In vivo application of histone deacetylase inhibitor trichostatin-a impairs murine male meiosis.
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.
Department of Urology and Pediatric Urology, University of Giessen, Germany.
Irina
I
Fenic
Hamid M
HM
Hossain
Violetta
V
Sonnack
Svetlin
S
Tchatalbachev
Felix
F
Thierer
Johannes
J
Trapp
Klaus
K
Failing
Kai S
KS
Edler
Martin
M
Bergmann
Manfred
M
Jung
Trinad
T
Chakraborty
Klaus
K
Steger
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D017403:In Situ Hybridization; D007248:Infertility, Male / Q000139:chemically induced; D008297:Male; D008540:Meiosis / Q000187:drug effects*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013091:Spermatogenesis / Q000187:drug effects
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A