001. ORIGINS OF DNA DAMAGE IN SPERMATOZOA

Abstract

DNA damage is frequently encountered in the spermatozoa of sub-fertile male mammals and is correlated with a range of adverse clinical outcomes including impaired fertilization, disrupted embryonic development, increased rates of miscarriage and an enhanced risk of disease in the progeny. The etiology of DNA fragmentation in human spermatozoa is closely correlated with the appearance of oxidative base adducts and evidence of impaired chromatin remodelling during spermiogenesis. In light of these associations we propose a two step hypothesis for the origins of DNA damage in spermatozoa. In Step 1, a variety of intrinsic (diabetes, varicocele, testicular torsion, obesity) and extrinsic (radiofrequency electromagnetic radiation, heat, cigarette smoke, diet, environmental toxicants) factors collude to generate a state of oxidative stress in the testes. This stress impedes spermiogenesis resulting in the generation of spermatozoa with poorly remodelled chromatin. These defective cells readily default to an apoptotic pathway comprising motility loss, caspase activation, phosphatidylserine exteriorization and the production of reactive oxygen species (ROS) by the mitochondria. In Step 2, these mitochondrial ROS attack the spermatozoa inducing lipid peroxidation and oxidative DNA damage, which then leads to DNA strand breakage and cell death. Nucleases activated and released during the apoptotic process are denied access to the sperm nucleus because the unique physical architecture of this cell prevents it. For this reason, a majority of the DNA damage encountered in human spermatozoa is oxidative. Given the importance of oxidative stress in the etiology of DNA damage, there should be a significant therapeutic role for antioxidants in the treatment of this condition. Furthermore, if oxidative DNA damage in spermatozoa is providing a sensitive readout of systemic oxidative stress, the implications of these findings could stretch beyond our immediate goal of trying to minimize DNA damage in spermatozoa as a prelude to assisted conception therapy.