these standards.

However, the timing of folate administration during pregnancy is tricky. The neural tube forms early in pregnancy and usually closes about 28 days after conception. This meant that targeted folate supplements would likely come too late.

The solution was to fortify foods and vitamins with folic acid, the synthetic form of folate, to ensure that pregnant women get enough. In the decades since folic acid fortification began, neural tube defects have declined significantly.

During the same period, the prevalence of neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder (ADHD) has increased. Epilepsy rates have also increased. The researchers wanted to determine if there was a possible link between these increases and excess folic acid.

Green notes that folic acid fortification may be an imperfect solution.

“The food industry has added folic acid to breakfast cereals, snacks and vitamins, which has likely increased intake beyond recommended guidelines,” Green said. “The safe upper limit for folate is 1,000 micrograms per day. Data from the National Health and Nutrition Examination Survey showed that a substantial percentage of women’s diets exceeded this limit.”

The consequences of high folate and low B12

Green and his colleagues have been studying this question for several years. In a 2020 article published in Cerebral cortex the group showed that both folate overabundance and folate deficiency could cause neurodevelopmental problems in mice.

In the new study, the team investigated the effects of high folic acid intake, vitamin B12 deficiency and high amounts of natural folic acid – folinic acid – which may act differently than normal. folic acid. The body needs B12 to adequately recycle and use folate.

Investigators provided one group of mice before and during pregnancy with a controlled diet containing normal levels of folic acid and B12 and four separate groups with a diet including:

• rich in folic acid
• low B12
• high in folic acid and low in B12
• rich in folinic acid

Using multiple imaging techniques, the offspring of these pregnancies were examined with a focus on the development of the cerebral cortex, the primary brain structure associated with important cognitive and emotional functions. The cerebral cortex plays a central role in a range of psychiatric disorders, particularly those that first appear in childhood.

“These different dietary conditions appear to influence how neurons appear in the developing brain,” said Konstantinos Zarbalis, professor of pathology and laboratory medicine, UC Davis MIND Institute faculty member, and co-senior author. .

“With high levels of folic acid or B12 deficiency, there was a change in neuronal development. Cortical neurons that usually emerge during a later stage of brain development were produced over a longer period and required a longer period to settle in and assume their role,” Zarbalis said.

The exception was folinic acid, natural folate. Even though it was administered at the same high levels as folic acid, there was virtually no impact on the mice’s brain development.

As the researchers expected, the group fed a diet combining high folic acid and low vitamin B12 had the most pronounced neurodevelopmental abnormalities.

Although these results are intriguing and may possibly be linked to human pathology, the authors emphasize the need for great caution. Animal models differ from humans in key ways, including metabolic rates and the efficiency with which they process folic acid.

In ongoing work, the team is studying the effects of folic acid and B12 in human brain organoids (clusters of 3D cells integrating several types of neural cells). This research could provide better information about how these nutrients affect human biology.

“How the body responds to folic acid, vitamin B12 and folinic acid is very complex. We are in the early stages of determining how these elements interact,” Zarbalis said. “Ultimately, we would like to find a definitive answer as to the optimal amount of folate and its optimal form to avoid neural tube defects and other potential brain health problems.”