In vitro cytogenetic results supporting a DNA nonreactive mechanism for ochratoxin A, potentially relevant for its carcinogenicity
Author(s)
Date Issued
2008
Type
Article
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.
Additional information
The present paper is dedicated
to Prof. A. T. Natarajan on the occasion of his 80th birthday.
to Prof. A. T. Natarajan on the occasion of his 80th birthday.
Citation
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
Subjects
File(s)![Thumbnail Image]()
Name
mosesso_et_al_abstract.pdf
Size
43.19 KB
Format
Adobe PDF
Checksum (MD5)
8e189c6298b4f79954231d34e77b371f
Sponsor(s)
Parts of this work were supported by the
Fifth RTD Framework Program of the European Union, Project
QLK1-2001-01614 “Mechanisms of Ochratoxin A Induced
Carcinogenicity as a Basis for an Improved Risk Assessment”
and by Italian M.U.R.S.T. (60%).
Fifth RTD Framework Program of the European Union, Project
QLK1-2001-01614 “Mechanisms of Ochratoxin A Induced
Carcinogenicity as a Basis for an Improved Risk Assessment”
and by Italian M.U.R.S.T. (60%).