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The Fas System is a Key Regulator of Germ Cell Apoptosis in the Testis
MALE INFERTILITY
The Fas System is a Key Regulator of Germ Cell Apoptosis in the Testis J. LEE,J. H. RICHBURG, S. C. YOUNKINAND K. BOEKELHEIDE, Department of Pathology and Laboratory Medicine, Brown University, Providence, Rho& Island Endocrinology, 138 2081-2088, 1997 Apoptosis occurs in the testis as an important physiological mechanism to limit the number of germ cells in the seminiferous epithelium. Sertoli cells, which tightly regulate germ cell proliferation and differentiation, are implicated in the control of germ cell apoptosis. Fas (AF’O-1,CD95), a transmembrane receptor protein, transmits an apoptotic signal within cells when bound by Fas ligand (FasL). The Fas system has been implicated in immune regulation, including cytotoxic T cell-mediated cytotoxicity, activation-induced suicide of T cells, and control of immune-privilegedsites. Here we propose the Fas system as a key regulator of spermatogenesis.In this model, FasL expressed by Sertoli cells initiates the apoptotic death of germ cells expressing Fas. Using immunohistochemistry, we localized Fas to germ cells and FasL to Sertoli cells. The expression of these genes was dramatically up-regulated after exposure to mono-(2-ethylhexyl)phthalate and 2,5-hexanedione,two widely studied Sertoli cell toxicants known to induce germ cell apoptosis. Mouse germ cells in vitro were susceptible to anti-Fas antibody-induceddeath, and the survival of rat germ cells was increased after disruption of FasL by antisense oligonucleotide treatment. Unlike its expression in other tissues, testicular expression of Fas in the lpr mouse, a spontaneousmutant of the Fas gene, is similar to that in the normal mouse, arguing for the importance of the Fas system in maintaining testicular homeostasis. These data implicate the Sertoli cell in the paracrine control of germ cell output during spermatogenesis by a Fas-mediated pathway. Editorial Comment: Apoptosis (programmed cell death) appears to have an important role in normal spermatogenesis and in pathological conditions, such as testosterone withdrawal and heat exposure. Improved understanding of the control of germ cell apoptosis may lead to interventions that could enhance male fertility. This study performed in a rat animal model demonstrates the key role of the Fas system in germ cell apoptosis. Fas is a transmembrane protein that, when activated by Fas ligand, triggers an intracellular cascade that ultimately results in cell death. Germ cells produce Fas and it appears that the Sertoli cells produce Fas ligand, which is also a transmembrane protein. Fas ligand cross-links the extracellular component of 3 Fas molecules, which allows interaction with intracellular Fas mediators, such as Fas associating protein with death domain. The authors demonstrated by immunohistochemistry Fas and Fas ligand within normal seminiferous tubules, and an increase following administration of a testicular toxicant. The accuracy of the anti-Fas and Fas ligand antibodies was confirmed by W e s t e r n blot analysis. Germ cell apoptosis could be inhibited in vitro by treatment with antisense oligonucleotides for Fas ligand, which reduced translation of Fas ligand by binding to its messenger ribonucleic acid. Conversely, germ cell apoptosis was induced in vitro by incubation with an anti-Fas antibody that is a known agonist of Fas by cross-linkage on the cell membrane. Thus, it appears that the Sertoli cells have an important role in active culling of germ cells from the germinal epithelium and as a mediator of severe germ cell loss, which is in contradistinction from their traditional supportive role. Jonathan P. Jarow, M.D. Effect of Increased Scrotal Temperature on Sperm Production in Normal Men C . WANG, V. MCDONALD, A. LEUNG, L. SUPERLANO, N. BERMAN, L. HULLAND R. s. SWERDLOFF, Division of Endocrinology, Department of Medicine, Harbor-University of California, Los Angeles Medical Center, Torrance, California Fertil. Steril., 6 8 334-339, 1997 Objective: To determine whether application of polyester-lined athletic supports to bring the testes closer to the abdomen increases scrotal temperature and decreases sperm production. Design: Prospective clinical study. Setting: University academic medical center. Patient(s): Twenty-one healthy male volunteers. Intemention(s): The study consisted of a pretreatment period of6 weeks, a treatment phase of 52 weeks, and a recovery phase until return to normal sperm production. During the treatment phase, the men wore polyester-lined athletic supports (single layer, double layer, or double layer impregnated with aluminum) throughout the day. Main Outcome Measure(s): Semen parameters and sperm function tests. In all three goups ofsubjects, scrotal temperature was consistently increased by 0.8 to 1C while the subjects were wearing the athletic supports. Mean sperm concentration; sperm motility, morpholow, and viability; sperm hyperactivation; and ability of spermatozoa to penetrate zone-free hamster 0 C q ” k S were not affected by the increase in scrotal temperature. ~ ~ ~ m ~ e increase ~ ~ in~scrota1 i temperature ~ ~ ( induced ~ ) by :polyester-lined athletic SUPPO* was significant suppression of spermatogenesis or alteration of sperm function. insufficient to
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The Fas System is a Key Regulator of Germ Cell Apoptosis in the Testis J. LEE,J. H. RICHBURG, S. C. YOUNKINAND K. BOEKELHEIDE, Department of Pathology and Laboratory Medicine, Brown University, Providence, Rho& Island Endocrinology, 138 2081-2088, 1997 Apoptosis occurs in the testis as an important physiological mechanism to limit the number of germ cells in the seminiferous epithelium. Sertoli cells, which tightly regulate germ cell proliferation and differentiation, are implicated in the control of germ cell apoptosis. Fas (AF’O-1,CD95), a transmembrane receptor protein, transmits an apoptotic signal within cells when bound by Fas ligand (FasL). The Fas system has been implicated in immune regulation, including cytotoxic T cell-mediated cytotoxicity, activation-induced suicide of T cells, and control of immune-privilegedsites. Here we propose the Fas system as a key regulator of spermatogenesis.In this model, FasL expressed by Sertoli cells initiates the apoptotic death of germ cells expressing Fas. Using immunohistochemistry, we localized Fas to germ cells and FasL to Sertoli cells. The expression of these genes was dramatically up-regulated after exposure to mono-(2-ethylhexyl)phthalate and 2,5-hexanedione,two widely studied Sertoli cell toxicants known to induce germ cell apoptosis. Mouse germ cells in vitro were susceptible to anti-Fas antibody-induceddeath, and the survival of rat germ cells was increased after disruption of FasL by antisense oligonucleotide treatment. Unlike its expression in other tissues, testicular expression of Fas in the lpr mouse, a spontaneousmutant of the Fas gene, is similar to that in the normal mouse, arguing for the importance of the Fas system in maintaining testicular homeostasis. These data implicate the Sertoli cell in the paracrine control of germ cell output during spermatogenesis by a Fas-mediated pathway. Editorial Comment: Apoptosis (programmed cell death) appears to have an important role in normal spermatogenesis and in pathological conditions, such as testosterone withdrawal and heat exposure. Improved understanding of the control of germ cell apoptosis may lead to interventions that could enhance male fertility. This study performed in a rat animal model demonstrates the key role of the Fas system in germ cell apoptosis. Fas is a transmembrane protein that, when activated by Fas ligand, triggers an intracellular cascade that ultimately results in cell death. Germ cells produce Fas and it appears that the Sertoli cells produce Fas ligand, which is also a transmembrane protein. Fas ligand cross-links the extracellular component of 3 Fas molecules, which allows interaction with intracellular Fas mediators, such as Fas associating protein with death domain. The authors demonstrated by immunohistochemistry Fas and Fas ligand within normal seminiferous tubules, and an increase following administration of a testicular toxicant. The accuracy of the anti-Fas and Fas ligand antibodies was confirmed by W e s t e r n blot analysis. Germ cell apoptosis could be inhibited in vitro by treatment with antisense oligonucleotides for Fas ligand, which reduced translation of Fas ligand by binding to its messenger ribonucleic acid. Conversely, germ cell apoptosis was induced in vitro by incubation with an anti-Fas antibody that is a known agonist of Fas by cross-linkage on the cell membrane. Thus, it appears that the Sertoli cells have an important role in active culling of germ cells from the germinal epithelium and as a mediator of severe germ cell loss, which is in contradistinction from their traditional supportive role. Jonathan P. Jarow, M.D. Effect of Increased Scrotal Temperature on Sperm Production in Normal Men C . WANG, V. MCDONALD, A. LEUNG, L. SUPERLANO, N. BERMAN, L. HULLAND R. s. SWERDLOFF, Division of Endocrinology, Department of Medicine, Harbor-University of California, Los Angeles Medical Center, Torrance, California Fertil. Steril., 6 8 334-339, 1997 Objective: To determine whether application of polyester-lined athletic supports to bring the testes closer to the abdomen increases scrotal temperature and decreases sperm production. Design: Prospective clinical study. Setting: University academic medical center. Patient(s): Twenty-one healthy male volunteers. Intemention(s): The study consisted of a pretreatment period of6 weeks, a treatment phase of 52 weeks, and a recovery phase until return to normal sperm production. During the treatment phase, the men wore polyester-lined athletic supports (single layer, double layer, or double layer impregnated with aluminum) throughout the day. Main Outcome Measure(s): Semen parameters and sperm function tests. In all three goups ofsubjects, scrotal temperature was consistently increased by 0.8 to 1C while the subjects were wearing the athletic supports. Mean sperm concentration; sperm motility, morpholow, and viability; sperm hyperactivation; and ability of spermatozoa to penetrate zone-free hamster 0 C q ” k S were not affected by the increase in scrotal temperature. ~ ~ ~ m ~ e increase ~ ~ in~scrota1 i temperature ~ ~ ( induced ~ ) by :polyester-lined athletic SUPPO* was significant suppression of spermatogenesis or alteration of sperm function. insufficient to
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