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Caspase-3 and Caspase-Activated Deoxyribonuclease Are Associated with Testicular Germ Cell Apoptosis Resulting from Reduced Intratesticular Testosterone

Division of Reproductive Biology, Department of Biochemistry and Molecular Biology, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Dr. Jong-Min Kim, Division of Reproductive Biology, Department of Biochemistry and Molecular Biology, Johns Hopkins University School of Hygiene and Public Health, 615 North Wolfe Street, Baltimore, Maryland 21205. E-mail: jmkim{at}jhsph.edu

The purpose of the present study was to examine the possible involvement of caspase-3 and caspase-activated deoxyribonuclease in rat testicular germ cell apoptosis resulting from reduced intratesticular testosterone concentration. Adult Sprague Dawley rats received LH-suppressive testosterone- and estradiol-filled SILASTIC capsules of 2.5 and 0.1 cm, respectively, a regimen known to rapidly reduce testosterone production by the testes and to produce azoospermia within 8 wk. Germ cell internucleosomal DNA cleavage increased compared with control levels by 1 wk postimplantation and increased further through 4 wk. In situ terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling revealed that spermatocytes represented the predominant apoptotic cell type. Modest immunoreactivity for active caspase-3 was localized to the cytoplasm or perinuclear region of the germ cells of control testes. After testosterone and estradiol administration, however, intense staining for caspase-3 was localized to the nuclei of spermatocytes. Western blotting revealed significantly increased caspase-3 cleavage (activation) in nuclei isolated from germ cells after rats were administered testosterone and estradiol. Cleavage of the caspase-3 substrate protein, poly(ADP-ribose) polymerase, was seen after testosterone and estradiol treatment. Additionally, the caspase-activated deoxyribonuclease protein content was significantly increased in germ cells after rats were administered testosterone and estradiol, and caspase-activated deoxyribonuclease immunoreactivity was localized to the nuclei of apoptotic spermatocytes. Taken together, these results indicate that germ cell apoptosis resulting from a reduced intratesticular testosterone concentration is caspase-3 activation dependent and suggest that the translocation of active caspase-3 and caspase-activated deoxyribonuclease to the nucleus may be involved in the induction of germ cell apoptosis.

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