title: T-2 toxin induced skin inflammation and cutaneous injury in mice.
abstract: T-2 toxin is one of the most toxic among several trichothecenes involved in both human and animal poisoning cases. We investigated the biochemical and histological alterations behind inflammation and cutaneous injury caused by T-2 toxin. Swiss albino mice were exposed to T-2 toxin topically at doses of 0.5, 1 and 2 LD50 (2.97, 5.94 and 11.88 mg/kg respectively) and observed till 3, 24 and 72 h. Topical application of T-2 toxin resulted in skin oxidative stress in terms of increased reactive oxygen species generation, lipid peroxidation and neutrophil mediated myeloperoxidase activity. The histological alterations include degenerative changes like vacuolation, ballooning of basal keratinocytes and infiltration of inflammatory cells in dermis. The mRNA levels of skin pro-inflammatory cytokines TNF-α, IL-6, and IL-1β showed significant up regulation. Anti-inflammatory cytokines IL-10 showed significant up regulation at 24h whereas IL-4 showed down regulation for all the doses and time points. Gelatin zymography and immunoblot analysis of matrix metalloproteinases (MMP)-9 and 2 indicated MMP activation and their role in degenerative skin histological changes. Time dependent increase in inducible nitric oxide synthase levels was seen. Immunoblot analysis revealed significant increase in the levels of phosphorylated p38 mitogen activated protein kinase (MAPK). Flow cytometry analysis of propidium iodide stained epidermal cells showed increase in sub-G1 population at all the doses and time points indicating apoptosis. In summary, T-2 toxin induced skin inflammation and cutaneous injury is mediated through oxidative stress, activation of myeloperoxidase, MMP activity, increase in inflammatory cytokines, activation of p38 MAPK and apoptosis of epidermal cells leading to degenerative skin histological changes.
authors.affiliation: Division of Pharmacology & Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India.
authors.forename: Mona
authors.initials: M
authors.lastname: Agrawal
authors.forename: Preeti
authors.initials: P
authors.lastname: Yadav
authors.forename: Vinay
authors.initials: V
authors.lastname: Lomash
authors.forename: A S B
authors.initials: AS
authors.lastname: Bhaskar
authors.forename: P V
authors.initials: PV
authors.lastname: Lakshmana Rao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003872:Dermatitis / Q000209:etiology / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005670:Fusarium / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007928:Lethal Dose 50; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013605:T-2 Toxin / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D013605:T-2 Toxin