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Irradiation Causes Acute and Long-Term Spermatogonial Depletion in Cultured and Xenotransplanted Testicular Tissue from Juvenile Nonhuman Primates

Department of Cell Biology and Physiology (K.J., J.E., S.S.), Center for Research in Reproductive Physiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261; Pediatric Endocrinology Unit (K.J.), Department of Woman and Child Health, Karolinska Institute and University Hospital, SE-171 76 Stockholm, Sweden; and Departments of Pediatrics (K.J.) and Physiology (M.N.), University of Turku, FIN-20520 Turku, Finland

Address all correspondence and requests for reprints to: Stefan Schlatt, Ph.D., Associate Professor, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, W952 Biomedical Science Tower, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261. E-mail: schlatt{at}pitt.edu.

Infertility is a serious late effect in childhood cancer survivors. Little is known about acute irradiation effects in immature primate testis. Radiation defects have previously only been studied in postpubertal primates. Here we use the juvenile rhesus monkey as a preclinical model. We expose fragments of testicular tissue to 0, 0.5, 1.0, and 4.0 Gy irradiation in vitro. We then maintain the fragments in organ culture for 24–48 h or xenograft the fragments into nude mice for 4 months. Histological endpoints were determined to explore the cellular responses to the irradiation. At the highest dose, irradiation provoked an acute depletion of A-spermatogonia and a rise of apoptotic germ and Sertoli cells in organ culture. A dose-dependent decrease in the number of seminiferous tubules containing type A dark and type A pale spermatogonia was observed in irradiated xenografts. The number of Sertoli-cell only tubules increased respectively. Outgrowth of grafts was affected by the 4-Gy dose. Our observations reveal that irradiation evoked an immediate and sustained depletion of A-spermatogonia. We conclude that spermatogonia in the juvenile primate testis are highly sensitive to irradiation and that spermatogonial depletion and cessation of proliferation is an acute response. In contrast to adult testes, where such damage is immediately visible, this damage in immature testes becomes apparent only when spermatogonial insufficiency leads to spermatogenic failure, and thus infertility, at the onset of puberty. Our methods are applicable to immature human testis and might serve as powerful tool to study irradiation toxicity in the juvenile human testis.