Deoxynivalenol induced mouse skin cell proliferation and inflammation via MAPK pathway

Journal Article · Mon Sep 01 04:00:00 EDT 2014 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2014.06.003· OSTI ID:22439817

Mishra, Sakshi ^[1]; Tripathi, Anurag ^[1]; Chaudhari, Bhushan P. ^[2]; Dwivedi, Premendra D. ^[1]; Pandey, Haushila P. ^[3]; Das, Mukul ^[1]

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1. 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)
2. Pathology Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Mahatma Gandhi Marg, PO Box 80, Lucknow 226001, Uttar Pradesh (India)
3. Department of Biochemistry, Banaras Hindu University (BHU), Varanasi (India)

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 (84–672 nmol/mouse) significantly enhanced dermal hyperplasia and skin edema. DON (336 and 672 nmol) caused significant enhancement in [{sup 3}H]-thymidine uptake in DNA along with increased myeloperoxidase and ornithine decarboxylase activities, suggesting tissue inflammation and cell proliferation. Furthermore, DON (168 nmol) 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 168 nmol) showed no tumorigenesis after 24 weeks, 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 24 weeks 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. - Highlights: • Topical application of DON enhanced epidermal inflammation and cell proliferation. • DON follows PI3K/Akt/MAPK signaling cascade, with activation of AP-1 and NF-κB. • DON caused over expression of target proteins, COX-2, cyclin D1 and iNOS in skin. • No tumor promotion was observed up to 24 weeks of topical application of DON. • Enhanced Peyer's patches and inflammatory cytokines suggested inflammation in skin.

• OSTI ID: 22439817
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 279; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTHRACENE
CELL PROLIFERATION
DECARBOXYLASES
DNA
EDEMA
EPIDERMIS
HAIR FOLLICLES
HYPERTROPHY
INFLAMMATION
LYMPHOKINES
MICE
NEOPLASMS
ORNITHINE
PHOSPHORYLATION
SIGNALS
THYMIDINE
TOXICITY
TRANSCRIPTION FACTORS
TRITIUM
UPTAKE