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Saxena N, Ansari KM, Kumar R, Dhawan A, Dwivedi PD, Das M.
Patulin causes DNA damage leading to cell cycle arrest and apoptosis through
modulation of Bax, p(53) and p(21/WAF1) proteins in skin of mice.
Toxicol Appl Pharmacol. 2009 Jan 15;234(2):192-201
Food Toxicology Division, Indian Institute of Toxicology Research (formerly:
Industrial Toxicology Research Centre), Council of Scientific and Industrial
Research, Mahatma Gandhi Marg, P.O. Box #80, Lucknow-226001, India.
Patulin (PAT), a mycotoxin found in apples, grapes, oranges, pear and peaches,
is a potent genotoxic compound. WHO has highlighted the need for the study of
cutaneous toxicity of PAT as manual labour is employed during pre and post
harvest stages, thereby causing direct exposure to skin. In the present study
cutaneous toxicity of PAT was evaluated following topical application to Swiss
Albino mice. Dermal exposure of PAT, to mice for 4 h resulted in a dose (40-160
mug/animal) and time (up to 6 h) dependent enhancement of ornithine
decarboxylase (ODC), a marker enzyme of cell proliferation. The ODC activity was
found to be normal after 12 and 24 h treatment of patulin. Topical application
of PAT (160 mug/100 mul acetone) for 24-72 h caused (a) DNA damage in skin cells
showing significant increase (34-63%) in olive tail moment, a parameter of Comet
assay (b) significant G 1 and S-phase arrest along with induction of apoptosis
(2.8-10 folds) as shown by annexin V and PI staining assay through flow
cytometer. Moreover PAT leads to over expression of p(21/WAF1) (3.6-3.9 fold),
pro apoptotic protein Bax (1.3-2.6) and tumor suppressor wild type p(53)
(2.8-3.9 fold) protein. It was also shown that PAT induced apoptosis was
mediated through mitochondrial intrinsic pathway as revealed through the release
of cytochrome C protein in cytosol leading to enhancement of caspase-3 activity
in skin cells of mice. These results suggest that PAT has a potential to induce
DNA damage leading to p(53) mediated cell cycle arrest along with intrinsic
pathway mediated apoptosis that may also be correlated with enhanced polyamine
production as evident by induction of ODC activity, which may have dermal
toxicological implications.
PMID: 19000704
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