title: DON shares a similar mode of action as the ribotoxic stress inducer anisomycin while TBTO shares ER stress patterns with the ER stress inducer thapsigargin based on comparative gene expression profiling in Jurkat T cells.
abstract: Previously, we studied the effects of deoxynivalenol (DON) and tributyltin oxide (TBTO) on whole genome mRNA expression profiles of human T lymphocyte Jurkat cells. These studies indicated that DON induces ribotoxic stress and both DON and TBTO induced ER stress which resulted into T-cell activation and apoptosis. The first goal of the present study was to provide final proof for these mode of actions by comparing the effects of 6 h exposure to DON and TBTO on mRNA expression to those of positive controls of ribotoxic stress (anisomycin), ER stress (thapsigargin) and T cell activation (ionomycin). Genes affected by anisomycin and the majority of genes affected by thapsigargin were affected in the same direction by DON and TBTO, respectively, confirming the expected modes of action. Pathway analysis further sustained that DON induces ribotoxic stress and both DON and TBTO induce unfolded protein response (UPR), ER stress, T cell activation and apoptosis. The second goal was to assess whether DON and/or TBTO affect other pathways above those detected before. TBTO induced groups of genes that are involved in DNA packaging and heat shock response that were not affected by thapsigargin. DON did not affect other genes than anisomycin indicating the effect of DON to be restricted to ribotoxic stress. This study also demonstrates that comparative gene expression analysis is a very promising tool for the identification of modes of action of immunotoxic compounds.
authors.affiliation: RIKILT-Institute of Food Safety, Wageningen University and Research Centre, P.O. Box 230, 6700 AE Wageningen, The Netherlands; Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: peter_oss@hotmail.com.
authors.forename: Peter C J
authors.initials: PC
authors.lastname: Schmeits
authors.affiliation: RIKILT-Institute of Food Safety, Wageningen University and Research Centre, P.O. Box 230, 6700 AE Wageningen, The Netherlands; Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address: maddycdfd@gmail.com.
authors.forename: Madhumohan R
authors.initials: MR
authors.lastname: Katika
authors.affiliation: RIKILT-Institute of Food Safety, Wageningen University and Research Centre, P.O. Box 230, 6700 AE Wageningen, The Netherlands. Electronic address: ad.peijnenburg@wur.nl.
authors.forename: Ad A C M
authors.initials: AA
authors.lastname: Peijnenburg
authors.affiliation: Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands; National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands. Electronic address: henk.van.loveren@rivm.nl.
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
authors.affiliation: RIKILT-Institute of Food Safety, Wageningen University and Research Centre, P.O. Box 230, 6700 AE Wageningen, The Netherlands. Electronic address: peter.hendriksen@wur.nl.
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Hendriksen
mesh_terms: D000841:Anisomycin / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002874:Chromosome Mapping; D003627:Data Interpretation, Statistical; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D020869:Gene Expression Profiling; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells; D046228:Microarray Analysis; D024101:Mitochondrial Proteins / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000633:toxicity*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000302:isolation & purification; D013601:T-Lymphocytes / Q000187:drug effects; D019284:Thapsigargin / Q000633:toxicity*; D014220:Trialkyltin Compounds / Q000633:toxicity*; D014255:Trichothecenes / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D019384:Nucleic Acid Synthesis Inhibitors; D012334:RNA, Neoplasm; D014220:Trialkyltin Compounds; D014255:Trichothecenes; C005961:bis(tri-n-butyltin)oxide; D015759:Ionomycin; D019284:Thapsigargin; D000841:Anisomycin; C007262:deoxynivalenol
keywords: ER stress; Immunotoxicity; Jurkat T cells; Ribotoxic stress; Toxicogenomics; Transcriptomics