title: Region-specific expression of androgen and growth factor pathway genes in the rat epididymis and the effects of dual 5alpha-reductase inhibition.
abstract: 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 5alpha-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 5alpha-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 5alpha-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 5alpha-reductase inhibition; the two inhibitors had parallel effects. Specifically, in proximal regions, 5alpha-reductase 1, androgen receptor, and TGF-beta1 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.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montréal, Québec, Canada.
authors.forename: Natali Anne
authors.initials: NA
authors.lastname: Henderson
authors.forename: Gerard M
authors.initials: GM
authors.lastname: Cooke
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaire
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D030201:Activin Receptors, Type I / Q000235:genetics; D000728:Androgens / Q000378:metabolism*; D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D013196:Dihydrotestosterone / Q000378:metabolism; D004822:Epididymis / Q000187:drug effects / Q000201:enzymology*; D005346:Fibroblast Growth Factors / Q000235:genetics; D020869:Gene Expression Profiling; D007211:Indoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010654:Phenylbutyrates / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D011944:Receptors, Androgen / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: C093354:4-(3-(3-(bis(4-isobutylphenyl)methylamino)benzoyl)-1H-indol-1-yl)butyric acid; D058891:5-alpha Reductase Inhibitors; D000728:Androgens; D000736:Androstenes; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; C112526:PNU 157706; D010654:Phenylbutyrates; D011944:Receptors, Androgen; D017468:Receptors, Fibroblast Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D013196:Dihydrotestosterone; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D040301:Vascular Endothelial Growth Factor Receptor-2; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat