title: Direct but no transgenerational effects of decitabine and vorinostat on male fertility.
abstract: Establishment and maintenance of the correct epigenetic code is essential for a plethora of physiological pathways and disturbed epigenetic patterns can provoke severe consequences, e.g. tumour formation. In recent years, epigenetic drugs altering the epigenome of tumours actively have been developed for anti-cancer therapies. However, such drugs could potentially also affect other physiological pathways and systems in which intact epigenetic patterns are essential. Amongst those, male fertility is one of the most prominent. Consequently, we addressed possible direct effects of two epigenetic drugs, decitabine and vorinostat, on both, the male germ line and fertility. In addition, we checked for putative transgenerational epigenetic effects on the germ line of subsequent generations (F1-F3). Parental adult male C57Bl/6 mice were treated with either decitabine or vorinostat and analysed as well as three subsequent untreated generations derived from these males. Treatment directly affected several reproductive parameters as testis (decitabine & vorinostat) and epididymis weight, size of accessory sex glands (vorinostat), the height of the seminiferous epithelium and sperm concentration and morphology (decitabine). Furthermore, after decitabine administration, DNA methylation of a number of loci was altered in sperm. However, when analysing fertility of treated mice (fertilisation, litter size and sex ratio), no major effect of the selected epigenetic drugs on male fertility was detected. In subsequent generations (F1-F3 generations) only subtle changes on reproductive organs, sperm parameters and DNA methylation but no overall effect on fertility was observed. Consequently, in mice, decitabine and vorinostat neither affected male fertility per se nor caused marked transgenerational effects. We therefore suggest that both drugs do not induce major adverse effects-in terms of male fertility and transgenerational epigenetic inheritance-when used in anti-cancer-therapies.
authors.affiliation: Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Kläver
authors.affiliation: Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors.forename: Victoria
authors.initials: V
authors.lastname: Sánchez
authors.affiliation: Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors.forename: Oliver S
authors.initials: OS
authors.lastname: Damm
authors.affiliation: Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Redmann
authors.affiliation: Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Lahrmann
authors.affiliation: Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors.forename: Reinhild
authors.initials: R
authors.lastname: Sandhowe-Klaverkamp
authors.affiliation: Department of Hematology and Oncology, University of Halle, Halle, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rohde
authors.affiliation: Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Wistuba
authors.affiliation: Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany; Central Animal Facility of the Medical Faculty, University of Münster, Münster, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Ehmcke
authors.affiliation: Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schlatt
authors.affiliation: Institute of Reproductive and Regenerative Biology, Centre of Reproductive Medicine and Andrology, University of Münster, Münster, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Gromoll
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000009:adverse effects / Q000031:analogs & derivatives*; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D052244:Endocrine Disruptors / Q000009:adverse effects; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism; D005298:Fertility / Q000187:drug effects*; D005434:Flow Cytometry; D006877:Hydroxamic Acids / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013094:Spermatozoa / Q000187:drug effects / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D052244:Endocrine Disruptors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D000077209:Decitabine; D001374:Azacitidine