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Testicular Xenografts: A Novel Approach to Study Cytotoxic Damage in Juvenile Primate Testis

¹ Center for Research in Reproductive Physiology, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; ² Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institute and University Hospital, Stockholm, Sweden; and ³ Department of Pediatrics, University of Turku, Turku, Finland

Requests for reprints: Kirsi Jahnukainen, Center for Research in Reproductive Physiology, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. Phone: 412-648-8175; Fax: 412-648-8315; E-mail: Kirsi.Jahnukainen{at}kbh.ki.se.

The underlying primary damage to the testis caused by chemotherapeutic regimens during childhood is largely unknown. Xenografting of monkey testes was successfully applied in maturation of juvenile testis to the point of complete spermatogenesis. This allows us to manipulate developing primate testis without direct treatment of patients. This new model is validated establishing the effects of cytotoxic treatment in the immature primate testis. Male castrated nude mice received eight s.c. grafts of juvenile monkey testicular tissue and, 28 weeks later, were injected with busulfan (38 mg/kg, i.p.) or vehicle. Graft numbers, size, and histology were examined. Grafts showed pubertal induction of spermatogenesis to the level of pachytene spermatocytes at point of busulfan treatment and further progressed to the level of round spermatids in control samples at 4 weeks. Busulfan treatment caused a statistically significant decrease in the number of seminiferous tubules containing germ cells. Type B spermatogonia and more advanced stages of spermatogenesis were depleted. A statistically significant decrease to pretreatment level was observed in the number of type A pale and centrally located spermatogonia. Busulfan did not affect type A dark spermatogonia. Occasionally, elongating spermatids were detected in busulfan-treated grafts. Observations show that busulfan selectively destroys differentiating spermatogonia whereas some of the spermatocytes present at the moment of cytotoxic insult are able to continue differentiation. Data indicate that xenografting of testicular monkey tissue is a valid approach to detect the busulfan-induced germ cell damage and serves as a powerful experimental tool to study cytotoxic effects in developing primate testis. (Cancer Res 2006; 66(7): 3813-8)

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