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

Toxicol Appl Pharmacol. 1997 Jan;142(1):192-200. doi: 10.1006/taap.1996.7966.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Androgen Antagonists / pharmacology*
  • Androgen-Binding Protein / genetics
  • Animals
  • Clusterin
  • Dichlorodiphenyl Dichloroethylene / pharmacology*
  • Drug Implants
  • Flutamide / pharmacology
  • Gene Expression Regulation / drug effects*
  • Glycoproteins / genetics
  • Male
  • Molecular Chaperones*
  • Orchiectomy
  • Organ Size / drug effects
  • Oxazoles / pharmacology*
  • Prostate / drug effects
  • Prostate / pathology
  • Prostatein
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Androgen / drug effects*
  • Receptors, Androgen / metabolism
  • Secretoglobins
  • Seminal Vesicles / drug effects
  • Seminal Vesicles / pathology
  • Testosterone / administration & dosage
  • Testosterone / pharmacology
  • Uteroglobin

Substances

  • Androgen Antagonists
  • Androgen-Binding Protein
  • Clusterin
  • Drug Implants
  • Glycoproteins
  • Molecular Chaperones
  • Oxazoles
  • Prostatein
  • RNA, Messenger
  • Receptors, Androgen
  • Scgb1d2 protein, rat
  • Scgb1d4 protein, rat
  • Scgb2a2 protein, rat
  • Secretoglobins
  • Testosterone
  • Dichlorodiphenyl Dichloroethylene
  • Flutamide
  • Uteroglobin
  • vinclozolin