title: Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress.
abstract: Stress-induced downregulation of spermatogenesis remains poorly understood. This study examined the induction of heme oxygenase-1 (HO-1), a carbon monoxide-generating inducible enzyme, in modulation of spermatogenesis. Rats were exposed to cadmium chloride (CdCl(2)), a stressor causing oligozoospermia, and HO-1-induction was monitored by following HO isozyme expression. CdCl(2)-treated testes increased HO-1 activity and suppressed microsomal cytochromes P450, which are required for steroidogenesis. CdCl(2)-elicited HO-1 occurred mostly in Leydig cells and coincided with CO generation, as judged by bilirubin-IXalpha immunoreactivity. Under these circumstances, germ cells in peripheral regions of seminiferous tubules exhibited apoptosis; laser flow cytometry revealed that these apoptotic cells involve diploid and tetraploid germ cells, suggesting involvement of spermatogonia and primary spermatocytes in CdCl(2)-elicited apoptosis. Pretreatment with zinc protoporphyrin-IX, an HO inhibitor, but not copper protoporphyrin-IX, which does not block the enzyme, attenuated the CdCl(2)-induced apoptosis. Such antiapoptotic effects of zinc protoporphyrin-IX were repressed by supplementation of dichloromethane, a CO donor. Upon CdCl(2)-treatment, both Sertoli cells and the germ cells upregulated Fas ligand; this event was also suppressed by zinc protoporphyrin-IX and restored by dichloromethane. Thus, Leydig cells appear to use HO-1-derived CO to trigger apoptosis of premeiotic germ cells and thereby modulate spermatogenesis under conditions of stress.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ozawa
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Goda
authors.forename: Nobuya
authors.initials: N
authors.lastname: Makino
authors.forename: Tokio
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019256:Cadmium Chloride / Q000633:toxicity; D002248:Carbon Monoxide / Q000378:metabolism; D004171:Diploidy; D004790:Enzyme Induction / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1; D007150:Immunohistochemistry; D007985:Leydig Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D009845:Oligospermia / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D011123:Polyploidy; D051381:Rats; D017208:Rats, Wistar; D013091:Spermatogenesis / Q000187:drug effects / Q000502:physiology*; D013312:Stress, Physiological / Q000201:enzymology / Q000473:pathology; D013737:Testis / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
chemical_list: D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D019256:Cadmium Chloride