Apoptosis and DNA damage in human spermatozoa

Abstract

DNA damage is frequently encountered in spermatozoa of subfertile males and is correlated with a range of adverse clinical outcomes including impaired fertilization, disrupted preimplantation 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 spermiogenesis. We hypothesize that oxidative stress impedes spermiogenesis, resulting in the generation of spermatozoa with poorly remodelled chromatin. These defective cells have a tendency to default to an apoptotic pathway associated with motility loss, caspase activation, phosphatidylserine exteriorization and the activation of free radical generation by the mitochondria. The latter induces lipid peroxidation and oxidative DNA damage, which then leads to DNA fragmentation and cell death. The physical architecture of spermatozoa prevents any nucleases activated as a result of this apoptotic process from gaining access to the nuclear DNA and inducing its fragmentation. It is for this reason that a majority of the DNA damage encountered in human spermatozoa seems to be oxidative. Given the important role that oxidative stress seems to have in the etiology of DNA damage, there should be an important role for antioxidants in the treatment of this condition. 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.

Figure 1

A possible mechanism by which DNA damage in human spermatozoa can impact on the health and wellbeing of the offspring. As soon as fertilization occurs, the oocyte scans the DNA introduced into the ooplasm by the fertilizing spermatozoon to determine the level of DNA damage. If excessive, the oocyte embarks on a round of DNA repair and will put DNA replication on hold until this process has been completed. If the oocyte should make a mistake at this point, a mutation may be created that will subsequently impact on the normality of embryonic development and the incidence of disease in the progeny. Such an effect will be compounded if the capacity of the oocyte for DNA repair is diminished by, for example, age or exposure to environmental toxicants.

Figure 2

Two-step hypothesis for the origins of DNA damage in the male germ line. This hypothesis posits that a wide variety of clinical and environmental factors are capable, alone or in combination, of creating oxidative stress in the testes. In step 1, this stress impairs spermiogenesis resulting in the production of defective spermatozoa possessing poorly protaminated chromatin. These defective spermatozoa have a tendency to default to an apoptotic cascade that involves the generation of ROS by the sperm mitochondria. In step 2, these ROS attack the poorly remodelled chromatin generating oxidized DNA base adducts (8OHdG) that ultimately result in DNA strand breakage and cell death.