Valproic acid — a drug commonly used to treat epilepsy and bipolar disorder – can cause birth defects and developmental disabilities if taken during pregnancy, but the reason for this has long remained a mystery. Now, in a study using mice and human tissue, scientists have found that the drug locks certain embryonic cells into a suspended state where they can’t grow or divide properly.
By forcing key stem cells into this state, called senescence, valproic acid can disrupt brain development in the womb and therefore cause cognitive and developmental impairment down the line, according to the study, published Tuesday, June 14 in the journal PLOS Biology (opens in a new tab). An estimated 30% to 40% of infants exposed to the drug in the womb develop cognitive impairment or autism spectrum disorder, the study authors noted in their report, and these lab studies suggest why this is happening. .
In a subset of affected children, exposure to valproic acid can also cause birth defects beyond the brain, including heart malformations and spina bifida, where part of the spine does not form properly and thus leaves the spinal cord exposed. However, the new study suggests that these physical birth defects, although also linked to valproic acid, are triggered by a different mechanism than cognitive impairment, Bill Keyes, team leader at the Institute of Genetics, Biology molecular and cellular laboratory from Strasbourg, France and lead author of the study, told Live Science.
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Mice and mini-brains
When taken as a treatment for epilepsy or bipolar disorder, valproic acid affects the body in several ways, according to the Online Medical Database StatPearls (opens in a new tab). For example, the drug alters the levels of certain chemical messengers in the brain and alters which genes can be turned on in a cell at any given time.
Valproic acid first hit the market in the 1960s as an anticonvulsant drug, but by the 1980s the drug’s link to birth defects became apparent, according to BBC News (opens in a new tab). Further research in rodents (opens in a new tab) and monkeys (opens in a new tab) suggested that when taken during the first weeks of pregnancy, the drug could disrupt the early stages of the nervous system training. This upheaval appears to occur as the “neural tube” – a hollow tube of tissue that later becomes the brain and spinal cord – forms and closes. In human embryos, it is usually between the fourth and sixth week of pregnancy, according to the Centers for Disease Control and Prevention (opens in a new tab) (CDC).
To understand how valproic acid disrupts this early stage of development, Keyes and his colleagues exposed mouse embryos to the drug. The neural tubes of these exposed embryos often did not close, and later in development the fetal mice also developed unusually small heads and brains.
Rodent cells exposed to valproic acid carried enzymes that appear only in senescent cells; the same enzymes did not appear in cells from healthy, unexposed mice. These markers of senescence appeared specifically in exposed neuroepithelial cells, a type of stem cell that later produces brain cells.
To test whether valproic acid could trigger senescence in human cells, the team conducted a similar experiment using 3D clusters of human nerve cells, known as brain organoids. These organoids resemble miniature human brains, in that their structure and function are similar to those of a full-sized organ. The researchers exposed the organoids to valproic acid and found that the drug caused neuroepithelial cells in the organoids to senescence, just as it had in mouse embryos.
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“It was just really nice validation for us to be able to set up and test organoids and then see that we were seeing senescence in the exact same cell type,” Keyes said. And because exposure to valproic acid pushed the neuroepithelial cells of the organoids into a suspended state, the exposed organoids were found to be much smaller than the organoids that had not been exposed to the drug.
How exactly does valproic acid push cells towards senescence? It puts the brakes on a specific gene that typically remains inactive throughout embryonic development, the team found.
This gene codes for a molecule called p19Arf, which typically becomes active in adulthood and helps eliminate cancerous and aging cells from the body. Although useful in adults, the presence of the molecule in embryos leads to senescence of key cells and disrupts the development of the nervous system.
When the team genetically modified mice so that they could not produce p19Arf, the rodents became immune to some of the effects of valproic acid, and the mice’s brains were able to grow to normal size. However, the mice still developed deformities in their spinal cords, suggesting that valproic acid causes these defects through a different mechanism, Keyes said.
“I think it’s a strength of the study to use both human organoids and mouse model systems,” said Richard H. Finnell, a professor at the Center for Precision Environmental Health and various other departments. of Baylor College of Medicine, which was not involved. in research. The organoid experiments confirmed which genes are affected by exposure to valproic acid, and the mouse model revealed how the drug’s effects play out in ongoing pregnancies, he told Live Science in a E-mail.
Nonetheless, “there are many caveats to our model,” Keyes said.
For example, the team exposed their mice and organoids to multiple high doses of valproic acid over a short period of time, whereas in real life patients consistently take a lower dose of the drug over a longer period. The high-dose, short-term regimen in the experiments may therefore have triggered an “exaggerated” effect in mice and organoid cells that would not necessarily be matched in human embryos, Keyes said.
In other words: Although the mice and organoids in the study showed senescence in much of their neuroepithelial cells, the effect on human embryos would likely be more patchy, he said. “So the child would ultimately be born with defects in a population of cells,” he said, and in theory, “this then gives rise to cognitive and behavioral defects.”
In the future, the team hopes to repeat their lab experiments with a valproic acid regimen that more accurately reflects real-world, i.e. low-dose, long-term exposure, said Keyes. These experiments, along with extensive genetic analyses, should reveal more details about the impact of valproic acid exposure on growing human embryos.
Originally posted on Live Science.
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