Oxidative Stress A Major Challenge for Epididymal Spermatozoa

Aerobic organisms use oxygen to support cell metabolism but, doing so, they generate highly reactive oxygen derivatives. Oxidative stress results from an imbalanced situation, where generation of reactive oxygen species (ROS) exceeds recycling and/or when there is failure of all the systems eukaryotic cells have evolved to fight the inherent dangerous by-products of oxygen consumption. This equilibrium between ROS generation and removal is precisely regulated not only within the cells but also in the extracellular compartments through a large variety of pathways. Although generally presented as negative bystanders, it should not be forgotten that ROS are normal products of cell metabolism and physiologically important in regulating cell functions, such as innate immunity processes, signal transduction, and cell fate, through for example apoptosis. However, when present in excess, their high level of reactivity and possible penetration of most cell compartments render them dangerous for cell metabolism and cell structural integrity. This is particularly true in the epididymis, and with no other cell than the spermatozoa the "friend and foe" roles of ROS are highlighted. The silent nature of epididymal maturing spermatozoa mentioned above makes them particularly vulnerable to any oxidative stress situation in this compartment. In addition, during epididymal maturation of spermatozoa, the lipid fraction of the male gamete plasma membrane is subjected to modifications that increase the representation in polyunsaturated fatty acids (PUFAs) bearing double bonds that greatly facilitate ROS-mediated sperm membrane oxidative damage [1, 2]. The level of unsaturated fatty acids in sperm plasma membrane reaches a figure that is nowhere else seen being above 50% of the total FA of the membrane with docosahexanoic acid (DHA) alone, representing more than 20% of the sperm plasma membrane PUFA [3]. Thus, a post-testicular structural modification of spermatozoa designed to facilitate sperm/oocyte plasma fusion at fertilization puts the spermatozoa in a risky situation of oxidative injury. It has been argued that, paradoxically, it could be seen as a means to protect spermatozoa from peroxidative attacks since such a large amount of double bond-containing FA would probably exert a quenching effect by blocking a large quantity of free radicals. However, it is rather unlikely since, when attacked by free radicals, PUFAs in membranes readily generate new intermediates propagating peroxidative injury throughout in the so-called radical chain reaction [4].

The "oxygen paradox" is very evident in the epididymal compartment because while post-testicular spermatozoa are very susceptible to oxidative injury they evolve in a luminal environment that is surprisingly rather pro-oxidant. This is particularly the case of the proximal part of the epididymis tubule, where an oxidative environment serves at least two major functions. It is first used to complete the structural maturation of the male gamete through spontaneous or enzyme-mediated disulfide-bridging events that both required hydrogen peroxide (H2O2) or/and lipid peroxides (LOOH). Secondly, it is part of the epididymal immune strategy. As it is the case in the testis, the epididymal luminal compartment must establish a tolerogenic environment toward spermatozoa while preserving itself from infectious situations. Recent data suggest that a peculiar state of inflammation is triggered in the proximal epididymis by the spermatozoa themselves [5]. ROS are normal products of inflammatory situations and part of the ROS generated in the caput epididymis is most likely attributable to the inflammatory status of the tissue. In addition to the caput epididymidis, the terminal portion of the epididymis tubule, the so-called cauda, is also a compartment where spermatozoa risk oxidative injury. However, here, the reasons for oxidative damage are somehow different, since the risk of oxidative insult comes essentially from spermatozoa themselves. The millions of cauda-stored spermatozoa ready to fulfill their function although maintained in a nonpermissive environment (low oxygen tension, low energy supply, presence of proteins that immobilize them) are likely to leak free radicals from now operational mitochondria. Taken together, these situations, where ROS are both required and feared by epididy-mal spermatozoa, imply that very efficient regulation of the luminal concentration of these potentially dangerous intermediates is essential whatever their origin.

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