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High Folic Acid and Low B12 Impairs Mouse Brain Development

Supplements coming out of a container.
Credit: Amanda Jones / Unsplash.
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Why is food fortified with folic acid?

Getting the right amount of folic acid intake is important for women who are planning to become – or are – pregnant. Folic acid helps to support the development of the neural tube, which eventually forms the baby’s brain and spinal cord.

In 1998, a public health intervention commenced in the United States requiring manufacturers to fortify products such as cereal grains with folic acid. The intervention was the result of mounting evidence demonstrating folic acid deficiencies can contribute to neural tube defects (NTDs).

While guidelines advising women capable of becoming pregnant to take 400 micrograms (mcg) of folic acid daily have been published, many pregnancies are unplanned. This limits the effectiveness of targeted supplementation, as the neural tube closes ~28 days post-conception.

What is folic acid?

Folate is an essential B vitamin, which is called folic acid in its synthetic form. B vitamins play important roles in physiological pathways throughout the body, including the synthesis of DNA and the formation of red blood cells.

Mandatory folic acid fortification led to a reduction in the number of pregnancies and babies impacted by NTDs, and many countries have since adopted the same approach.

“There's no doubt the introduction of folic acid diet fortification has been beneficial, substantially lowering the incidence of neural tube defects,” Dr. Ralph Green, a distinguished professor in the department of pathology and laboratory medicine at the University of California, Davis, said. Green played a pivotal role in developing the US Food and Drug Administration (FDA)’s guidelines for folic acid recommendations.

Could excessive folic acid consumption be causing side effects? 

While NTD figures declined after mandatory fortification was introduced, an increase in other neurodevelopmental conditions – including autism and attention deficit/hyperactivity disorder (ADHD) – was observed.

“Too much folic acid may have detrimental impacts on brain development, and that’s something we need to sort out,” Green said. Could excessive folic acid consumption be contributing to the rising cases? “The food industry has been adding folic acid to breakfast cereals, snack foods, and vitamins, and that has likely increased intake above recommended guidelines. The safe upper limit for folate is 1,000 micrograms per day. The National Health and Nutrition Examination Survey data showed that a substantial percentage of women’s diets were above that limit,” Green added.

In 2020, Green and colleagues published a paper demonstrating that folate overabundance and deficiency can cause neurodevelopmental problems in mice.

In a new study published in Communications Biology, the research team explored the impact of high folic acid intake, B12 deficiency and high amounts of folinic acid – a natural folate. B12 is another example of a B vitamin, and the body needs adequate B12 intake to recycle and utilize folate.

High levels of folic acid or B12 deficiency cause changes in neural development

Green and colleagues used mice for this research, supplying a controlled diet before and during pregnancy. Mice were divided into five groups and provided a diet that contained either:

  • Normal levels of folic acid and B12
  • Low B12
  • High folic acid and B12
  • High Folic acid
  • Low folic acid

The offspring’s brains were analyzed post-mortem using a combination of immunohistochemistry, imaging and mass spectrometry approaches. The researchers focused particularly on the cerebral cortex, a brain region that is involved in emotions and cognitive function.

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

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“With high levels of folic acid or B12 deficiency, there was a change in neural development. Cortical neurons that usually emerge during a later stage of brain development were produced over a longer period of time and required a longer period to settle in and assume their proper position in the developing brain,” Zarbalis said. “In addition, both high folic acid and B12 deficiency appear to cause many neurons to develop fewer interconnections.” Folinic acid, however, did not appear to have any effect on the developing brain.

“The novel findings in our mouse model lend support to the notion of a detrimental effect of even moderately excessive amounts of folic acid on prenatal cortical development that can be further aggravated by B12 deficiency,” the researchers write.

Green and colleagues stress that these findings are from animal research. Whether these effects would be observed in humans is not yet known. “There’s a lot of complexity in how the body responds to folic acid, vitamin B12 and folinic acid. We are at the early stages of determining how these elements interact,” Zarbalis said. “Ultimately, we would like to find a definitive answer for how much folate, and what form, is optimal to avoid neural tube defects and other potential brain health issues.”

The team is now using human brain organoids, sometimes nicknamed “mini-brains”, to continue their investigations.

Reference: Tat L, Cannizzaro N, Schaaf Z, et al. Prenatal folic acid and vitamin B12 imbalance alter neuronal morphology and synaptic density in the mouse neocortex. Comms Bio. 2023;6(1):1133. doi: 10.1038/s42003-023-05492-9

This article is a rework of a press release issued by the University of California, Davis. Material has been edited for length and content.