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Title: | In vitro cytogenetic results supporting a DNA nonreactive mechanism for ochratoxin A, potentially relevant for its carcinogenicity | Authors: | Mosesso, Pasquale Cinelli, Serena Piñero, Joaquin Bellacima, Raffaela Pepe, Gaetano |
Keywords: | Genotoxicity of OTA;Mycotoxins;Genotossicità del'OTA;Micotossine | Issue Date: | 2008 | Publisher: | American Chemical Society | Source: | Mosesso, P. et al. 2008. In vitro cytogenetic results supporting a DNA nonreactive mechanism for ochratoxin A, potentially relevant for its carcinogenicity. "Chemical Research in Toxicology" 21(6): 1235-1243 | Abstract: | Ochratoxin A (OTA) is a widespread mycotoxin of cereals and many agricultural products and causes high incidences of renal tumors in rodents. Although its carcinogenic properties have been known since the eighties, the precise mechanism of action is still relatively undefined. At present, increasing evidence suggests that OTA does not act with a direct genotoxic mechanism, opposed to other previous evidence where the formation of DNA adducts by 32P-postlabeling was observed. The genotoxic activity of OTA assessed in a variety of in vitro and in vivo studies was very low if genotoxic at all. In this study, we clearly show that OTA does not bear any clastogenic or aneugenic activity based on the absence of the induction of chromosome aberrations, sister chromatid exchanges, and micronuclei in human lymphocytes and V79 cells in vitro in both the absence and the presence of S9 metabolism. Alternatively, cytogenetic analyses evidenced significant increases in endoreduplicated cells and highly condensed metaphases with separated chromatids. This implies that OTA or its possible metabolites do not covalently bind DNA through the formation of adducts since structural chromosome aberrations are a very sensitive end points to detect chemical carcinogens with electrophilic substituents. Alternatively, induction of endoreduplication and chromatid separation provides strong evidence for a DNA nonreactive mechanism of OTA carcinogenicity involving the disruption of mitosis by interfering with key regulators of chromosome separation and progression of mitosis. This causes a temporary arrest of mitoses and premature exit from it (mitotic slippage) to generate endoreduplication and polyploidy accompanied by increased risk of aneuploidy and subsequent tumor formation. |
Description: | The present paper is dedicated to Prof. A. T. Natarajan on the occasion of his 80th birthday. L'articolo è disponibile sul sito dell'editore: http://pubs.acs.org/ |
URI: | http://hdl.handle.net/2067/1346 | ISSN: | 0893-228X | DOI: | 10.1021/tx800029f |
Appears in Collections: | DABAC - Archivio della produzione scientifica |
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