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BROMATE-INDUCED TRANSCRIPTIONAL CHANGES IN LONG-EVANS RAT KIDNEYS
Citation:
Wolf, D C., K. S. McDorman, G W. Knapp, G M. Nelson, AND S D. Hester. BROMATE-INDUCED TRANSCRIPTIONAL CHANGES IN LONG-EVANS RAT KIDNEYS. Presented at Oncogenomics 2002: Dissecting cancer through genome research, Dublin, Ireland, May 1-5, 2002.
Description:
Bromate-Induced Transcriptional Changes in Long-Evans Rat Kidneys.
Ozone disinfection of surface waters containing bromide ion (Br-) results in the oxidation of bromide to bromate, which can be found in finished drinking water as a by-product. Potassium bromate (KBrO3) is a rodent carcinogen and a nephro- and neurotoxic ant in humans. Male and female F344 rats develop renal cell tumors and thyroid follicular tumors, and the males also have in increased incidence of abdominal mesotheliomas after 2-years of exposure to bromate in the drinking water. The suspected mechanism by which bromate causes renal tumors is via
oxidative DNA damage with subsequent mutation, Clear cell renal tumors, the most common form of human renal epithelial neoplasm, are rare in animals but are inducible by KBrO3 in F344 rats and these rat clear cell tumors contain periodic acid Schiff positive granules like their human counterparts, Proximal tubule epithelium have treatment related increased eosinophilic cytoplasmic droplets consistent with oxidized lipid membranous material within vacuoles. Bromate causes a significant increase of 8oxoguanine adducts in kidney DNA but no increase in abasic sites, suggesting enhanced base excision repair. The present study investigated the transcriptional changes associated with bromate-induced renal lesions and oxidative DNA
damage in male Long-Evans rats treated for 21 days with 0.4 grams/liter of potassium bromate in the drinking water. Half of one kidney was processed for microscopic examination and the remaining kidney was processed for extraction of genomic DNA and total RNA. The RNA was hybridized to a Clontech Atlas@ Rat 1.0 Glass Microarray using a 2 flourescent dye procedure. Array data were analyzed using GeneSpring@. Additional RNA was isolated in order to identify the expression level of a subset of genes mostly involved in DNA repair, DNA polymerase beta, oxoguanine glycosylase, flag structure-specific endonuclease, AP endonuclease 1, and DNA
ligase I, by quantitative real-time reverse transcriptase (RT) PCR. Only 13 of the 1090 genes in the array (1.2%) were significantly altered, 5 increased and 8 decreased. Only 8 (0.7%) of the genes on the array were increased in expression by 20% or more and 41 (3.8%) were decreased y 20% or more. The expression of genes typically associated with renal cancer in the rat such as TGF-alpha, EGF-receptor, VHL, and Wilms Tumor were not altered. The expression levels fthe genes analyzed with real-time RT -PCR were not significantly different from control. Control male Long-Evans rat kidney has a uniform expression level among the 1090 genes on the Clontech 1K array. Bromate-induces only mild increases and decreases of transcripton levels 1 a small percentage of the genes. Exposure for 21 days to a carcinogenic, but not clinically toxic, concentration of, KBrO3 causes only subtle alterations in the transcriptome. Small changes in transcription of important regulatory genes, coupled with chronic exposure, may be sufficient to drive the cancer process in chemically induced carcinogenesis.
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