title: Effects of the protein kinase inhibitor PKC412 on gene expression and link to physiological effects in zebrafish Danio rerio eleuthero-embryos.
abstract: To identify molecular effects of the antineoplastic agent protein kinase C inhibitor 412 (PKC412) (midostaurin), we applied gene expression profiling in zebrafish using whole-genome microarrays. Behavioral, developmental, and physiological effects were investigated in order to analyze for correlations between altered gene expression profiles with effects on development and physiology. Zebrafish blastula-stage embryos were exposed for 6 days postfertilization to nominal levels of 2 and 40 μg/l PKC412. Among the 259 and 511 altered transcripts at both concentrations, respectively, the expressions of genes involved in the circadian rhythm were further investigated. Alteration of swimming behavior was not observed. Pathways of interest affected by PKC412 were angiogenesis, apoptosis, DNA damage response, and response to oxidative stress. Angiogenesis was analyzed in double-transgenic zebrafish embryos Tg(fli1a:EGFP)y1;Tg(gata1:dsRed)sd2; no major defects were induced by PKC412 treatment at both concentrations. Apoptosis occurred in olfactory placodes of embryos exposed to 40 μg/l, and DNA damage was induced at both PKC412 concentrations. However, there were no significant effects on reactive oxygen species formation. This study leads to the conclusion that PKC412-induced alterations of gene transcripts are partly paralleled by physiological effects at high, but not at low PKC412 concentrations expected to be of environmental relevance.
authors.affiliation: University of Applied Sciences Northwestern Switzerland, School of Life Sciences, CH-4132 Muttenz, Switzerland.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Oggier
authors.forename: Anna
authors.initials: A
authors.lastname: Lenard
authors.forename: Michael
authors.initials: M
authors.lastname: Küry
authors.forename: Birgit
authors.initials: B
authors.lastname: Hoeger
authors.forename: Markus
authors.initials: M
authors.lastname: Affolter
authors.forename: Karl
authors.initials: K
authors.lastname: Fent
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D020552:Comet Assay; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D020287:In Situ Nick-End Labeling; D009043:Motor Activity / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000633:toxicity; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D019311:Staurosporine; C059539:midostaurin