title: Effects of oral exposure to naturally-occurring and synthetic deoxynivalenol congeners on proinflammatory cytokine and chemokine mRNA expression in the mouse.
abstract: The foodborne mycotoxin deoxynivalenol (DON) induces a ribotoxic stress response in mononuclear phagocytes that mediate aberrant multi-organ upregulation of TNF-α, interleukins and chemokines in experimental animals. While other DON congeners also exist as food contaminants or pharmacologically-active derivatives, it is not known how these compounds affect expression of these cytokine genes in vivo. To address this gap, we compared in mice the acute effects of oral DON exposure to that of seven relevant congeners on splenic expression of representative cytokine mRNAs after 2 and 6h. Congeners included the 8-ketotrichothecenes 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), fusarenon X (FX), nivalenol (NIV), the plant metabolite DON-3-glucoside (D3G) and two synthetic DON derivatives with novel satiety-inducing properties (EN139528 and EN139544). DON markedly induced transient upregulation of TNF-α IL-1β, IL-6, CXCL-2, CCL-2 and CCL-7 mRNA expressions. The two ADONs also evoked mRNA expression of these genes but to a relatively lesser extent. FX induced more persistent responses than the other DON congeners and, compared to DON, was: 1) more potent in inducing IL-1β mRNA, 2) approximately equipotent in the induction of TNF-α and CCL-2 mRNAs, and 3) less potent at upregulating IL-6, CXCL-2, and CCL-2 mRNAs. EN139528's effects were similar to NIV, the least potent 8-ketotrichothecene, while D3G and EN139544 were largely incapable of eliciting cytokine or chemokine mRNA responses. Taken together, the results presented herein provide important new insights into the potential of naturally-occurring and synthetic DON congeners to elicit aberrant mRNA upregulation of cytokines associated with acute and chronic trichothecene toxicity.
authors.affiliation: College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China; Dept. of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Wenda
authors.initials: W
authors.lastname: Wu
authors.affiliation: Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA; Dept. of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: He
authors.affiliation: Dept. of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Hui-Ren
authors.initials: HR
authors.lastname: Zhou
authors.affiliation: Christian Doppler Laboratory for Mycotoxin Metabolism and Center for Analytical Chemistry, University of Natural Resources and Life Sciences, Tulln, Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Berthiller
authors.affiliation: Dept. of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Vienna, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Adam
authors.affiliation: Food and Life Sciences, Azabu University, 1-17-71 Fuchinobe Chuo-ku, Sagamihara, Kanagawa Pref., 252-5201, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Sugita-Konishi
authors.affiliation: Division of Microbiology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Dept. of Cellular and Molecular Medicine, University of Ottawa, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Krantis
authors.affiliation: Dept. of Chemistry, University of Ottawa, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Durst
authors.affiliation: College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Dept. of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA; Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA; Dept. of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA. Electronic address: pestka@msu.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Pestka
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018925:Chemokines / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D018836:Inflammation Mediators / Q000819:agonists / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000819:agonists / Q000096:biosynthesis*; D016896:Treatment Outcome; D014255:Trichothecenes / Q000008:administration & dosage* / Q000138:chemical synthesis*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D014255:Trichothecenes; C007262:deoxynivalenol
keywords: 8-Ketotrichothecenes; Chemokine; Cytokine; Deoxynivalenol-3-glucoside; EN139528; EN139544