title: Comparison of gene expression regulation in mouse- and human embryonic stem cell assays during neural differentiation and in response to valproic acid exposure.
abstract: Embryonic stem cell tests (EST) are considered promising alternative assays for developmental toxicity testing. Classical mouse derived assays (mEST) are being replaced by human derived assays (hEST), in view of their relevance for human hazard assessment. We have compared mouse and human neural ESTn assays for neurodevelopmental toxicity as to regulation of gene expression during cell differentiation in both assays. Commonalities were observed in a range of neurodevelopmental genes and gene ontology (GO) terms. The mESTn showed a higher specificity in neurodevelopment than the hESTn, which may in part be caused by necessary differences in test protocols. Moreover, gene expression responses to the anticonvulsant and human teratogen valproic acid were compared. Both assays detected pharmacological and neurodevelopmental gene sets regulated by valproic acid. Common significant expression changes were observed in a subset of homologous neurodevelopmental genes. We suggest that these genes and related GO terms may provide good candidates for robust biomarkers of neurodevelopmental toxicity in hESTn.
authors.affiliation: Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. Electronic address: 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.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Theunissen
authors.affiliation: Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
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; 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: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D002478:Cells, Cultured; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005819:Genetic Markers; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D018570:Risk Assessment; D013045:Species Specificity; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D005819:Genetic Markers; D014635:Valproic Acid
keywords: Developmental neuro toxicity; Embryonic stem cells; Neural differentiation; Transcriptomics; Valproic acid