title: Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay.
abstract: Differentiating pluripotent stem cells in vitro have proven useful for the study of developmental toxicity. Here, we studied the effects of anticonvulsant drug exposure in a human embryonic stem cell (hESC)-based neurodevelopmental toxicity test (hESTn). During neural differentiation the cells were exposed, for either 1 or 7 days, to noncytotoxic concentration ranges of valproic acid (VPA) or carbamazepine (CBZ), antiepileptic drugs known to cause neurodevelopmental toxicity. The effects observed on gene expression and correlated processes and pathways were in line with processes associated with neural development and pharmaceutical mode of action. In general, VPA showed a higher number of genes and molecular pathways affected than CBZ. The response kinetics differed between both compounds, with CBZ showing higher response magnitudes at day 1, versus VPA at day 7. With this study, we demonstrated the potential and biological relevance of the application of this hESC-based differentiation assay in combination with transcriptomics, as a tool to study neurodevelopmental toxicity.
authors.affiliation: *Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands and Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands sjors.schulpen@rivm.nl.
authors.forename: Sjors H W
authors.initials: SH
authors.lastname: Schulpen
authors.affiliation: *Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands and.
authors.forename: Jeroen L A
authors.initials: JL
authors.lastname: Pennings
authors.affiliation: *Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands and Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
mesh_terms: D000927:Anticonvulsants / Q000633:toxicity*; D002220:Carbamazepine / Q000633:toxicity*; D053595:Embryonic Stem Cells / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009420:Nervous System / Q000187:drug effects* / Q000196:embryology; D025341:Principal Component Analysis; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid
keywords: carbamazepine; human embryonic stem cells; neural differentiation; neurodevelopmental toxicity; transcriptomics; valproic acid