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Apoptosis

, Volume 8, Issue 1, pp 101–108 | Cite as

Cisplatin-induced pulse of germ cell apoptosis precedes long-term elevated apoptotic rates in C57/BL/6 mouse testis

  • F. Seaman
  • P. Sawhney
  • C. J. Giammona
  • J. H. Richburg
Article

Abstract

Chemotherapeutic doses of cisplatin impair spermatogenesis and ultimately cause azoospermia and infertility in some men. The mechanism by which cisplatin damages testicular germ cells is poorly understood. Cisplatin's impact is first detected hours after exposure in the formation of DNA cross-links followed by weeks of testicular damage. Here, we report in 11-week-old male mice an early and massive rise of germ cell apoptosis after a single intraperitoneal (I.P.) injection of either 5 or 10 mg/kg cisplatin. For the lower dose, a roughly 9-fold peak increase in the apoptotic index over the control level is observed at 36 h, and for the higher dose, a 24-fold rise is seen at 24 h. At these peak levels, the lower dose produced a higher ratio of apoptotic early spermatocytes to apoptotic spermatogonia than did the higher dose. In addition to this early wave of germ cell die-off, our data show that while the post-wave apoptotic rates for both dose regimes diminish, at 12 days the apoptotic rates appear significantly higher (5 mg/kg) than controls. In summary, our findings show two events set in motion by acute cisplatin exposure: (1) a previously unreported massive apoptotic die-off of germ cells followed by (2) an elevated apoptotic rate possibly reflecting long-term or permanent damage to the seminiferous tubule.

apoptosis cisplatin germ cell testis TUNEL 

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References

  1. 1.
    Einhorn LH. Treatment of testicular cancer: A new and improved model. J Clin Oncol 1990; 8: 1777–1781.Google Scholar
  2. 2.
    Muggia FM. Cisplatin update. Semin Oncol 1991; 18: 1–4.Google Scholar
  3. 3.
    Zamble DB, Lippard SJ. Cisplatin and DNA repair in cancer chemotherapy. Trends Biochem Sci 1995; 20: 435–439.Google Scholar
  4. 4.
    Burger H, Nooter K, Boersma AW, Kortland CJ, Stoter G. Lack of correlation between cisplatin-induced apoptosis, p53 status and expression of Bcl-2 family proteins in testicular germ cell tumour cell lines. Int J Cancer 1997; 73: 592–599.Google Scholar
  5. 5.
    Sark MW, Timmer-Bosscha H, Meijer C, et al. Cellular basis for differential sensitivity to cisplatin in human germ cell tumour and colon carcinoma cell lines. Br J Cancer 1995; 71: 684–690.Google Scholar
  6. 6.
    Lutzker SG, Barnard NJ. Testicular germ cell tumors: Molecular understanding and clinical implications. Mol Med Today 1998; 4: 404–411.Google Scholar
  7. 7.
    Blanco-Rodriguez J, Martinez-Garcia C. Spontaneous germ cell death in the testis of the adult rat takes the form of apoptosis: Re-evaluation of cell types that exhibit the ability to die during spermatogenesis. Cell Prolif 1996; 29: 13–31.Google Scholar
  8. 8.
    Rodriguez I, Ody C, Araki K, Garcia I, Vassalli P. An early and massive wave of germinal cell apoptosis is required for the development of functional spermatogenesis. Embo J 1997; 16: 2262–2270.Google Scholar
  9. 9.
    Kerr JF, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239–257.Google Scholar
  10. 10.
    Russell LD, Clermont Y. Degeneration of germ cells in normal, hypophysectomized and hormone treated hypophysectomized rats. Anat Rec 1977; 187: 347–366.Google Scholar
  11. 11.
    Huckins C. The morphology and kinetics of spermatogonial degeneration in normal adult rats: An analysis using a simplified classification of the germinal epithelium. Anat Rec 1978; 190: 905–926.Google Scholar
  12. 12.
    Oakland E. A Description of spermatogenesis in the mouse and its use in the analysis of the cycle of the seminiferous epithelium and germ cell renewal. American Journal of Anatomy 1956; 99: 391–413.Google Scholar
  13. 13.
    De Rooij DG, Lok D. Regulation of the density of spermatogonia in the seminiferous epithelium of the Chinese hamster: II. Differentiating spermatogonia. Anat Rec 1987; 217: 131–136.Google Scholar
  14. 14.
    Roosen-Runge EC. Germinal-cell loss in normal metazoan spermatogenesis. J Reprod Fertil 1973; 35: 339–348.Google Scholar
  15. 15.
    Richburg JH, Boekelheide K. Mono-(2-ethylhexyl) phthalate rapidly alters both Sertoli cell vimentin filaments and germ cell apoptosis in young rat testes. Toxicol Appl Pharmacol 1996; 137: 42–50.Google Scholar
  16. 16.
    Blanchard KT, Allard EK, Boekelheide K. Fate of germ cells in 2, 5-hexanedione-induced testicular injury. I. Apoptosis is the mechanism of germ cell death. Toxicol Appl Pharmacol 1996; 137: 141–148.Google Scholar
  17. 17.
    Miraglia SM, Hayashi H. Histomorphometry of immature rat testis after heating. J Morphol 1993; 217: 65–74.Google Scholar
  18. 18.
    Meistrich M. Effects of chemotherapy and radiotherapy on spermatogenesis. Eur J Eurol 1993; 23: 136–141.Google Scholar
  19. 19.
    Zhang X, Yamamoto N, Soramoto S, Takenaka I. Cisplatininduced germ cell apoptosis in mouse testes. Arch Androl 2001; 46: 43–49.Google Scholar
  20. 20.
    Richburg JH, Nanez A, Gao H. Participation of the Fassignaling system in the initiation of germ cell apoptosis in young rat testes after exposure to mono-(2-ethylhexyl) phthalate. Toxicol Appl Pharmacol 1999; 160: 271–278.Google Scholar
  21. 21.
    Meistrich ML, Finch M, da Cunha MF, Hacker U, Au WW. Damaging effects of fourteen chemotherapeutic drugs on mouse testis cells. Cancer Res 1982; 42: 122–131.Google Scholar
  22. 22.
    Kopf-Maier P. Effects of carboplatin on the testis. A histological study. Cancer Chemother Pharmacol 1992; 29: 227–235.Google Scholar
  23. 23.
    Reed E, Litterst CL, Thill CC, Yuspa SH, Poirier MC. cis-Diamminedichloroplatinum (II)-DNA adduct formation in renal, gonadal, and tumor tissues of male and female rats. Cancer Res 1987; 47: 718–722.Google Scholar
  24. 24.
    Terheggen PM, Floot BG, Scherer E, Begg AC, Fichtinger-Schepman AM, den Engelse L. Immunocytochemical detection of interaction products of cis-diamminedichloroplatinum(II) and cis-diammine(1, 1-cyclobutanedicarboxylato)platinum(II) withDNAin rodent tissue sections. Cancer Res 1987; 47: 6719–6725.Google Scholar
  25. 25.
    Johnsson A, Olsson C, Nygren O, Nilsson M, Seiving B, Cavallin-Stahl E. Pharmacokinetics and tissue distribution of cisplatin in nude mice: Platinum levels and cisplatin-DNA adducts. Cancer Chemother Pharmacol 1995; 37: 23–31.Google Scholar
  26. 26.
    Vawda AI, Davies AG. Effects of cisplatin on the mouse testis. Acta Endocrinol (Copenh) 1986; 112: 436–441.Google Scholar
  27. 27.
    Meistrich ML, Chawla SP, Da Cunha MF, et al. Recovery of sperm production after chemotherapy for osteosarcoma. Cancer 1989; 63: 2115–2123.Google Scholar
  28. 28.
    Pogach LM, Lee Y, Gould S, Giglio W, Meyenhofer M, Huang HF. Characterization of cis-platinum-induced Sertoli cell dysfunction in rodents. Toxicol Appl Pharmacol 1989; 98: 350–361.Google Scholar
  29. 29.
    Monsees TK, Franz M, Gebhardt S, Winterstein U, Schill WB, Hayatpour J. Sertoli cells as a target for reproductive hazards. Andrologia 2000; 32: 239–246.Google Scholar
  30. 30.
    Howell SJ, Shalet SM. Testicular function following chemotherapy. Hum Reprod Update 2001; 7: 363–369.Google Scholar
  31. 31.
    Boekelheide K, Lee JW, Hall SJ, Rhind NR, Zaret KS. A tumorigenic murine Sertoli cell line that is temperaturesensitive for differentiation. Am J Pathol 1993; 143: 1159–1168.Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • F. Seaman
    • 1
  • P. Sawhney
    • 1
  • C. J. Giammona
    • 1
  • J. H. Richburg
    • 1
  1. 1.Division of Pharmacology and Toxicology, College of PharmacyThe University of Texas at AustinAustinUSA

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