The Capacitation-Apoptosis Highway: Oxysterols and Mammalian Sperm Function

The notion that densely packed populations of spermatozoa generate toxicants that inhibit respiration has been around since the 1920s, when the concept of allelostasis (an increase in oxygen uptake that accompanies the dilution of sperm populations) was born [1]. It was not until 1946 that Tosic and Walton [2] identified the molecule responsible for this allelostatic effect in bull spermatozoa as hydrogen peroxide. Mammalian spermatozoa were thus the first cell type in which the cellular generation of reactive oxygen species (ROS) was biochemically confirmed, predating the discovery of this activity in leukocytes by more than a decade. Since Tosic and Walton's original report, the cellular production of ROS has been confirmed in the spermatozoa of a wide variety of mammals, including human, mouse, hamster, rat, rabbit, and horse [3]. This potential for ROS production is curious given the susceptibility of mammalian spermatozoa to oxidative stress. These cells are well known to possess high concentrations of unsaturated fatty acids, particularly docosahexaenoic acid (22:6), that are very vulnerable to attack by reactive oxygen metabolites and the consequent initiation of lipid peroxidation cascades [4]. Such peroxidative damage impacts these cells in such a way that motility, their competence for sperm-oocyte fusion, and DNA integrity become rapidly compromised [3, 4]. The spectacular ability of ROS to damage sperm function has been understood since the pioneering studies of MacLeod in the 1930s [5], Jones and Mann in the 1970s [6, 7] and Alvarez and Storey in the 1980s [8, 9]. Given this background, it is clear that if spermatozoa are such active generators of ROS, they must have a very good reason for engaging in this potentially fatal activity.