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Title: Chemical disruption of spermatogenesis
Author: Allenby, Gary
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1990
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Over the past decade many publications attest to the substantial increase in public and scientific concern regarding the potential of industrial and environmental chemicals to interfere with male reproductive function. Spermatogenesis, (the process of sperm formation) depends on a series of complex biological interactions which can be interrupted at various stages by chemical insult. Recently a number of these chemicals have been used experimentally to directly disrupt testicular function to provide an insight into the processes involved in normal spermatogenesis. Based on these investigations the primary objective of the work in this thesis was to study the time course of development of testicular lesions, their stage specificity, and subsequent recovery of normal spermatogenesis using morphological and functional characteristics of function in vivo and in vitro. The chemicals used in these studies included meta dinitrobenzene (mDNB), nitrobenzene (NB), the isomers of mononitrotoluene (mNT) and 2-methoxyacetic acid (MAA). Within 24h of a single oral administration of mDNB or NB to rats there was a progressive decrease in testicular weight and increase in serum follicle stimulating hormone (FSH) levels coincident with widespread germ cell degeneration, as determined by histological examination of the testis. The degree of disruption induced by mDNB and its reversibility were time - but not stage - dependent with a decline in both sperm number and motility in parallel with germ cell degeneration. NB however had a more specific effect causing the initial degeneration of leptotene spermatocytes and subsequently more extensive germ cell loss involving round spermatids at a number of stages. During the recovery of spermatogenesis a considerable change was observed in the frequency of occurrence of spermatogenic stages in comparison to controls. These changes remained significantly different up to at least 70 days post-treatment. The isomers of mNT induced small but statistically significant dose-dependent decreases in testicular weight. Spermatogenesis in these animals remained qualitatively normal, so detailed histological studies were not undertaken. Further investigation into the effects of the testicular toxicants listed above was performed in vitro using Sertoli cell monocultures and Sertoli cell-germ cell co-cultures. mDNB, NB and the isomers of mNT produced dose-dependent increases in germ cell exfoliation (from co-cultures). mDNB and NB also produced histological changes in culture including Sertoli cell vacuolation and phagocytosis of germ cells, and induced dose-dependent increases in the secretion of lactate and pyruvate, two established indices of Sertoli cell function in vitro. Sertoli cells secrete over 100 different proteins, only a handful of which have been characterised and a role in spermatogeneis proposed. One of these proteins is inhibin. The potenial of inhibin secretion as a further index of Sertoli cell function (or dysfunction) in monocultures and co-cultures has been investigated. mDNB, NB, 2-mNT and 3-mNT all induced dose-dependent alterations in the secretion of inhibin in vitro. Historically, FSH has been postulated to control inhibin secretion in a classical negative feedback manner. Recent evidence obtained in vivo and in co-culture suggests that its secretion may be controlled by specific type(s) of germ cells. Seminiferous tubule cultures represent a potentially more useful culture system to investigate this further. They present a unique opportunity to study Sertoli cell-germ cell interactions under more physiological conditions since the integrity of the seminiferous epithelium is maintained in vitro. Previous investigators have demonstrated that MAA specifically destroys pachytene spematocytes in vivoand this specificity of action was utilised to study which germ cel-Sertoli cell interactions control the secretion of inhibin. At selected times after MAA treatment when specific complements of germ cells were absent or grossly depleted, seminiferous tubules were isolated and cultured to measure inhibin secretion under basal or stimulated conditions. The results demonstrate that elongate spematids are the primary germ cell type which exerts major control over inhibin secretion under both basal and FSH-stimulated conditions. In conclusion, these studies demonstrate: Firstly that these compounds can be used as a means to investigate normal spermatogenesis. Secondly, effects of these compounds on spermatogenesis can be demonstrated both in vivo and in vitro. Finally, that the seminiferous tubule culture technique represents a more physiological approach with which to investigate in vivo - in vitro comparative toxicity with respect to chemically induced disruption of spermatogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available