Comparison of prostate gene expression and tissue weight changes as monitors of antiandrogen activity in GNRH-inhibited rats.
BACKGROUND
The Hershberger assay for antiandrogens and modifiers of steroid biosynthesis uses surgically-castrated rats. We described an adaptation of the assay using the GnRH inhibitor Antarelix in place of surgical castration [Ashby J, Lefevre PA, Deghenghi R, Wallis N. Regulatory Toxicology and Pharmacology 34:188-203, 2001], and concomitantly described changes in expression of the androgen-dependent prostatic genes PBP C3, TRPM-2, and ODC as a possible complement to gravimetric analysis of the sex accessory tissues (SAT) [Nellemann C, Vinggaard AM, Dalgaard M, Hossaini A, Larsen J-J. Toxicology 163:29-38, 2001.


METHODS
The present study describes the results of combining these two modifications into a single assay. During the course of these experiments it was shown that SD rats gave similar results to AP rats and that the higher stimulatory dose of testosterone propionate (TP) used in our experiments gave stronger assay responses to FLU than the lower dose of TP used by some earlier investigators. The potent antiandrogen flutamide (FLU) and the weak antiandrogen DDE were used to evaluate this modified assay.


RESULTS
For all parameters studied (SAT weights and changes in expression of the 3 prostatic genes) FLU gave the expected positive results. The weak antiandrogen DDE gave variable and mainly non-reproducible responses. Use of DDE as a weak antiandrogen accelerated assessment of the new assay.


CONCLUSIONS
Possible reasons for this failure to detect DDE are discussed, and it is concluded that the modified assay is unsuitable for use in its present form. The use of gene expression analyses together with evaluation of SAT weights is a promising tool as an early and sensitive marker of antiandrogen action, but more work is needed on the choice of time frame as well as the selection of genes to monitor.
Nellemann
C
C
Institute of Food Satety and Toxicology, Danish Veterinary and Food Administration, Soborg, Denmark.
Lefevre
P A
PA
Ashby
J
J
D000726:Androgen Antagonists / Q000494:pharmacology*; D000727:Androgen-Binding Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D051152:Clusterin; D003633:Dichlorodiphenyl Dichloroethylene / Q000494:pharmacology; D005485:Flutamide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects*; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000378:metabolism* / Q000601:surgery; D060789:Prostatein; D051381:Rats; D017207:Rats, Sprague-Dawley; D060765:Secretoglobins; D043343:Testosterone Propionate / Q000494:pharmacology; D014598:Uteroglobin; D060788:Mammaglobin B
D000726:Androgen Antagonists; D000727:Androgen-Binding Protein; D015415:Biomarkers; D051152:Clusterin; D003633:Dichlorodiphenyl Dichloroethylene; D005485:Flutamide; D006023:Glycoproteins; D007987:Gonadotropin-Releasing Hormone; D018832:Molecular Chaperones; D009842:Oligopeptides; D009955:Ornithine Decarboxylase; D060789:Prostatein; D060765:Secretoglobins; D043343:Testosterone Propionate; D014598:Uteroglobin; C511484:Scgb1d2 protein, rat; C511483:Scgb1d4 protein, rat; C084350:antarelix; C556468:Scgb2a1 protein, rat; D060788:Mammaglobin B