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ToxSci Advance Access published online on November 16, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl169
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 26, 2006
Accepted November 14, 2006

Carcinogenicity

Reduction in Antioxidant Defences May Contribute to Ochratoxin A Toxicity and Carcinogenicity

C. Cavin 1 *, T. Delatour 1, M. Marin-Kuan 1, D. Holzhäuser 1, L. Higgins 2, C. Bezençon 1, G. Guignard 1, S. Junod 1, D. Piguet 1, J. Richoz-Payot 1, E. Gremaux 1, J. D. Hayes 2, S. Nestler 3, P. Mantle 4, and B. Schilter 1

1 Quality and Safety Dpt, Nestlé Research Center, PO Box 44, Vers-chez-les-Blanc, CH-1000 Lausanne 26, Switzerland
2 Quality and Safety Dpt, Nestlé Research Center, PO Box 44, Vers-chez-les-Blanc, CH-1000 Lausanne 26, Switzerland; Biomedical Research Centre, University of Dundee, Dundee DD1 9SY
3 Quality and Safety Dpt, Nestlé Research Center, PO Box 44, Vers-chez-les-Blanc, CH-1000 Lausanne 26, Switzerland; Nephro-Urology Unit, Institute of Child Health, University College London, WC1E 1EH, UK
4 Quality and Safety Dpt, Nestlé Research Center, PO Box 44, Vers-chez-les-Blanc, CH-1000 Lausanne 26, Switzerland; Imperial College London, Department of Environmental Science and Technology, London, SW7 2AZ, UK

* To whom correspondence should be addressed.
C. Cavin, E-mail: Christophe.Cavin{at}rdls.nestle.com


  Abstract

Ochratoxin A (OTA) is a renal carcinogen in rodents. Its human health significance is unclear. It likely depends upon the mechanism of carcinogenesis. In a previous microarray study a reduction in NF-E2 p45 related factor 2 (Nrf2)-dependent gene expression was observed in the kidney but not in the liver of rats fed OTA up to 12 months. Nrf2 regulates detoxification and antioxidant gene expression. The present report shows that OTA decreased the protein expression of several markers of the Nrf2-regulated gene battery in kidney in vivo indicating that the effects observed at mRNA level may be of biological significance. The OTA-mediated Nrf2 response could be reproduced in an NRK renal cell line and in primary hepatocyte cultures. In in vitro systems, an OTA -mediated inhibition of Nrf2 activity was demonstrated by electrophoretic mobility shift and ARE-driven luciferase reporter assays. The reduction of Nrf2-regulated gene expression resulted in oxidative DNA damage as evidenced by formation of abasic sites in vitro and confirmed in kidney in vivo. All OTA-mediated effects observed were prevented by pre-treatment of cell cultures with inducers of Nrf2 activity. Our data suggest that reduction of cellular defence against oxidative stress by Nrf2 -inhibition may be a plausible mechanism of OTA nephrotoxicity and carcinogenicity.

Keywords: Mycotoxin; ochratoxin A; nuclear factor-erythroid 2 p45-related factor 2 (Nrf2); oxidative stress; nephrotoxicity; carcinogenicity.
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