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.