In vivo effects of histone-deacetylase inhibitor trichostatin-A on murine spermatogenesis.
The acetylation state of core histones is controlled by two classes of enzymes, histone acetyl transferases (HATs) and histone deacetylases (HDACs). HDAC inhibitors, such as trichostatin-A (TSA), are able to induce cell cycle arrest by stimulating transcription of genes that negatively regulate cell growth and survival. However, little is known about the effect of HDAC inhibitors on spermatogenesis. TSA treatment of cultured murine germ cells from whole testes resulted in an increase of histone H4 acetylation in round spermatids, suggesting that a hypoacetylated state of these cells is important for their normal differentiation. In the present study, the in vivo effects of TSA on murine spermatogenesis were investigated. Subcutaneously applied TSA resulted in a dose-dependent decrease in relative testis weight due to impaired spermatogenesis. No obvious toxic effects of TSA treatment could be found. A second animal experiment confirmed that male mice receiving TSA under the same conditions as in the first experiment became infertile. This phenomenon was completely reversible. No evidence of histone H4 hyperacetylation in round spermatids could be found; however, the number of spermatids significantly decreased with increasing TSA concentrations. Additionally, a dramatic loss of pachytene-diplotene spermatocytes due to increased apoptosis was observed. This suggests that TSA was mainly effective at the level of meiosis. The other male reproductive organs showed no morphological changes compared to controls, suggesting that TSA action on the testis was not mediated by sex hormones.
Fenic
Irina
I
Institute of Veterinary Anatomy, Histology and Embryology, Giessen, University of Giessen, Germany.
Sonnack
Violetta
V
Failing
Klaus
K
Bergmann
Martin
M
Steger
Klaus
K
D000818:Animals; D003267:Contraception; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007248:Infertility, Male / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013091:Spermatogenesis / Q000187:drug effects*; D013094:Spermatozoa / Q000187:drug effects*; D013737:Testis / Q000187:drug effects
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D006655:Histone Deacetylases