GSE59575
Direct but No Transgenerational Effects of Decitabine and Vorinostat on Male Fertility
Epigenetic drugs actively altering the epigenome of tumours have been developed for use in anti-cancer therapies. However, these drugs could potentially also affect the DNA methylome of spermatozoa that seems to be essential for male fertility. Here, we analysed possible direct and transgenerational effects of the epigenetic drug decitabine on the DNA methylome of spermatozoa. Our analysis revealed the absence of gross differences between the spermatozoal methylome of decitabine treated and untreated animals as well as between their F3 generations. Interestingly, the methylomes of spermatozoa from the selected mice of the F3-generations were also highly similar to the analysed parental samples. Overall design: We studied genome-wide DNA methylation changes in decitabine treated mice and their F3-generation. For this, we treated male C57BL/6 mice (seven weeks old) for seven weeks (intraperitoneal, three times per week) with the DNMT inhibitor decitabine (5-aza-2'-deoxycytidine, 0.1 µg/g, n = 17) or with vehicle (7.5 % dimethyl sulfoxide in phosphate buffered saline, n = 16). The dose of decitabine per treatment was chosen according to the clinical application regimens in humans and refer to previous mice studies using this drug (Kelly et al, 2003; Oakes et al, 2007). For the investigation of transgenerational effects, 10 treated and untreated male mice were mated with four untreated female C57BL/6 mice each. The offspring was considered as F1-generation. The F2- and F3-generations were obtained by an identical mating scheme. Thus, only the P-generation males were treated with decitabine or control vehicle, the F1-, F2- and F3-generations were not subjected to any treatment. During this study, all mice were housed at 24 °C on a 12-h light, 12-h dark cycle and provided with food and tap-water ad libitum.