The findings could help explain a longstanding puzzle: why does folic acid prevent many neural tube defects, but not all of them?
By Pesach Benson, TPS
Israeli and Portuguese scientists have identified a previously unknown pathway that may help explain how folic acid protects developing embryos from neural tube defects, potentially shedding light on why the vitamin does not prevent all such birth defects, Hebrew University of Jerusalem announced Wednesday.
Neural tube defects affect more than 300,000 newborns worldwide each year, according to the World Health Organization.
These defects occur very early in pregnancy, when the structure that develops into the brain and spinal cord fails to close properly.
The most common include spina bifida, which affects development around the spinal cord, and anencephaly, in which much of the brain and skull fails to develop normally.
For more than 30 years, women have been advised to take folic acid before and during early pregnancy to reduce the risk.
But scientists have not fully understood how the vitamin provides that protection.
The study, published in the peer-reviewed journal *Proceedings of the National Academy of Sciences* (PNAS), identifies a previously unknown link between folic acid and the ALDH1L1-retinoic acid pathway.
Researchers found that when ALDH1L1 was switched off, folic acid could no longer prevent neural tube defects in their embryo model.
The discovery gives scientists a new pathway to investigate in developing more effective prevention strategies.
The research was led by Prof. Abraham Fainsod and MD/Ph.D. student Tamir Edri of Hebrew University’s Faculty of Medicine, together with Prof. José António Belo of NOVA Medical School in Portugal and an international team of researchers.
The New Pathway
The researchers found that folic acid appears to activate the ALDH1L1 gene, which produces an enzyme involved in converting retinaldehyde, a molecule derived from vitamin A, into retinoic acid.
Retinoic acid is an important developmental signal that helps regulate how cells grow, develop and move as the nervous system forms.
The key evidence came when the researchers disrupted ALDH1L1 in frog embryos, a common model for studying early development.
Folic acid was able to reduce neural tube closure problems in the embryos, but when ALDH1L1 was switched off, the protective effect disappeared.
Without ALDH1L1, the protective effect of folic acid disappeared in the embryo model, the researchers reported.
The team also demonstrated that the human form of ALDH1L1 can produce retinoic acid and found evidence that the same pathway is active in mammalian cells, providing additional evidence that the pathway may also be relevant to humans.
The researchers found that when retinoic acid levels were too low, cells destined to form the nervous system multiplied too quickly, causing the neural plate to become abnormally expanded.
Folic acid helped restore more normal cell growth, but only when ALDH1L1 was functioning.
The findings could help explain a longstanding puzzle: why does folic acid prevent many neural tube defects, but not all of them?
The researchers said problems in the ALDH1L1-retinoic acid pathway could be one possible explanation, although further research is needed to determine whether the same mechanism operates during human pregnancy.
The study also found that small amounts of retinol, a form of vitamin A, enhanced the effect of low-dose folic acid in experiments.
The researchers cautioned that this does not mean pregnant women should take additional vitamin A, since excessive vitamin A can itself cause birth defects.
The findings could eventually contribute to more effective prevention strategies.
However, the researchers stressed that the study does not establish any new pregnancy or dietary recommendations and that further research is needed before the findings can be applied to human pregnancy.
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