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In Vivo Application of Histone Deacetylase Inhibitor Trichostatin-A Impairs Murine Male Meiosis

HAMID M. HOSSAIN^,#

SVETLIN TCHATALBACHEV

FELIX THIERER

JOHANNES TRAPP

KLAUS FAILING

MANFRED JUNG

TRINAD CHAKRABORTY

From the ^* Department of Urology and Pediatric Urology and the Institute of Medical Microbiology University of Giessen, Germany; the Institute of Pharmaceutical Sciences University of Freiburg, Germany; and the Institute of Veterinary Physiology, Department of Biomathematics, the ^|| Department of Forensic Medicine, and the ^¶ Institute of Veterinary Anatomy, Histology, and Embryology, University of Giessen, Germany.

Correspondence to: Prof Dr Klaus Steger, Klinik und Poliklinik für Urologie und Kinderurologie, Rudolf-Buchheim-Strasse 7, 35385 Giessen, Germany (e-mail: Klaus.Steger{at}chiru.med.uni-giessen.de).

In vivo application of histone deacetylase (HDAC) inhibitor trichostatin-A (TSA) in mice results in male infertility. To get more insight into the mechanisms underlying this phenomenon, we performed a genome-wide expression analysis and investigated HDAC activity and degree of histone H3 and H4 acetylation in murine testes after TSA treatment. A significant decrease in HDAC activity and a weak increase in histone acetylation could be demonstrated at 2.5, 5.0, and 7.5 hours after TSA application. Gene expression analysis revealed 507 significantly regulated genes. Transcripts expressed in the somatic cells of the testis (Sertoli, Leydig, peritubular cells, and testis macrophages) or extratubular matrix were regulated as early as 2.5 hours after TSA application, whereas very few meiosis-specific genes were modulated after TSA treatment. In addition, members of the p53-noxa-caspase-3 proapoptotic pathway were regulated early. Applying in-situ hybridization, caspase-3-mRNA was found only in apoptotic spermatocytes, whereas TRP53/p53- and PMAIP1/noxa-mRNA could be demonstrated in spermatogonia and spermatocytes. Our data suggest that TSA impaired male meiosis, possibly through an indirect mechanism implicating somatic cells of the testis.

     Key words: Apoptosis, histone-deacetylase, mouse, spermatogenesis