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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg073
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 13, 2002; accepted February 20, 2003
© 2003 Society of Toxicology

Molecular and Genetic Toxicology

A New Approach to Study Ochratoxin A (OTA) Induced Nephrotoxicity: Expression Profiling In Vivo and In Vitro Employing cDNA-Microarrays

Anke Luehe 1*, Heinz Hildebrand 1, Ute Bach 2, Theodor Dingermann 3, Hans-Jürgen Ahr 1

1 Bayer AG, Dept. of Molecular and Genetic Toxicology, Aprather Weg 18a, 42096 Wuppertal, Germany
2 Bayer AG, Dept. of Pathology, Aprather Weg 18a, 42096 Wuppertal, Germany
3 Inst. of Pharmaceutical Biology, Johann Wolfgang Goethe Universität, Marie-Curie-Str. 9, 60439 Frankfurt/Main, Germany

* To whom correspondence should be addressed. E-mail: anke.luehe.al{at}bayer-ag.de.


  Abstract

Ochratoxin A is a mycotoxin often found in cereals as a contaminant and is known to cause severe nephrotoxicity in animals and humans. There have been several investigations studying the mode of action of this toxicant, suggesting inhibition of protein synthesis, formation of DNA adducts, as well as provocation of DNA single-strand breaks as a result of oxidative stress, but little is known about the transcriptional alterations underlying OTA-derived nephrotoxicity so far. We carried out DNA microarray analyses to assess OTA-specific expression profiles in vivo and in vitro. Cultures of primary rat proximal tubular cells and male Wistar rats were treated with a low dose (5µM and 1 mg/kg, respectively) or a high dose (12.5µM and 10 mg/kg, respectively) of OTA for 24 hours or for 72 hours. Microarray experiments were carried out after dual fluorescent labelling of sample cDNA and data analysis was performed utilizing different statistical methods. Validity of selected microarray data was confirmed by quantitative real time PCR. We were able to demonstrate that microarray data derived from our PTC culture model were highly comparable to the in vivo situation. Marked treatment-specific transcriptional changes were detected for genes involved in DNA damage response and apoptosis (upregulation of GADD 153, GADD 45, annexin V), response to oxidative stress (differential expression of hypoxia-inducible factor 1 and catalase) and inflammatory reactions (upregulation of alpha 2 macroglobulin, ceruloplasmin and cathepsin S). We conclude that our results provide a molecular basis for interpretation of OTA-induced nephrotoxicity.

Toxicogenomics, microarray, expression profiling, Ochratoxin A, nephrotoxicity, kidney, proximal tubule, cell culture .


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