title: Deoxynivalenol induced mouse skin cell proliferation and inflammation via MAPK pathway.
abstract: Several toxicological manifestations of deoxynivalenol (DON), a mycotoxin, are well documented; however, dermal toxicity is not yet explored. The effect of topical application of DON to mice was studied using markers of skin proliferation, inflammation and tumor promotion. Single topical application of DON (84-672nmol/mouse) significantly enhanced dermal hyperplasia and skin edema. DON (336 and 672nmol) caused significant enhancement in [(3)H]-thymidine uptake in DNA along with increased myeloperoxidase and ornithine decarboxylase activities, suggesting tissue inflammation and cell proliferation. Furthermore, DON (168nmol) caused enhanced expression of RAS, and phosphorylation of PI3K/Akt, ERK, JNK and p38 MAPKs. DON exposure also showed activation of transcription factors, c-fos, c-jun and NF-κB along with phosphorylation of IkBα. Enhanced phosphorylation of NF-κB by DON caused over expression of target proteins, COX-2, cyclin D1 and iNOS in skin. Though a single topical application of DMBA followed by twice weekly application of DON (84 and 168nmol) showed no tumorigenesis after 24weeks, however, histopathological studies suggested hyperplasia of the epidermis and hypertrophy of hair follicles. Interestingly, intestine was also found to be affected as enlarged Peyer's patches were observed, suggesting inflammatory effects which were supported by elevation of inflammatory cytokines after 24weeks of topical application of DON. These results suggest that DON induced cell proliferation in mouse skin is through the activation of MAPK signaling pathway involving transcription factors NFκB and AP-1, further leading to transcriptional activation of downstream target proteins c-fos, c-jun, cyclin D1, iNOS and COX-2 which might be responsible for its inflammatory potential.
authors.affiliation: Food Drug and Chemical Toxicology, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), P.O. Box No. 80, Mahatma Gandhi Marg, Lucknow 226 001, India; Department of Biochemistry, Banaras Hindu University (BHU), Varanasi, India.
authors.forename: Sakshi
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Food Drug and Chemical Toxicology, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), P.O. Box No. 80, Mahatma Gandhi Marg, Lucknow 226 001, India.
authors.forename: Anurag
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: Pathology Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Mahatma Gandhi Marg, PO Box 80, Lucknow 226001, Uttar Pradesh, India.
authors.forename: Bhushan P
authors.initials: BP
authors.lastname: Chaudhari
authors.affiliation: Food Drug and Chemical Toxicology, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), P.O. Box No. 80, Mahatma Gandhi Marg, Lucknow 226 001, India.
authors.forename: Premendra D
authors.initials: PD
authors.lastname: Dwivedi
authors.affiliation: Department of Biochemistry, Banaras Hindu University (BHU), Varanasi, India.
authors.forename: Haushila P
authors.initials: HP
authors.lastname: Pandey
authors.affiliation: Food Drug and Chemical Toxicology, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), P.O. Box No. 80, Mahatma Gandhi Marg, Lucknow 226 001, India. Electronic address: mditrc@rediffmail.com.
authors.forename: Mukul
authors.initials: M
authors.lastname: Das
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003872:Dermatitis / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D006965:Hyperplasia; D006984:Hypertrophy; D018836:Inflammation Mediators / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010581:Peyer's Patches / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D010766:Phosphorylation; D018570:Risk Assessment; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014255:Trichothecenes / Q000633:toxicity*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D014157:Transcription Factors; D014255:Trichothecenes; D009195:Peroxidase; D009955:Ornithine Decarboxylase; C007262:deoxynivalenol
keywords: Cytokines; Deoxynivalenol; Mycotoxins; Peyer's patches; Skin cell proliferation; Skin inflammation