General Discussion

We reviewed what is presently known on the positive effects of a mild oxidative stress in sperm activation. All these reports demonstrate that the controlled generation of low amounts of ROS by spermatozoa themselves plays an essential role in the modulation of signal transduction events related to the acquisition of fertilizing ability.

We identified main actors involved at the initiation of capacitation: (1) the sperm oxidase and NOS as ROS generators; (2) Zn2+ and Sg as physiological inhibitors originating from the seminal plasma; and (3) SH/SS redox couple as target for ROS, Zn2+ chelators, and also regulator for ROS generators. One of the very interesting observations at this point is that there seem to be several cross talks and interactions involving ROS, Zn-+, Sg, and the protein SH/SS couple. First, O-'- induces NO' synthesis and vice versa, and this type of double-sided ROS-induced ROS formation is, at the present time, found only in spermatozoa. Second, Sg and Zn2+ inhibit ROS generation and capacitation, but ROS also help to the disposal (degradation and release) of Sg so that capacitation can proceed. Third, modification of the SH/ SS couple promotes capacitation and ROS formation, maybe via the release of Zn2+, but ROS could also promote the release of Zn2+ by oxidation of protein SH. Finally, even if Zn2+ binds to Sg and promotes Sg binding to spermatozoa, Zn2+ is not needed for Sg action but anyhow prevents Sg degradation. It is also probable that other interactions also play a role in the initiation of capacitation. We cannot at this time know what is really the first event, whether it is the removal of Sg or Zn2+, induction of O-'- or NO' production, modification of the SH/SS couple, or something else. What is more important is to realize that several mechanisms are possible, that they potentially all interact together, and that this apparent redundancy provides superior reliability and resilience to the system and gives better guarantee that capacitation can proceed.

We also described several points at which ROS, O2'- and/or NO', modulate the signal transduction pathways known to be activated during capacitation and ultimately leading to the well-known Tyr phosphorylation of fibrous sheath proteins. Pathways involving cAMP/PKA, PI3K/Akt, and ERK cascade and ultimately leading to protein Tyr phosphorylation are all regulated by ROS and these ROS could act at various levels and on several kinases (directly or via other proteins). The phosphorylation events related to these enzymatic systems are needed for the early, intermediate, and late steps of capacitation. Some of these pathways seem to be independent and act in parallel, but others are rather characterized by cross talks and interdependency. Taken together, all these cascades and their elements demonstrate the complexity of signal transduction during capacitation and its regulation by ROS and, again, evidence redundancy of mechanisms to assure that spermatozoa acquire their fertility potential.

We have to keep an opened mind on the possible, and even probable, involvement of other ROS (H2O2, ONOO-, etc.) at minute amounts during capacitation. Also, ROS surely act on other targets than those mentioned here that could include not only other kinases and phosphatases but also ion channels, actin cytoskeleton, phospholipases (A2, C, D), etc. [24]. Future research may prove that they link those that we already evidenced.

It is important to go on with these studies because unraveling the positive actions of ROS may suggest new diagnosis tools as well as improvement of artificial reproduction techniques. Also, they may very well indicate that it is really time to reconsider protocols involving the use of high levels of antioxidants in vitro (media for assisted reproduction) and in vivo (treatments with vitamins, Zn2+, etc.) as they may prove to be inefficient or even decrease rather than improve fertility.

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