Vinclozolin and p,p'-DDE alter androgen-dependent gene expression: in vivo confirmation of an androgen receptor-mediated mechanism.
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.
Kelce
W R
WR
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. Kelce@her145.herl.epa.gov
Lambright
C R
CR
Gray
L E
LE
Roberts
K P
KP
D000726:Androgen Antagonists / Q000494:pharmacology*; D000727:Androgen-Binding Protein / Q000235:genetics; D000818:Animals; D051152:Clusterin; D003633:Dichlorodiphenyl Dichloroethylene / Q000494:pharmacology*; D004343:Drug Implants; D005485:Flutamide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics; D008297:Male; D018832:Molecular Chaperones; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D010080:Oxazoles / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D060789:Prostatein; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D060765:Secretoglobins; D012669:Seminal Vesicles / Q000187:drug effects / Q000473:pathology; D013739:Testosterone / Q000008:administration & dosage / Q000494:pharmacology; D014598:Uteroglobin; D060788:Mammaglobin B
D000726:Androgen Antagonists; D000727:Androgen-Binding Protein; D051152:Clusterin; D003633:Dichlorodiphenyl Dichloroethylene; D004343:Drug Implants; D005485:Flutamide; D006023:Glycoproteins; D018832:Molecular Chaperones; D010080:Oxazoles; D060789:Prostatein; D012333:RNA, Messenger; D011944:Receptors, Androgen; D060765:Secretoglobins; D013739:Testosterone; D014598:Uteroglobin; C511484:Scgb1d2 protein, rat; C511483:Scgb1d4 protein, rat; C025643:vinclozolin; C556468:Scgb2a1 protein, rat; D060788:Mammaglobin B