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¹ Departments of Pharmacology and Therapeutics,
² Obstetrics and Gynecology, McGill University, 3655 Promenade Sir-William-Osler, Montréal, Québec, Canada H3G 1Y6
³ Toxicology Research Division, Health Products and Foods Branch, Food Directorate, Health Canada, Ottawa, Ontario, Canada
⁴ Reproductive Biology Unit, Departments of Cellular and Molecular Medicine and Obstetrics and Gynecology, University of Ottawa, Sir Frederick G Banting Research Centre, 2202D1 Tunney’s Pasture, Ottawa, Ontario, Canada K1A 0L2

(Requests for offprints should be addressed to B Robaire; Email: bernard.robaire{at}mcgill.ca)

Dihydrotestosterone (DHT) is the primary androgen acting in the epididymis, the site of sperm maturation. Previously, we showed that the treatment of male rats with PNU157706, an inhibitor that acts on both isoforms of 5-reductase to prevent DHT formation, has effects on the expression of genes implicated in processes that create the optimal luminal microenvironment required for sperm maturation, and on sperm maturation itself. However, signaling pathways involved in regulating or mediating DHT actions in the epididymis remain largely unknown. The goals of this study were to determine the expression profiles of potential signaling systems in the epididymis and assess their DHT-dependence using two different dual 5-reductase inhibitors. Rats were untreated or gavaged with vehicle, 10 mg/kg per day PNU157706 or 32 mg/kg per day FK143 for 28 days and epididymal gene expression was analyzed. Gene array analysis revealed analogous effects of FK143 on overall epididymal gene expression when compared with previous PNU157706 studies. Quantitative RT-PCR analysis of the expression of the 5-reductase isozymes, androgen receptor, and members of the IGF, FGF, TGF, and VEGF families revealed novel region-specific expression profiles in the epididymis that were differentially affected by 5-reductase inhibition; the two inhibitors had parallel effects. Specifically, in proximal regions, 5-reductase 1, androgen receptor, and TGF-ß1 expression increased after treatment, while in distal regions expression of IGF-I, IGFBP-5, IGFBP-6, and FGF-10 decreased. These results provide insight into epididymal signaling mechanisms and indicate potential candidates acting either upstream or downstream of DHT to regulate and/or mediate its actions in the epididymis.