title: Unexpected common mechanistic pathways for embryotoxicity of warfarin and lovastatin.
abstract: Novel molecular content for fast in vitro strategies in the context of safety tests concerning developmental toxicity has a potential to substantially reduce animal experiments according to the "3R" concept (Reduce/Refine/Replace). Here we present and discuss data from a differential proteomic profiling of samples generated using embryonic stem cell derived in vitro models treated with a set of model substances. Among substance-dependent proteomic changes, potential surrogate markers were some isoforms of heat shock proteins and a component of the Ras pathway, present in several redundant isoforms due to posttranslational modifications. Both proteins are implicated in cell migration, cell survival, growth and embryonic development. Using the examples of warfarin and lovastatin, two substances with entirely different primary targets, the surrogate marker signature nevertheless indicates a common embryotoxic mode of action. We discuss these findings observed in in vitro toxicity tests, in a context of clinical validation and evidence-based toxicology.
authors.affiliation: ProteoSys AG, Mainz, Germany.
authors.forename: Karlfried
authors.initials: K
authors.lastname: Groebe
authors.forename: Katrin
authors.initials: K
authors.lastname: Hayess
authors.forename: Martina
authors.initials: M
authors.lastname: Klemm-Manns
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schwall
authors.forename: Woijciech
authors.initials: W
authors.lastname: Wozny
authors.forename: Margino
authors.initials: M
authors.lastname: Steemans
authors.forename: Annelieke K
authors.initials: AK
authors.lastname: Peters
authors.forename: Chaturvedala
authors.initials: C
authors.lastname: Sastri
authors.forename: Petra
authors.initials: P
authors.lastname: Jaeckel
authors.forename: Werner
authors.initials: W
authors.lastname: Stegmann
authors.forename: Helmut
authors.initials: H
authors.lastname: Zengerling
authors.forename: Rainer
authors.initials: R
authors.lastname: Schöpf
authors.forename: Slobodan
authors.initials: S
authors.lastname: Poznanovic
authors.forename: Tina C
authors.initials: TC
authors.lastname: Stummann
authors.forename: Andrea
authors.initials: A
authors.lastname: Seiler
authors.forename: Horst
authors.initials: H
authors.lastname: Spielmann
authors.forename: André
authors.initials: A
authors.lastname: Schrattenholz
mesh_terms: D016475:3T3 Cells; D000826:Animal Testing Alternatives; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D023381:Endpoint Determination; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D020128:Inhibitory Concentration 50; D008148:Lovastatin / Q000633:toxicity*; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D015203:Reproducibility of Results; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013723:Teratogens / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods* / Q000592:standards; D014859:Warfarin / Q000633:toxicity*; D018631:ras Proteins / Q000096:biosynthesis
chemical_list: D006360:Heat-Shock Proteins; D013723:Teratogens; D014859:Warfarin; D008148:Lovastatin; D018631:ras Proteins