ToxSci Advance Access originally published online on March 6, 2007
Toxicological Sciences 2007 97(2):288-298; doi:10.1093/toxsci/kfm042
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Ochratoxin A: 13-Week Oral Toxicity and Cell Proliferation in Male F344/N Rats
* Department of Toxicology, University of Würzburg, 97078 Würzburg, Germany
Private Consultant, Tairua 2853, New Zealand
RCC Ltd, CH-4414 Füllinsdorf/CH-4452 Itingen, Switzerland
Department of Surgery, University of Würzburg, 97078 Würzburg, Germany
1 To whom correspondence should be addressed at Department of Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany. Fax: +49-931-20148865. E-mail: mally{at}toxi.uni-wuerzburg.de.
Received February 5, 2007; accepted March 2, 2007
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Abstract |
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Ochratoxin A (OTA) is nephrotoxic and a potent renal carcinogen. Male rats are most susceptible to OTA toxicity, and chronic administration of OTA (70 and 210 µg/kg bw) for 2 years has been shown to induce high incidences of adenomas and carcinomas arising from the straight segment of the proximal tubule epithelium. In contrast, treatment with a lower dose of 21 µg/kg bw did not result in increased tumor rates, suggesting a nonlinear dose response for renal tumor formation by OTA. Since the mechanism of OTA carcinogenicity is still largely unknown, this study was conducted to investigate early functional and pathological effects of OTA and to determine if sustained stimulation of renal cell proliferation plays a role. Male F344/N rats were treated with OTA for up to 13 weeks under conditions of the National Toxicology Program (NTP) bioassay. Cell proliferation in the renal cortex and outer stripe of the outer medulla (OSOM) was determined using bromodeoxyuridine incorporation and immunohistochemistry. Histopathological examination showed renal alterations in mid- and high-dose–treated animals involving single-cell death and prominent nuclear enlargement within the straight proximal tubules. Treatment with OTA at doses of 70 and 210 µg/kg bw led to a marked dose- and time-dependent increase in renal cell proliferation, extending from the medullary rays into the OSOM. No effects were evident in kidneys of low-dose–treated animals or in the liver, which is not a target for OTA carcinogenicity. A no observed effect level in this study was established at 21 µg/kg bw, correlating with the dose in the NTP 2-year bioassay that did not produce renal tumors. The apparent correlation between enhanced cell turnover and tumor formation induced by OTA indicates that stimulation of cell proliferation may play an important role in OTA carcinogenicity and provides further evidence for an epigenetic, thresholded mechanism.
Key Words: ochratoxin A; kidney; carcinogenicity; cell proliferation; karyomegaly.
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