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ASSESSING VINCLOZOLIN FOR ANTIANDROGENIC ACTIVITY: A DOSE-RESPONSE STUDY OF GENE EXPRESSION IN THE RAT VENTRAL PROSTATE
Citation:
JACKSON, T., M. B. ROSEN, J. FURR, J. E. SCHMID, AND L. E. GRAY. ASSESSING VINCLOZOLIN FOR ANTIANDROGENIC ACTIVITY: A DOSE-RESPONSE STUDY OF GENE EXPRESSION IN THE RAT VENTRAL PROSTATE. Presented at Society for the Study of Reproduction, Quebec, QC, CANADA, July 24 - 27, 2005.
Description:
The United States Environmental Protection Agency, along with agencies within the European Union, are currently evaluating in vitro and in vivo assays to detect compounds that display antiandrogenic orandrogenic activity. Thein vivo assay is based on weight changes in androgen dependent tissues in the castrated immature male rat. In the current project, we are evaluating the ability of genomic data to enhance the sensitivity of this assay. In the first study, castrate-immature androgen-treated male rats were dosed with vinclozolin (V), a fungicide that acts as an AR antagonist, at 0, 25, 50, 100 and 200 mg/kg/day for 7 days. Organ weight changes were observed across all V dose groups. In a second study, gene expression at various exposure time points was considered. In this study, 200 mg/kg/day of Vwas found to alter the expression of a specific group of genes in a manner similar to castrated animals not treated with androgens. Transcriptional changes in the androgen receptor, mitochondrial aspartate aminotransferase, Dad1, Grp78 and Grp94were found, within the first day of dosing, to be robust indicators of antiandrogenic activity(Rosen et al., 2005). A third study has been initiated to compare the effects of V on gene expression and sex accessory tissue weights using dosage levels ranging from a No Observed Effect Level (NOEL) to a highly effective dose (0, 3, 10, 30, and 100 mg/kg/day). After ten days of treatment, the rats will be killed, accessory sex organs weighed, and a portion of the ventral prostate reserved for preparation of total RNA. Gene profiling will be conducted using Affymetrix rat 230_ver.2 gene arraysto establish a gene expression dose response in the ventral prostate for V-treated animalswith particular interest to dose levels that have little or no effect on organ weights. The goal of this work will be to contrast the sensitivity and specificity of androgen-dependent gene expression data to that obtained from weights of androgen-dependent tissues in thisshort-term in vivo assay.
This is an abstract and does not necessarily reflect EPA policy. Fund by EPA/North Carolina Central University Training agreement # CT829460.