Comparison of anti-androgenic activity of flutamide, vinclozolin, procymidone, linuron, and p, p′-DDE in rodent 10-day Hershberger assay

• Published in: Toxicology (Amsterdam) 2004-07, Vol.199 (2), p.145-159
• Main Authors: Kang, Il Hyun, Sik Kim, Hyung, Shin, Jae-Ho, Kim, Tae Sung, Moon, Hyun Ju, Kim, In Young, Choi, Kwang Sik, Kil, Kwang Sup, Park, Young In, Dong, Mi Sook, Han, Soon Young
• Format: Article
• Language: English
• Subjects: Administration, Oral; Androgen Antagonists - administration & dosage; Androgen Antagonists - toxicity; Androgenic/anti-androgenic; Animals; Biological and medical sciences; Bridged Bicyclo Compounds - toxicity; Dichlorodiphenyl Dichloroethylene - toxicity; Dose-Response Relationship, Drug; Drug Interactions; Flutamide; Flutamide - toxicity; Genitalia, Male - drug effects; Genitalia, Male - pathology; Hershberger assay; Injections, Subcutaneous; Linuron; Linuron - toxicity; Luteinizing Hormone - blood; Male; Medical sciences; Orchiectomy; Organ Size - drug effects; Oxazoles - toxicity; p, p′-DDE; Procymidone; Rats; Rats, Sprague-Dawley; Testosterone - administration & dosage; Testosterone - blood; Testosterone - pharmacology; Toxicology; Vinclozolin
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2004.02.019

The rodent Hershberger assay proposed by the Organization for Economic Co-operation and Development (OECD) is in the process of the validating a test method to detecting the androgenic or anti-androgenic compounds. The aim of this study was to compare the anti-androgenic properties of flutamide, vinclozolin, procymidone, linuron, and p, p′-DDE in a 10-day Hershberger assay. In the present study, we used immature Sprague–Dawley male rats castrated at 6 weeks of age. Testosterone propionate (TP) was subcutaneously injected for 10 consecutive days at doses of 0.1, 0.2, 0.4, 0.8, or 1.6 mg/kg per day. To compare the anti-androgenic activity of test compounds, flutamide (1, 5, 10, or 20 mg/kg per day), a pure androgen antagonist was used as a positive control, and administered by oral gavage after TP (0.4 mg/kg per day) treatment. In addition, vinclozolin (25, 50, or 100 mg/kg per day), procymidone (25, 50, or 100 mg/kg per day), linuron (25, 50, or 100 mg/kg per day), and p, p ′-DDE (25, 50, or 100 mg/kg per day) were also administered by oral gavage after TP (0.4 mg/kg per day) treatment. As expected, TP dose-dependently increased accessory sex organ weights, and statistically significant effects were observed at doses of 0.1 (only seminal vesicles) or 0.2 mg/kg per day and above. Serum testosterone levels increased significantly at 0.4 mg/kg per day and above, while serum LH levels were decreased in a dose-dependent manner. Flutamide significantly inhibited the TP-induced re-growth of seminal vesicles, ventral prostate, and Levator ani plus bulbocavernosus muscles (LABC) at 1 mg/kg per day and above, and Cowper’s glands and glans penis at 5 mg/kg per day and above. In contrast to accessory sex organ weights, flutamide did not affect the serum testosterone levels compared to the control at any concentration, but serum LH levels were significantly increased at doses of 10 and 20 mg/kg per day. Similar to flutamide, vinclozolin caused a statistically significant decrease in the weights of seminal vesicles (to 65 and 40% of the control), ventral prostate (to 66 and 51% of the control), LABC (to 81 and 66% of the control), and Cowper’s glands (to 81 and 65% of the control) at 50 and 100 mg/kg per day, respectively. Glans penis weight was also significantly reduced (to 79% of the control), but only at 100 mg/kg per day. The most pronounced effects were observed in the procymidone treatment groups. Procymidone significantly inhibited TP-induced re-growth of accesso