| Healthy gametes are essential for the survival of the species. Epigenetic marks, including DNA methylation, are crucial components of proper germ cell development and have been shown to be important for fertility and embryo development. DNA methylation patterns in male germ cells are initially acquired during prenatal development and continue to be acquired, maintained and remodeled in postnatal life during spermatogenesis. Altered genomic methylation patterns have been linked to developmental abnormalities, cancer and, in the case of an abnormal sperm epigenome, infertility. The overall objective of the work presented was to determine the susceptibility of the male germ cell epigenome to perturbations occurring during key periods of DNA methylation programming, in the prenatal and postnatal testis, using animal and human models. Firstly, early neonatal germ cells and mature sperm were analyzed in two strains of mice carrying an ablation of 5,10-methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in supplying methyl groups for methylation reactions. Results demonstrated important strain-specific differences in early germ cell development and the appearance of an altered sperm epigenome affecting both genic and intergenic regions. Secondly, an inbred rat model was used in order to identify the types of loci with DNA methylation defects following exposures of postnatal male germ cells to bleomycin, etoposide and cis-platinum (BEP), at doses equivalent to those used in chemotherapy regimens for human testicular cancer. The findings indicated the presence of susceptible regions in the sperm epigenome that differed from those affected by MTHFR deficiency and showed that damage may originate in different populations of maturing male germ cells. Finally, DNA methylation was examined in the sperm from men with testicular cancer prior to, and at several intervals following, the administration of BEP chemotherapy regimens. As a basis of comparison, the sperm of community controls and Hodgkin's disease patients were examined at several points over time. In addition to finding large inter-individual variations in sperm DNA methylation, low intra-individual variability was notable in community control subjects. In contrast, patients demonstrated increased intra-individual variation post-treatment that persisted up to two years following chemotherapy. Collectively, these studies have revealed that, across species, the male germ cell genome can carry epigenetic defects following prenatal and postnatal perturbations and exposures. Such epigenetic defects have the potential to alter fertility and the health of the progeny. |
