title: A Bmp Reporter Transgene Mouse Embryonic Stem Cell Model as a Tool to Identify and Characterize Chemical Teratogens.
abstract: Embryonic stem cells (ESCs) were first isolated from mouse embryos more than 30 years ago. They have proven invaluable not only in generating genetically modified mice that allow for analysis of gene function in tissue development and homeostasis but also as models for genetic disease. In addition, ESCs in vitro are finding inroads in pharmaceutical and toxicological testing, including the identification of teratogenic compounds. Here, we describe the use of a bone morphogenetic protein (Bmp)-reporter ESC line, isolated from a well-characterized transgenic mouse line, as a new tool for the identification of chemical teratogens. The Bmp-mediated expression of the green fluorescent protein enabled the quantification of dose- and time-dependent effects of valproic acid as well as retinoic acid. Significant effects were detectable at concentrations that were comparable to the ones observed in the classical embryonic stem cell test, despite the fact that the reporter gene is expressed in distinct cell types, including endothelial and endodermal cells. Thus these cells provide a valuable new tool for the identification and characterization of relevant mechanisms of embryonic toxicity.
authors.affiliation: *German Federal Institute for Risk Assessment (BfR), Department of Chemicals and Product Safety Berlin, 10589 Berlin, Germany;
authors.forename: Josephine
authors.initials: J
authors.lastname: Kugler
authors.affiliation: *German Federal Institute for Risk Assessment (BfR), Department of Chemicals and Product Safety Berlin, 10589 Berlin, Germany;
authors.forename: Julian
authors.initials: J
authors.lastname: Tharmann
authors.affiliation: Leiden University Medical Center, Department of Anatomy and Embryology, 2300 RC Leiden, The Netherlands;
authors.forename: Susana M
authors.initials: SM
authors.lastname: Chuva de Sousa Lopes
authors.affiliation: Max-Planck Institute of Immunobiology and Epigenetics, Emeritus Laboratory, 79108 Freiburg, Germany and.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kemler
authors.affiliation: *German Federal Institute for Risk Assessment (BfR), Department of Chemicals and Product Safety Berlin, 10589 Berlin, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Luch
authors.affiliation: German Federal Institute for Risk Assessment (BfR), Department of Experimental Toxicology and Center for Alternatives to Animal Testing, 10589 Berlin, Germany michael.oelgeschlaeger@bfr.bund.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Oelgeschläger
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011725:Pyridines / Q000633:toxicity; D011743:Pyrimidines / Q000633:toxicity; D013723:Teratogens / Q000633:toxicity*; D019076:Transgenes; D014635:Valproic Acid / Q000633:toxicity
chemical_list: C473711:Chir 99021; D011725:Pyridines; D011743:Pyrimidines; D013723:Teratogens; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D014635:Valproic Acid
keywords: Bmp; GFP; differentiation; embryo; reportergene; stem cells