Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress

Nobuaki Ozawa, Nobuhito Goda, Nobuya Makino, Tokio Yamaguchi, Yasunori Yoshimura, Makoto Suematsu

Research output: Contribution to journalArticle

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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 (CdCl2), a stressor causing oligozoospermia, and HO-1-induction was monitored by following HO isozyme expression. CdCl2-treated testes increased HO-1 activity and suppressed microsomal cytochromes P450, which are required for steroidogenesis. CdCl2-elicited HO-1 occurred mostly in Leydig cells and coincided with CO generation, as judged by bilirubin-IXα 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 CdCl2-elicited apoptosis. Pretreatment with zinc protoporphyrin-IX, an HO inhibitor, but not copper protoporphyrin-IX, which does not block the enzyme, attenuated the CdCl2-induced apoptosis. Such antiapoptotic effects of zinc protoporphyrin-IX were repressed by supplementation of dichloromethane, a CO donor. Upon CdCl2-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.

Original languageEnglish
Pages (from-to)457-467
Number of pages11
JournalJournal of Clinical Investigation
Volume109
Issue number4
DOIs
Publication statusPublished - 2002

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Cadmium Chloride
Heme Oxygenase-1
Leydig Cells
Germ Cells
Carbon Monoxide
Apoptosis
Spermatogenesis
Methylene Chloride
Oligospermia
Spermatogonia
Seminiferous Tubules
Fas Ligand Protein
Spermatocytes
Tetraploidy
Sertoli Cells
Enzymes
Diploidy
Bilirubin
Cytochrome P-450 Enzyme System
Isoenzymes

ASJC Scopus subject areas

  • Medicine(all)

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Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress. / Ozawa, Nobuaki; Goda, Nobuhito; Makino, Nobuya; Yamaguchi, Tokio; Yoshimura, Yasunori; Suematsu, Makoto.

In: Journal of Clinical Investigation, Vol. 109, No. 4, 2002, p. 457-467.

Research output: Contribution to journalArticle

Ozawa, Nobuaki ; Goda, Nobuhito ; Makino, Nobuya ; Yamaguchi, Tokio ; Yoshimura, Yasunori ; Suematsu, Makoto. / Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress. In: Journal of Clinical Investigation. 2002 ; Vol. 109, No. 4. pp. 457-467.
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