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KIDNEY TOXICOGENOMICS OF CHRONIC POTASSIUM BROMATE EXPOSURE IN F344 MALE RAT
Citation:
GETER, D. R., W. O. WARD, G. W. KNAPP, A. B. DEANGELO, J. A. RUBIS, R. D. OWEN, J. W. ALLEN, AND D. A. DELKER. KIDNEY TOXICOGENOMICS OF CHRONIC POTASSIUM BROMATE EXPOSURE IN F344 MALE RAT. Translational Oncogenomics. Libertas Academica Ltd, North Harbour, New Zealand, 2:33-52, (2006).
Impact/Purpose:
To gain insight into the carcinogenic mechanism of action and provide possible biomarkers of KBrO3 exposure
Description:
Potassium bromate (KBrO3), used in both the food and cosmetics industry, and a drinking water disinfection by-product, is a nephrotoxic compound and rodent carcinogen. To gain insight into the carcinogenic mechanism of action and provide possible biomarkers of KBrO3 exposure, the gene expression in kidneys from chronically exposed male F344 rats was investigated.
Methods-Male F344 rats were exposed to KBrO3 in drinking water for 52 and 100 wk. Kidneys were removed, frozen and stored at -800C, then used for Affymetrix microarray analysis. Gene expression patterns were examined in a non-cancer (20 ppm) and cancer-causing dose (400 ppm)at 52 wk, and compared to 100 wk high dose (400 ppm) and adenoma gene expression.
Results-Statistical analysis revealed 144, 224, 43, and 994 genes out of 15919 from the 52 wk low, 52 wk high, 100 wk high, and adenomas respectively, were significantly altered. Gene ontology classification of the 52 wk high dose showed alterations of gene transcripts involved in oxidative stress, lipid metabolism, kidney function/ion transport, and cellular function. In a comparison of kidney development gene expression, alterations were seen in the adenomas but not in the 52 wk bromate-treated kidneys. However, the high dose kidney, but not the low, resembled the adenoma expression pattern with early kidney development genes being up-regulated and adult phase genes being down-regulated. Moreover, eight genes which could serve as biomarkers of carcinogenic exposure were identified. The most promising of these was Pendrin, or Slc26a4, a solute carrier of chloride and iodide active in the kidney, thyroid and inner ear. All these tissues
are targets of KBrO3toxicity. Expression array results were verified with quantitative real-time -rtPCR
Conclusions-
These data suggest the 400 ppm carcinogenic dose of KBrO3 showed marked gene expression differences from the non-cancer dose. Comparison of kidney development gene expression showed that the adenoma patterns were more characteristic of embryonic than adult kidneys, and that the high dose kidney gene expression resembled an adenoma-like expression pattern. Taken together, the analysis from this study identifies potential biomarkers of exposure and illuminates a possible carcinogenic mode of action for KBrO3.