The development of miniature brains demonstrates how a popular medicine can stop cell division in the womb, leading to birth abnormalities

Mice, as well as human organoids, were employed in the study.

 

When used during pregnancy, the chemical valproic acid, often used to treat epilepsy and bipolar illness can lead to congenital disabilities and developmental issues in the child. However, the reason why this occurs has been a mystery for a very long time. In a study utilizing mice and human tissue, scientists have revealed that the medication locks some embryonic cells into a suspended state where they cannot grow or divide in the usual way. This discovery was made possible because the study used mouse and human tissue.

 

According to a study published on Tuesday (June 14) in the journal PLOS Biology, valproic acid may alter brain development in the womb and cause cognitive and developmental issues in later life because it causes critical stem cells to enter a condition that is termed senescence. The authors of the study indicated in their paper that cognitive deficits or autism spectrum disorders emerge in an estimated 30–40 per cent of infants exposed to the drug while they were still in the womb. These laboratory investigations provide some insight into why this occurs.

 

The exposure of some of the affected children to valproic acid can also cause congenital disabilities in organs other than the brain. These include deformities of the heart and spina bifida, a condition in which a portion of the spinal column does not form correctly, leaving the spinal cord exposed. According to Bill Keyes, a team leader at the Institute of Genetics, Molecular and Cellular Biology in Strasbourg, France and the senior author of the study, the new research suggests that even though these congenital physical disabilities are also linked to valproic acid, they are caused by a different mechanism than the cognitive impairments. This information was shared with Live Science.

 

Mice and other tiny brains

 

According to the online medical database StatPearls, the effects of valproic acid on the body are multifaceted when the medication is utilized in treating conditions such as epilepsy and bipolar disorder. For example, the drug varies the quantities of specific chemical messengers in the brain and modifies the genes that may be activated at any particular time in a cell. In addition, the medication changes which genes can be activated.

 

According to BBC News, valproic acid was introduced to the market for the first time as an anticonvulsant treatment in the 1960s. However, by the 1980s, the link between the drug and birth abnormalities had become apparent. Later studies conducted on rodents and monkeys revealed that the pregnant woman taking the drug in the first few weeks of her pregnancy would be able to alter the early phases of the creation of the nervous system. This disturbance appears to occur close to the moment the "neural tube," a hollow tube of tissue that later develops into the brain and spinal cord, begins to form and then closes. According to the Centers for Disease Control and Prevention, this stage of development occurs typically during the fourth and sixth weeks of pregnancy in human embryos (CDC).

 

To gain an understanding of how valproic acid disrupts such an early stage of development, Keyes and his colleagues experimented with administering the drug to mouse embryos. The neural tubes of these exposed embryos frequently failed to close, and later in the development process, the fetal mice also produced heads and brains that were exceptionally tiny.

 

Cells taken from rodents that had been subjected to valproic acid contained enzymes that are unique to ageing cells; these enzymes did not manifest in the cells taken from mice that had not been exposed to the compound. These signs of ageing manifest themselves most prominently in the neuroepithelial cells, a type of stem cell that differentiates into brain cells later in life.

 

The scientists performed a similar experiment with three-dimensional clusters of human nerve cells known as cerebral organoids to determine whether or not valproic acid may induce senescence in human cells. These organoids are reminiscent of smaller versions of human brains because their structure and function are comparable to those of full-sized organs. The substance, the researchers discovered, caused the neuroepithelial cells of the organoids to enter senescence, just as it did in mouse embryos.

 

"This was just wonderful validation for us to be able to set up and test organoids and then saw that we were experiencing senescence in the same cell type," said Keyes. "This was just a very nice validation for us to be able to set up and test organoids." The exposure to valproic acid caused the neuroepithelial cells of the organoids to enter a suspended state, which resulted in the organoids being significantly smaller than organoids that had not been exposed to the drug.

 

Valproic acid induces senescence in cells, but how exactly does it achieve this? The research group found that it causes a particular gene to become activated throughout embryonic development when it usually remains dormant throughout the process.

 

This gene provides the instructions for making a molecule known as p19Arf, which typically becomes functional in adulthood and contributes to eliminating malignant and aged cells from the body. The molecule's presence in embryos causes critical cells to enter senescence and interferes with the development of the nervous system, even though it is beneficial in adults.

 

The researchers found that when they genetically changed mice such that they couldn't manufacture p19Arf, the rodents became immune to some of the effects of valproic acid, and their brains were able to expand to their usual size. However, the mice still developed abnormalities in their spinal cords, which implies that valproic acid caused such deficits through a separate mechanism, as stated by Keyes.

 

Richard H. Finnell, a professor at the Center for Precision Environmental Health and various other departments at Baylor College of Medicine who was not involved in the research, said, "I think it is a strength of the study to utilize both human organoids and mouse model systems." "I think it is a strength of the study to utilize both human organoids and mouse model systems." In an email to Live Science, he explained how the organoid experiments helped clarify which genes are altered when exposed to valproic acid and how the mouse model helped reveal how the effects of the drug unfold when it is taken during an ongoing pregnancy.

 

Nevertheless, "there are many drawbacks to our model," added Keyes. "Our model has many cautions."

 

For example, the researchers gave their mice and organoids multiple high doses of valproic acid over a short period. In contrast, in real life, patients take a consistently lower amount of the drug over a more extended period. This was done so that the team could compare the results of their experiments. According to Keyes, the high-dose, short-term regimen used in the research may have produced an "exaggerated" effect on the organoid cells and mice, which would not necessarily be replicated in human embryos.

 

According to him, the effect on human embryos would most likely be more variable, even though a significant number of the mice and organoids used in the study displayed signs of senescence in the neuroepithelial cells of their bodies. According to him, "so then the child would ultimately be born with some flaws in some population of cells," and he said that, in principle, "this then gives rise to the cognitive and behavioural problems."

 

According to Keyes, the group's ultimate goal is to redo their laboratory tests with a dosage and administration schedule for valproic acid that resembles actual exposure conditions more closely. This would entail using a low dose over a prolonged period. In conjunction with in-depth genetic studies, these tests should disclose more specifics regarding how exposure to valproic acid affects the development of human embryos.

Article source : https://www.livescience.com/valproic-acid-birth-defects-study

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