Testosterone-stimulated weanlings as an alternative to castrated male rats in the Hershberger anti-androgen assay.
We showed previously that stimulation of weanling male rats with the synthetic androgen 17-methyltestosterone (17MT) caused premature growth of the sex accessory tissues such that the activity of the two anti-androgens flutamide and DDE could be demonstrated (Regul. Toxicol. Pharmacol. 35 (2002) 280). We suggested that that protocol should be evaluated as an alternative to the castrated male rat Hershberger assay. In the present paper we justify changing the assay protocol to use testosterone propionate (TP), in place of 17MT, as the stimulating androgen. This change enables biochemical formation of dihydrotestosterone from testosterone, a conversion not possible when using 17MT. This change in the protocol enables detection of the testosterone-5-reductase inhibitor finasteride. The modified TP-stimulated weanling male rat assay is shown to have similar sensitivity to that of the castrated male rat Hershberger assay in detection of the anti-androgens flutamide, procymidone, vinclozolin, and DDE, and of the biochemical inhibitor finasteride. The anti-androgen linuron and the anabolic steroid trenbolone were also detected as positive by the TP-stimulated weanling male assay. It is suggested that this modified assay for anti-androgens should be validated as an alternative to the Hershberger assay, thereby reducing animal stress by obviating the need for surgical castration.
Ashby
J
J
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, UK. john.ashby@syngenta.com
Lefevre
P A
PA
Tinwell
H
H
Odum
J
J
Owens
W
W
D000726:Androgen Antagonists / Q000009:adverse effects*; D000818:Animals; D001681:Biological Assay / Q000379:methods; D001835:Body Weight / Q000187:drug effects; D013196:Dihydrotestosterone / Q000378:metabolism; D005837:Genitalia, Male / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012680:Sensitivity and Specificity; D012741:Sexual Maturation / Q000187:drug effects*; D043343:Testosterone Propionate / Q000494:pharmacology*
D000726:Androgen Antagonists; D013196:Dihydrotestosterone; D043343:Testosterone Propionate