Valproic acid, a drug used to treat epilepsy, migraine, and bipolar disorder, has shown to cause birth defects when taken during pregnancy, according to a new study by the Institute of Genetics and Molecular and Cellular Biology (IGMCB), France.
Mr. Bill Keyes, Head of Development and stem cells Department of the IGMCB, and colleagues revealed one reason that valproic acid (VPA) puts some cells of the developing nervous system into senescence, a kind of halted state that keeps them from growing and dividing correctly.
VPA is widely used to treat a number of illnesses. However, since its initial use, there have been many thousands of cases of women taking VPA during pregnancy and subsequently giving birth to children with birth defects, including spina bifida, facial alterations, and heart malformation. In addition, about a third of exposed infants develop cognitive impairment and Autism Spectrum Disorder.
In the new study, Mr. Keyes and colleagues used both human organoids, three-dimensional clusters of human cells grown in the lab, as well as mice to study embryonic exposure to VPA. They discovered that VPA induces cellular senescence in neuroepithelial cells, the stem cells that give rise to the central nervous system. Moreover, the researchers pinpointed one particular molecule, p19Arf, as being responsible for this VPA-induced senescence.
VPA exposure during pregnancy no longer caused microcephaly (small head size) or changes in gene expression patterns linked with Autism Spectrum Disorder in mice lacking p19Arf, while VPA did cause other abnormalities in these mice.
The work is first-of-its-kind to associate cellular senescence with developmental defects, the authors say. “Overall, the discovery that atypical activation of senescence in the embryo can perturb development raises the intriguing possibility that it may also contribute to defects in developmental contexts beyond those we studied here,” they said.