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.
Highlights
Epigenetics describes mitotically and/or meiotically stable modifications that function beyond the actual DNA sequence and regulatePLOS ONE | DOI:10.1371/journal.pone.0117839 February 18, 2015Effects of Epigenetic Drugs on Male Fertility
We investigated whether the administration of the two epigenetic drugs decitabine and vorinostat has any direct or transgenerational effects on male germ line and fertility
As only males of the P-generation were injected with epigenetic drugs and only male descendants thereof were mated, transmission of drug-related effects is only possible via the male germ line
Summary
Epigenetics describes mitotically and/or meiotically stable modifications (such as DNA methylation and histone modification) that function beyond the actual DNA sequence and regulate. Aberrant methylation patterns of sperm nuclear DNA have been associated with adverse effects on pregnancies and abnormal DNA methylation in the offspring [18,19,20,21,22] These findings suggest epigenetic processes during spermatogenesis to be specific and highly regulated and that their disruption could have severe consequences for fertilization and subsequent embryogenesis. As the number of cancer survivors is currently increasing and some of these patients are even at a reproductive age and might want to father a child after cure and recovery [36,37], it is essential to know whether the used epigenetic drugs could cause direct negative effects on fertility or could induce adverse multi- or transgenerational epigenetic effects in subsequent generations These experiments are important to gain basic insights on the safety of these treatments on reproduction and offspring
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