Details

Autor(en) / Beteiligte

• Zimmer, Bastian
• Lee, Gabsang
• Balmer, Nina V.
• Meganathan, Kesavan
• Sachinidis, Agapios
• Studer, Lorenz
• Leist, Marcel

Titel

Evaluation of Developmental Toxicants and Signaling Pathways in a Functional Test Based on the Migration of Human Neural Crest Cells

Ist Teil von

• Environmental health perspectives, 2012-08, Vol.120 (8), p.1116-1122

Ort / Verlag

Research Triangle Park, NC: National Institute of Environmental Health Sciences

Erscheinungsjahr

2012

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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 teratologie 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 arter 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(CH₃ CO₂)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.