Jun 16, 2022 07:00:00

Experiments with human 'mini-brain' and mouse embryos reveal the mechanism by which common drugs cause birth defects and developmental disorders

Sodium valproate , which is used as an antiepileptic drug and a treatment for bipolar disorder , is known to cause birth defects and developmental disorders in the fetus when taken by pregnant women, but the mechanism has long been elucidated. I didn't. A new French research team has conducted experiments using mouse embryos and human mini-brain ( cerebral organoids ) to investigate the effects of sodium valproate on development.

Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects | PLOS Biology
https://doi.org/10.1371/journal.pbio.3001664

Mini-brains show how common drug freezes cell division in the womb, causing birth defects | Live Science
https://www.livescience.com/valproic-acid-birth-defects-study

Sodium valproate, which has been on the market as an antiepileptic drug since the 1960s, was found to be associated with congenital defects by the 1980s, but is still used as an antiepileptic drug and a therapeutic drug for bipolar disorders in various countries. I have.

Experiments with rodents and monkeys have shown that taking sodium valproate in the first few weeks of pregnancy causes deficiencies in the early stages of nervous system formation, as well as in humans. There have been many reports of defects in the spine, heart, and head of children in Japan. Studies have also shown that an estimated 30-40% of infants exposed to sodium valproate in utero develop cognitive impairment and autism spectrum disorders.

To investigate how sodium valproate affects the fetus in the early stages of development, the research team conducted an experiment in which mouse embryos were exposed to sodium valproate. As a result, in mouse embryos exposed to sodium valproate, the

neural tubes that form early in development and differentiate into the brain and spinal cord do not close normally, and the head and brain become smaller than normal in the latter half of development. It turned out that.

The experiment also found that neuroepithelial cells of mice exposed to sodium valproate carry enzymes that appear only in aged cells. Neuroepithelial cells are stem cells that later produce brain cells, but the research team argues that when exposed to sodium valproate, they age and become unable to grow and divide properly, hindering embryonic development. I am.

The research team then used a small brain-like tissue called 'cerebral organoids' made by culturing human brain cells to investigate whether sodium valproate has a similar effect on human cells. And conducted a similar experiment. As a result, the neuroepithelial cells of the brain organoid also showed the aging phenomenon as in the mouse embryo.

When the research team investigated the mechanism of cellular senescence, it was found that a gene that produces a protein called 'p19Arf', which is suppressed during embryogenesis in mice, is expressed when exposed to sodium valproate. 'P19Arf' becomes active in adults and has the function of removing cancer cells and aged cells, but if 'p19Arf' is present at the embryonic development stage, important cells will age and disrupt development. That.

In mice that were actually genetically modified to prevent the research team from producing 'p19Arf,' the effects of exposure to sodium valproate were mitigated and the mouse brain grew to normal size. However, mice still had spinal cord damage, suggesting that sodium valproate causes spinal cord defects by another mechanism.

'It's very hard to set up and test brain organoids to see that aging is occurring in exactly the same type of cells as mice,' said Bill Keyes, team leader at the Institute for Molecular Biological Genetics, University of Strathbourg. It was a wonderful verification. ' On the other hand, the study admits that exposure to high doses of sodium valproate at once may exaggerate the effects on mouse embryos and human brain organoids. In the future, Keyes said he would like to experiment with low doses and long-term exposure conditions that are close to the actual dose.