The reason why Valproic acid can cause birth defects has been a mystery for many years.
Scientists discovered that the medication locks some embryonic cells into a suspended state where they can't grow or divide.
The study states that forcing stem cells into this state may disrupt brain development in the womb and lead to cognitive and developmental disorders down the line.
According to the report, 30 to 40% of infants exposed to the drug in the womb develop cognitive impairments, and these laboratory studies hint at why that happens.
Valproic acid exposure can cause birth defects beyond the brain, such as heart malformations and spina bifida, in a subgroup of affected children.
The new study suggests that the physical birth defects are triggered by a different mechanism than the cognitive impairments.
There are differences in the brain that can be seen in the womb.
According to the online medical database StatPearls, valproic acid can affect the body in a number of ways. The levels of certain chemical messengers in the brain can be changed by the medication.
Valproic acid was first used as an anticonvulsant in the 1960s, but by the 1980s it was found to cause birth defects.
The drug may disrupt the earliest stages of nervous system formation when taken in the first few weeks of pregnant women.
The neural tube is a hollow tube of tissue that eventually becomes the brain and spine. According to the CDC, that's between the fourth and sixth week of a pregnant woman's menstrual cycle.
Keyes and his colleagues exposed mouse embryo to the drug in order to understand how it messes with this early stage of development. Fetal mice grew small heads and brains when their neural tubes failed to close, because they were exposed to more than one embryo at a time.
Rodent cells that were exposed to valproic acid had the same enzymes that were found in cells that were undergoing senescence. A type of stem cell that produces brain cells was exposed to these markers.
The team ran an experiment with 3D clusters of cerebral organoids to see if valproic acid could cause senescence.
The structure and function of these organoids are similar to that of a full-sized organ. The researchers found that the drug pushed the organoids' cells into a state similar to that found in the mouse embryo.
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Keyes said that it was nice to see that the same cell type was being seen in organoids. The exposed organoids were smaller than the organoids that had not been exposed to the drug.
What happens when cells are pushed into senescence? The team found that it yanks the brakes off a specific gene.
p19Arf is a molecule that helps to clear cancer and aging cells from the body. Although helpful in adults, the molecule's presence in embryos can cause problems.
When the team genetically modified mice so that they couldn't produce p19Arf, the rodents became impervious to some of the effects of valproic acid.
The deformities in the mice's spine are thought to be caused by a different mechanism.
The study used both human organoids and mouse model systems, according to Richard H. Finnell, who was not involved in the research.
He told Live Science in an email that the organoid experiments confirmed which genes are affected by valproic acid exposure.
Keyes said that there are many caveat to the model.
The team exposed their mice and organoids to high amounts of valproic acid over a short period of time, whereas in real life, patients take a lower dose of the drug over a longer period of time.
Keyes said that the high-dose, short-term regimen may have caused an "exaggerated" effect in the mice and organoid cells.
He said that the effect on human embryos would likely be patchier than what was shown in the study.
He said that the child would eventually be born with some defects in some population of cells, and that this would lead to cognitive and behavioral defects.
Keyes said that the team hopes to repeat their lab experiments with a regimen that is low in dose and long-term.
The results of these experiments should show how exposure to valproic acid affects embryo development.
The mouse embryo exposed to valproic acid in the womb develops the same birth defects as humans. The far left mouse embryo was not exposed to the drug. The center embryo has a small head, while the far right embryo has a large head.
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The original article was published by Live Science. The original article can be found here.
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