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Functional Role of Caspases in Heat-Induced Testicular Germ Cell Apoptosis¹

Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, David Geffen School of Medicine at UCLA, Torrance, California 90509

In the present study, we determined whether a pan caspase inhibitor could prevent or attenuate heat-induced germ cell apoptosis. Groups of five adult (8 wk old) C57BL/6 mice pretreated with vehicle (DMSO) or Quinoline-Val-Asp (Ome)-CH₂-O-Ph (Q-VD-OPH), a new generation broad-spectrum caspase inhibitor, were exposed once to local testicular heating (43°C for 15 min) and killed 6 h later. The inhibitor (40 mg/kg body weight) or vehicle was administered intraperitoneally (i.p.) 1 h before local testicular heating. Germ cell apoptosis was detected by TUNEL assay and quantitated as number of apoptotic germ cells per 100 Sertoli cells at stages XI–XII. Compared with controls (16.8 ± 3.1), mild testicular hyperthermia within 6 h resulted in a marked activation (277.3 ± 21.6) of germ cell apoptosis, as previously reported by us. Q-VD-OPH at this dose markedly inhibited caspase 3 activation and significantly prevented (by 67.0%) heat-induced germ cell apoptosis. Q-VD-OPH-mediated rescue of germ cells was independent of cytosolic translocation of mitochondrial cytochrome c and DIABLO. Electron microscopy further revealed normal appearance of these rescued cells. Similar protection from heat-induced germ cell apoptosis was also noted after pretreatment with minocycline, a second-generation tetracycline that effectively inhibits cytochrome c release and, in turn, caspase activation. Collectively, the present study emphasizes the role of caspases in heat-induced germ cell apoptosis.

¹ Supported by NIH grants HD 39293 to A.P.S.H., HD 39293-02S1 to Y.V., and through the U*STAR (S.R., M.C.) GM 08683 program.

² Correspondence: Amiya P. Sinha Hikim, Division of Endocrinology, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Box 446, 1000 West Carson Street, Torrance, CA 90509. FAX: 310 533 0627; hikim{at}gcrc.rei.edu

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