Vinclozolin and p,p'-DDE alter androgen-dependent gene expression: In vivo confirmation of an androgen receptor-mediated mechanism

被引:286
作者
Kelce, WR [1 ]
Lambright, LR [1 ]
Gray, LE [1 ]
Roberts, KP [1 ]
机构
[1] UNIV MINNESOTA,SCH MED,DEPT UROL SURG,MINNEAPOLIS,MN 55455
关键词
RAT VENTRAL PROSTATE; BINDING-PROTEIN; MESSENGER-RNA; CELLS; SPECIFICITY; ANTAGONIST; CLUSTERIN; CLONING;
D O I
10.1006/taap.1996.7966
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Vinclozolin and p,p'-DDE induce antiandrogenic developmental effects in vivo and are potent inhibitors of androgen receptor (AR) binding and AR-dependent gene expression in vitro. To determine whether this molecular mechanism is operative in vivo, the effects of these compounds on two androgen-regulated prostatic mRNAs were studied. Rats were sham operated or castrated and immediately implanted with one or two empty 2.5-cm silastic capsules or with one (1X) or two (2X) 2.5-cm capsules containing testosterone (T). T-implanted rats were treated by gavage for 4 days with vehicle (corn oil), vinclozolin (200 mg/kg/day), p,p'-DDE (200 mg/kg/day), or the antiandrogen flutamide (100 mg/kg/day) as a positive control. Vinclozolin, p,p'-DDE, and flutamide all induced a reciprocal decline in seminal vesicle (p < 0.01) and prostate (p < 0.01) weight as well as a reduction in immunohistochemical staining of AR in epididymal nuclei compared to vehicle-treated T-implanted controls. Specific AR antagonism was assessed by determining the ability of these chemicals to induce a testosterone-repressed prostatic message (i.e., TRPM-2) and/or repress a testosterone-induced prostatic message (i.e., prostatein subunit C3). Densitometry scans of Northern blots indicated that vinclozolin, p,p'-DDE, and flutamide each induced TRPM-2 mRNA and repressed C3 mRNA compared to vehicle-treated T-implanted controls. These antiandrogenic effects were competitively reduced in castrate rats implanted with two 2.5-cm T capsules (2X), where serum T levels were elevated more than twofold above physiological levels. Taken together, these data indicate that vinclozolin and p,p'-DDE act as antiandrogens in vivo by altering the expression of androgen-dependent genes. (C) 1997 Academic Press
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页码:192 / 200
页数:9
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