title: Evaluation of developmental toxicants and signaling pathways in a functional test based on the migration of human neural crest cells.
abstract: BACKGROUND
  Information on the potential developmental toxicity (DT) of the majority of chemicals is scarce, and test capacities for further animal-based testing are limited. Therefore, new approaches with higher throughput are required. A screening strategy based on the use of relevant human cell types has been proposed by the U.S. Environmental Protection Agency and others. Because impaired neural crest (NC) function is one of the known causes for teratologic effects, testing of toxicant effects on NC cells is desirable for a DT test battery.
  
  
  OBJECTIVE
  We developed a robust and widely applicable human-relevant NC function assay that would allow for sensitive screening of environmental toxicants and defining toxicity pathways.
  
  
  METHODS
  We generated NC cells from human embryonic stem cells, and after establishing a migration assay of NC cells (MINC assay), we tested environmental toxicants as well as inhibitors of physiological signal transduction pathways.
  
  
  RESULTS
  Methylmercury (50 nM), valproic acid (> 10 µM), and lead-acetate [Pb(CH3CO2)4] (1 µM) affected the migration of NC cells more potently than migration of other cell types. The MINC assay correctly identified the NC toxicants triadimefon and triadimenol. Additionally, it showed different sensitivities to various organic and inorganic mercury compounds. Using the MINC assay and applying classic pharmacologic inhibitors and large-scale microarray gene expression profiling, we found several signaling pathways that are relevant for the migration of NC cells.
  
  
  CONCLUSIONS
  The MINC assay faithfully models human NC cell migration, and it reveals impairment of this function by developmental toxicants with good sensitivity and specificity.
authors.affiliation: Doerenkamp-Zbinden Chair of In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Zimmer
authors.forename: Gabsang
authors.initials: G
authors.lastname: Lee
authors.forename: Nina V
authors.initials: NV
authors.lastname: Balmer
authors.forename: Kesavan
authors.initials: K
authors.lastname: Meganathan
authors.forename: Agapios
authors.initials: A
authors.lastname: Sachinidis
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
mesh_terms: D002465:Cell Movement / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D009432:Neural Crest / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D013723:Teratogens / Q000633:toxicity*; D059467:Transcriptome
chemical_list: D013723:Teratogens