MINI-BRAINS SHOW HOW COMMON DRUG FREEZES CELL DIVISION IN THE WOMB, CAUSING BIRTH DEFECTS.

If used during pregnancy, valproic acid, a medicine routinely used to treat epilepsy and bipolar illness, can cause birth abnormalities 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 develop or divide in research utilizing mice and human tissue.

Valproic acid may affect brain development in the womb by driving critical stem cells into this condition, known as senescence, and so cause cognitive and developmental issues later on, according to research published Tuesday (June 14) in the journal PLOS Biology, an estimated 30% to 40% of babies exposed to the medication while in the womb have cognitive impairments or learning disabilities.

MICE AND MINI-BRAIN

When taken as a treatment for epilepsy or bipolar disorder, valproic acid affects the body in several ways, according to the online medical database. For instance, the medication changes the levels of certain chemical messengers in the brain and alters which genes can be switched on in a cell at any given time.

Valproic acid first hit the market in the 1960s as an anticonvulsant medication, but by the 1980s, the drug’s link to birth defects became apparent. Later research in rodents suggested that, when taken in the first few weeks of pregnancy, the drug might disrupt the earliest stages of nervous system formation. This upset seems to occur around the time that the “neural tube” — a hollow tube of tissue that later becomes the brain and spinal cord — forms and closes. In human embryos, that’s typically between the fourth and sixth week of pregnancy.

Valproic acid alters how these final stages of development proceed in mice. The neural tubes in the exposed embryos often did not close off, and this can affect the fetus later on.

Valproic acid (VPA) exposure leads to a variety of changes in mouse neuron cells, one of which is increased markers of senescence. These markers are not present in healthy cells, but they can be found in cells exposed to VPA. This provides some insight into the effects of VPA on the brain and may help us better understand.

To see if valproic acid could trigger senescence in human cells the team ran a similar experiment using cerebral organoids (a type of 3D cluster of human nerve cells). These resemble miniature brains, and their structure and function are very similar to that of a fully formed human brain. The researchers exposed the organoids to valproic acid and found that the drug pushed the organoids’ neuroepithelial cells into senescence, just as it did in the mouse embryos.

When taken as a cure for epilepsy or bipolar disorder, valproic acid affects the body in several ways. For example, the drug causes changes to certain chemical messengers in your brain and also alters at any given time.

Valproic acid first came to the market in the 1960s as a pharmaceutical medication, but its link to birth defects became apparent in the 1980s. Later research showed that when taken during pregnancy, it can significantly impact development in rodents. This process seems to start around the time that an embryo’s neural tube forms, which is typical during the fourth week of pregnancy.

To understand how valproic acid messes with this early stage of development, Keyes and his colleagues exposed mouse embryos to the drug. Neural tube closure sometimes failed in these embryos, affecting their later position & development.

Rodent cells exposed to valproic acid carried enzymes that only appear in cells undergoing senescence; the same enzymes did not crop up in the cells of healthy, unexposed mice. These markers of senescence specifically appeared in exposed neuroepithelial cells, a type of stem cell that later produces brain cells.

To verify whether valproic acid could contribute to senescence, the team ran a test using 3D clusters of human nerve cells, known as cerebral organoids. These miniature brains bear a striking resemblance to adults in their level of complexity and function. The researchers exposed the organoids to valproic acid and found that the drug pushed their neuroepithelial cells into senescence, just as it had in the project mouse embryos.

“This was just very nice validation for us to be able to set up and test organoids and then see that we were seeing senescence in the same cell type,” Keyes said because Organoids exposed to valproic acid ended up being much smaller than organoids from the control group. They also showed less active stem cells.

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