Abstract
Skin cancer is one of the most common forms of cancer and 2–3 million new cases are being diagnosed globally each year. Along with UV rays, environmental pollutants/chemicals including mycotoxins, contaminants of various foods and feed stuffs, could be one of the aetiological factors of skin cancer. In the present study, we evaluated the DNA damaging potential and dermal carcinogenicity of a mycotoxin, ochratoxin A (OTA), with the rationale that dermal exposure to OTA in workers may occur during their involvement in pre and post harvest stages of agriculture. A single topical application of OTA (20–80 µg/mouse) resulted in significant DNA damage along with elevated γ-H2AX level in skin. Alteration in oxidative stress markers such as lipid peroxidation, protein carbonyl, glutathione content and antioxidant enzymes was observed in a dose (20–80 µg/mouse) and time-dependent (12–72 h) manner. The oxidative stress was further emphasized by the suppression of Nrf2 translocation to nucleus following a single topical application of OTA (80 µg/mouse) after 24 h. OTA (80 µg/mouse) application for 12–72 h caused significant enhancement in- (a) reactive oxygen species generation, (b) activation of ERK1/2, p38 and JNK MAPKs, (c) cell cycle arrest at G0/G1 phase (37–67%), (d) induction of apoptosis (2.0–11.0 fold), (e) expression of p53, p21/waf1, (f) Bax/Bcl-2 ratio, (g) cytochrome c level, (h) activities of caspase 9 (1.2–1.8 fold) and 3 (1.7–2.2 fold) as well as poly ADP ribose polymerase cleavage. In a two-stage mouse skin tumorigenesis protocol, it was observed that a single topical application of OTA (80 µg/mouse) followed by twice weekly application of 12-O-tetradecanoylphorbol-13-acetate for 24 week leads to tumor formation. These results suggest that OTA has skin tumor initiating property which may be related to oxidative stress, MAPKs signaling and DNA damage.
Highlights
Skin being the largest organ of human body, is exposed to sunlight, air pollutants and other environmental factors which may lead to skin cancer
Tumorigenesis is a multistage process enumerated by initiation, promotion and progression steps and it is implicated that identification of the step where Ochratoxin A (OTA) interferes with this process would be of significance in understanding the risk associated with its exposure [4,6]
Two-stage mouse skin tumorigenesis model has been employed to study the tumorigenic property of OTA and related molecular events [23]
Summary
Skin being the largest organ of human body, is exposed to sunlight, air pollutants and other environmental factors which may lead to skin cancer. Ultra violet (UV) rays from sunlight are considered as the main cause of skin cancer; dermal exposure to other potential chemical carcinogens including mycotoxins can not be ruled out and their toxicity needs to be evaluated. Available epidemiological information is insufficient to assess the direct correlation of OTA consumption through food with human health risk [6,7]. It has been widely acknowledged that the risk assessment to OTA exposure requires more of animal data that would significantly help in the elucidation of the mechanism(s) of carcinogenicity [6,7]. Several epigenetic mechanisms including protein synthesis inhibition, oxidative stress, alterations of cell signaling pathways and apoptosis in cell lines have been reported for OTA carcinogenicity [6,7,9]
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