Mini-Brains Demonstrate how a Common Medicine Causes Birth Defects by Freezing Cell Division in the Womb.

When mouse embryos are exposed to valproic acid in the womb, they develop birth defects that are comparable to those seen in human embryos.

If taken during pregnancy, valproic acid, a medicine routinely used to treat epilepsy and bipolar illness, can cause birth defects and developmental issues, but the reason for this has long been a mystery. Scientists discovered that the medicine locks some embryonic cells into a suspended state where they can’t properly grow or divide in a study utilizing mice and human tissue.

Valproic acid may affect brain development in the womb by driving critical stem cells into this state, known as senescence, and so cause cognitive and developmental issues later on, according to a study published Tuesday (June 14) in the journal PLOS Biology (opens in new tab). According to the study authors, 30 to 40 percent of newborns exposed to the medication in the womb have cognitive deficits or autistic spectrum disorder, and these laboratory experiments may help to explain why.

Valproic acid exposure can induce birth problems other than brain defects in a subgroup of afflicted infants, such as heart deformities and spina bifida, a condition in which a portion of the spinal column does not form properly, leaving the spinal cord exposed. However, according to Bill Keyes, a team leader at the Institute of Genetics, Molecular and Cellular Biology in Strasbourg, France, and senior author of the study, these physical birth problems, while similarly connected to valproic acid, are produced by a different mechanism than the cognitive deficits.

Mini-brains and mice

Valproic acid, when used to treat epilepsy or bipolar illness, has a number of side effects, according to the online medical database StatPearls (opens in new tab). Medicine, for example, modifies the quantities of specific chemical messengers in the brain and the genes that can be turned on in a cell at any particular time.

According to BBC News, valproic acid was first introduced to the market in the 1960s as an anticonvulsant medication, but by the 1980s, the drug’s link to birth defects had become clear (opens in new tab). A later study in rodents(opens in new tab) and monkeys(opens in new tab) revealed that the drug could alter the early phases of nervous system formation if administered during the first few weeks of pregnancy. The “neural tube” — a hollow tube of tissue that later becomes the brain and spinal cord — appears to be disrupted around the time it forms and closes. According to the Centers for Disease Control and Prevention(opens in new tab), this occurs in human embryos during the fourth and sixth weeks of pregnancy (CDC).

Keyes and his colleagues subjected mouse embryos to valproic acid to see how it affects this early period of development. The neural tubes of these exposed embryos frequently failed to close, and the fetal mice had unusually small heads and brains later in development.

Rodent cells treated with valproic acid carried enzymes that only arise in cells going through senescence; the same enzymes did not exist in healthy, unexposed mice’s cells. These senescence markers were found only in exposed neuroepithelial cells, a type of stem cell that creates brain cells later.

To see if valproic acid may cause senescence in human cells, the researchers used cerebral organoids, which are 3D clusters of human nerve cells. These organoids resemble miniature human brains in that they have the same structure and function as the full-size organ. When the organoids were subjected to valproic acid, the researchers discovered that the treatment pushed the organoids’ neuroepithelial cells into senescence, precisely as it did in mouse embryos.

“To be able to set up and test organoids and then see that we were experiencing senescence in exactly the same cell type was simply extremely good validation,” Keyes said. Because the valproic acid exposure caused the neuroepithelial cells in the organoids to become suspended, the exposed organoids were substantially smaller than those that had not been exposed to the drug.

How does valproic acid cause cells to become senescent? The team discovered that it yanks the brakes off a certain gene that normally remains inactive throughout embryonic development.

This gene produces the chemical p19Arf, which is normally active in adulthood and aids in the removal of malignant and aging cells from the body. Although beneficial in adults, the presence of the chemical in embryos causes critical cells to senescence and affects nervous system development.

When the researchers genetically engineered mice to prevent them from producing p19Arf, the rodents became resistant to some of the effects of valproic acid, and their brains were able to expand to normal size. The mice’s spinal cords, however, developed abnormalities, suggesting that valproic acid caused the malformations through a separate mechanism, according to Keyes.

“I think it’s a strength of the work that it uses both human organoids and mouse model systems,” said Richard H. Finnell, a professor at Baylor College of Medicine’s Center for Precision Environmental Health and other departments who was not involved in the study. He told Live Science in an email that the organoid experiments established which genes are affected by valproic acid exposure, and the mouse model revealed how the drug’s effects develop in continuing pregnancies.

Nonetheless, “our model has a lot of drawbacks,” according to Keyes.

For example, the researchers gave their mice and organoids multiple high doses of valproic acid over a short period of time, but patients in real-life take a lower amount of the medicine over a longer length of time. According to Keyes, the high-dose, short-term regimen used in the trials may have caused an “exaggerated” effect in the mice and organoid cells that would not necessarily be replicated in human embryos.

In other words, while the study’s mice and organoids demonstrated senescence in a major fraction of their neuroepithelial cells, he believes the effect on human embryos would be patchier. “So the infant will eventually be born with some flaws in some population of cells,” he explained, “and this, in principle, leads to cognitive and behavioral impairments.”

The team hopes to replicate their lab tests in the future with a valproic acid regimen that more closely resembles real-world exposure, such as one that is low-dose and long-term, according to Keyes. These studies, together with in-depth genetic investigations, should give further information about how valproic acid affects developing human embryos.

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Author: Muhammad Asim

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