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Title: Ochratoxin A causes DNA damage and cytogenetic effects but no DNA adducts in rats
Authors: Mally, Angela
Pepe, Gaetano
Ravoori, Srivani
Fiore, Mario
Gupta, Ramesh C.
Dekant, Wolfgang
Mosesso, Pasquale
Issue Date: 2005
Publisher: American Chemical Society
Source: Mally, A. et al. 2005. Ochratoxin A causes DNA damage and cytogenetic effects but no DNA adducts in rats. "Chem. Res. Toxicol." 18: 1253-1261
Ochratoxin A (OTA) is a potent nephrotoxin and renal carcinogen in rats, but the mechanism
of OTA tumorigenicity is unknown. Ochratoxin A has been shown to be negative in many genetic
toxicology test in vitro. However, the potential of OTA to induce genotoxic effects has not been
investigated in male rats, the most sensitive species for OTA-induced tumor formation. In
this study, male F344 rats were repeatedly administered OTA (0, 250, 500, 1000, and 2000
íg/kg of body wt) or the non-chlorinated analogue ochratoxin B (OTB; 2000 íg/kg of body wt)
for 2 weeks (5 days/week), and DNA breakage was analyzed in target and nontarget tissues
using the comet assay both in the absence and presence of formamidopyrimidine-DNA (Fpg)
glycosylase. Potential DNA-adduct formation was also analyzed in the target organ kidney by
32P-postlabeling using two different solvent systems. DNA-strand breaks were evident in liver,
kidney, and spleen of animals treated with OTA, and a similar degree of DNA damage was
observed in rats treated with OTB, despite the lower toxicity of OTB. Moreover, the presence
of DNA damage did not correlate with histopathological alterations, which were evident in
the kidney but not in the liver. In liver and kidney, the extent of DNA damage was further
enhanced in the presence of Fpg glycosylase, which is known to convert oxidative DNA damage
into strand breaks, suggesting the presence of oxidative DNA damage. Oxidative DNA damage
as a mechanism of OTA-dependent DNA damage is consistent with the absence of lipophilic
DNA adducts as assessed by 32P-postlabeling analysis. No spots indicative of OTA-related DNA
adducts were observed in kidney DNA extracted from OTA-treated animals by 32P-postlabeling
analysis, despite the use of synthetic standard for postulated adducts. A small, but not
significant, increase in the incidence of chromosomal aberrations (essentially chromatid and
chromosome-type deletions) was observed in splenocytes from rats treated with OTA in vivo
and subsequently cultured in vitro to express chromosomal damage. These aberrations are
also compatible with oxidative DNA lesions since they are not typically caused by chemical
carcinogens which form covalent DNA adducts. Together, with the lack of evidence for formation
of lipophilic DNA adducts as assessed by postlabeling, these data suggest that OTA may cause
genetic damage in both target and nontarget tissues independent of direct covalent binding to
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ISSN: 0893-228X
DOI: 10.1021/tx049650x
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