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GENE EXPRESSION ANALYSIS IN THE VENTRAL PROSTATE OF RATS EXPOSED TO VINCLOZOLIN OR PROCYMIDONE
Rosen, M B., V S. Wilson, J E. Schmid, AND L E. Gray Jr. GENE EXPRESSION ANALYSIS IN THE VENTRAL PROSTATE OF RATS EXPOSED TO VINCLOZOLIN OR PROCYMIDONE. REPRODUCTIVE TOXICOLOGY 19(3):367-379, (2005).
Vinclozolin and procymidone are antiandrogens that are thought to share a common androgen receptor (AR) mediated mechanism of action. This assessment is based primarily on morphological, AR binding, and in vitro transcriptional activation studies. Studies designed to evaluate the gene expression profiles induced by these compounds have the potential to provide further information to test this hypothesis. We have used targeted gene arrays to examine gene expression in the ventral prostate (VP) of 100 day old Sprague Dawley male rats exposed to either vinclozolin or procymidone. Animals were castrated and administered silastic implants with or without testosterone. A subset of testosterone treated animals was then dosed with 200 mg/kg of either fungicide in corn oil. Four treatment groups were used: Castrated (C), Testosterone (T), Testosterone+Vinclozolin (V), and Testosterone+Procymidone (P). Tissue from the VP was collected from 6 animals per group (3 animals per block x 2 blocks) at 20 hrs and at 4 days after the start of treatment. Total RNA was then isolated and gene expression analyzed using Clontech Atlas Rat 1.2 Toxicology arrays. Similar changes in gene expression were observed in groups C, P and V at both the 20 hr and 4 day time points. After 20 hrs of treatment, 20 genes were similarly affected across these three treatment groups. Down-regulated genes included various molecular chaperones, the 11-kDa diazepam binding inhibitor, cyclin D1, and mitochondrial aspartate aminotransferase. Genes such as the androgen receptor, PTEN, and ERK2 were up-regulated. Three of the down-regulated genes, Grp78 (BiP), Dad1, and mitochondrial aspartate aminotransferase have been previously shown to be directly androgen regulated. Fifty four genes were affected at 20 hrs, whereas, 311 genes were altered 4 days after the start of treatment. These observations, in part, may reflect regression of the VP at the later time point. These results support the hypothesis that procymidone and vinclozolin share a common mechanism or mode of action, a critical step in a cumulative risk assessment.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
REPRODUCTIVE TOXICOLOGY DIVISION
GAMETE AND EARLY EMBRYO BIOLOGY BRANCH