Approximately 45% of men will develop cancer during their lifetime; some of which will be of reproductive age (Canadian Cancer Society, 2008). Current advances in treatment regimens such as radiotherapy have significantly lowered cancer-related mortality rates; however, one major quality-of-life issue in cancer survivors is the ability to produce healthy offspring. Exposure to ionizing radiation (IR) leads to genomic instability in the germline, and further to transgeneration genome instability in unexposed offspring of preconceptionally exposed parents. The results presented in this thesis define, in part, the molecular consequences of direct and indirect irradiation for the male germline. Direct exposure results in a significant accumulation of DNA damage, altered levels of global DNA methylation and microRNAome dysregulation of testis tissue. Localized cranial irradiation results in a significant accumulation of unrepaired DNA lesions and loss of global DNA methylation in the rodent (rat) germline. Biological consequences of the changes observed are discussed. / xii, 121 leaves : ill. ; 29 cm.

PiRNAs and their Piwi family protein partners are part of a germline specific epigenetic regulatory mechanism essential for proper spermatogenesis, silencing of transposable elements, and maintaining germline genome integrity, yet their role in the response of the male germline to genotoxic stress is unknown. Ionizing radiation (IR) is known to cause transgenerational genome instability that is linked to carcinogenesis. Although the molecular etiology of IR-induced transgenerational genomic instability is not fully understood, it is believed to be an epigenetically mediated phenomenon. IR-induced alterations in the expression pattern of key regulatory proteins involved in the piRNA pathway essential for paternal germline genome stability may be directly involved in producing epigenetic alterations that can impact future generations. Here we show whole body and localized X-irradiation leads to significant altered expression of proteins that are necessary for, and intimately involved in, the proper functioning of the germline specific piRNA pathway in mice and rats. In addition we found that IR-induced alterations to piRNA pathway protein levels were time and dose dependent. / ix, 123 leaves : ill. (some col.) ; 29 cm