Several thousand cases of women who took VPA during pregnancy have given birth to children with birth defects, including spina bifida, facial lesions, and heart defects. In addition, about a third of the exposed infants developed cognitive impairment and an autism spectrum disorder. Research conducted in mouse embryos describes for the first time how valproic acid can cause congenital neurodevelopmental abnormalities such as microcephaly and exencephaly.
The study is performed both in vitro on human organoids composed of laboratory-cultured human cells and in vivo on embryonic mice exposed to VPA. The team finds the following:
VPA induces cellular senescence in neuroepithelial cells,
stem cells, from which the central nervous system develops;
- a particular molecule, p19Arf, seems to be responsible for this VPA-induced senescence: mice deprived of this p19Arf protein and exposed to VPA during pregnancy in utero do not show these microcephaly effects nor the typical changes in gene expression, particularly in the context of Autism Spectrum Disorder (ASD). However, exposure to VPA induced other defects in these mice.
Cellular senescence is thus associated with developmental disorders for the first time observed in “babies” of mothers exposed to VPA during pregnancy/gestation. “This finding of atypical activation of senescence in the embryo that can disrupt development raises the intriguing possibility that it may also contribute to defects in developmental contexts beyond those studied here.”say the researchers.
“While cellular senescence has long been associated with aging and age-related diseases, we now show that defective induction of senescence can also contribute to developmental abnormalities. Because valproic acid is strongly associated with cognitive defects and autism spectrum disorders, this study hypothesizes an intriguing association with senescence and fuels interest for further studies.”