Gene expression analysis in the ventral prostate of rats exposed to vinclozolin or procymidone.
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 six animals per group (3 animals per block x 2 blocks) at 20 h 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. When compared to group T, similar changes in gene expression were observed in groups C, P and V at both the 20 h and 4 day time points. After 20 h 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 h, 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.
Rosen
Mitchell B
MB
United States Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Division, MD72, Research Triangle Park, NC 27711, USA. rosen.mitch@epa.gov
Wilson
Vickie S
VS
Schmid
Judith E
JE
Gray
L Earl
LE
D000284:Administration, Oral; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D000728:Androgens / Q000008:administration & dosage; D000818:Animals; D001835:Body Weight; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000633:toxicity*; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009919:Orchiectomy; D010080:Oxazoles / Q000008:administration & dosage / Q000633:toxicity*; D011467:Prostate / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000008:administration & dosage; D013997:Time Factors
D000726:Androgen Antagonists; D000728:Androgens; D001643:Bridged Bicyclo Compounds; D010080:Oxazoles; D013739:Testosterone; C035988:procymidone; C025643:vinclozolin