The epididymis functions in the transport, maturation, storage and protection of spermatozoa. The structure and functions of the epididymis are dependent on androgens, primarily dihydrotestosterone (DHT). 5a-Reductases (types 1 and 2) are thus key enzymes in this tissue because of their role in converting testosterone to DHT. The goal of this thesis was to examine the consequences on the rat epididymis and epididymal sperm of inhibiting DHT formation using novel dual 5alpha-reductase inhibitors (i.e. inhibitors specific to both isoforms of 5alpha-reductase). The first objective was to analyze the effects of 5alpha-reductase inhibitor treatment on gene expression in the four epididymal segments (initial segment, caput, corpus and cauda epididymidis) using cDNA arrays. Treatment had highly segment specific effects on epididymal gene expression. Affected genes included those involved in fatty acid and lipid metabolism, regulation of ion and fluid transport, luminal acidification, oxidative defense and protein processing and degradation; these are essential processes contributing to the formation of an optimal luminal microenvironment required for proper sperm maturation. The next objective was to determine whether the observed changes in gene expression actually translated into effects on epididymal sperm functions. Fertility and several key facets of epididymal sperm maturation were analyzed. The percentages of motile and progressively motile sperm from the cauda epididymidis decreased and characteristic sperm motion parameters were altered. An elevated proportion of sperm from this region also retained their cytoplasmic droplet. Matings with treated males resulted in fewer successful pregnancies and a higher rate of preimplantation loss. Lastly, cDNA arrays and quantitative real-time RT-PCR were used to elucidate potential signaling mechanisms via which DHT mediates and/or regulates its differential effects on epididymal gene expression and
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85917 |
| Date | January 2005 |
| Creators | Henderson, Natali Anne |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology and Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002260862, proquestno: AAINR21654, Theses scanned by UMI/ProQuest. |
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