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Chemical Anoxia Delays Germ Cell Apoptosis in the Human Testis¹

Program for Developmental and Reproductive Biology,³ Biomedicum Helsinki, and Hospital for Children and Adolescents, University of Helsinki, FIN-00029 HUS Helsinki, Finland Helsinki Bioenergetics Group,⁴ Program for Structural Biology and Biophysics, Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland Department of Anatomy,⁵ University of Turku, FIN-20520 Turku, Finland

An understanding of testicular physiology and pathology requires knowledge of the regulation of cell death. Previous observation of suppression of apoptosis by hypoxia suggested a role for ATP in germ cell death. However, the exact effects of ATP production on germ cell death and of apoptosis on the levels of ATP and other adenine nucleotides (ANs) have remained unclear. We investigated the levels of ANs during human testicular apoptosis (analyzed by HPLC) and the role of chemical anoxia in germ cell death (detected by Southern blot analysis of DNA fragmentation, in situ end labeling of DNA, and electron microscopy). Incubation of seminiferous tubule segments under serum-free conditions induced apoptosis and concomitantly decreased the levels of ANs. Chemical anoxia, induced with potassium cyanide (KCN), an inhibitor of mitochondrial respiration, dropped ATP levels further and suppressed apoptosis at 4 h. After 24 h, many of the testicular cells underwent delayed apoptosis despite ATP depletion. Some cells showed signs of necrosis or toxicity. The addition of 2-deoxyglucose, an antimetabolite of glycolysis, did not alter the results obtained with KCN alone, whereas a toxic concentration of hydrogen peroxide switched apoptosis to necrosis. In most of the testicular cells, mitochondrial respiration appears to play a crucial role in controlling primary cell death cascades. In the human testis, there seem to be secondary apoptotic pathways that do not require functional respiration (or ATP).

¹ This study was supported by the Foundation for Pediatric Research (Finland), the Finnish Medical Foundation, the Finnish Medical Society Duodecim, the Sigrid Juselius Foundation (Finland), the Cancer Society of Finland, and the Turku University Foundation (Finland).

² Correspondence: Krista Erkkilä, Hospital for Children and Adolescents, Program for Developmental and Reproductive Biology, Room B529b, Biomedicum Helsinki, University of Helsinki, P.O. Box 700, FIN-00029 HUS Helsinki, Finland. FAX: 358 9 4717 1947; krista.erkkila{at}hus.fi

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