ROS in Cell Physiology and Sperm Activation First Data and Clinical Relevance

It was first counterintuitive that ROS may be essential for cell physiology because the general idea is that ROS are toxic. However, the effects ROS produce on cells depend on several factors, such as the reactivity of each ROS and the cell compartment in which it is produced, but even more on the amount formed over a definite period of time and how much this overcomes the scavenging capacity of the system [3, 8, 13, 15-18].

Cell activation is often related to a mild oxidative stress. It is worth stressing at this point that ROS possess the main characteristics of second messengers: minute amounts are locally synthesized by the cells via specialized enzymes (e.g., oxidases, NOS) or normal metabolism; ROS are small and diffusible and have a short half-life and precise targets; and finally their effects are easily reversible. As such, ROS appear as simple, economical, and efficient molecules to trigger signal transduction cascades, affect ion pumps, etc. [3, 8, 15-18].

The number of reports on the essential role of ROS in cell activation increased strikingly over the last 10 years. It is now recognized that activating stimuli, whether physiological (e.g., hormone, such as insulin) or pharmacological (e.g., medication, enzyme activators, or inhibitors), often promote ROS formation [3, 8, 15-18] via oxidases, such as those of the NOX family for O2'- [25-28] and NOS (endothelial, neuronal, and epithelial isoforms) for NO' [29-34].

It is during our studies on the dose-dependent toxicity of ROS (O2'- and H2O2) on sperm motility and viability [35, 36] that we realized that the lowest concentrations promote hyperactivation [37, 38] . This result was definitely surprising and suggested that capacitation, as a closely related event, might also be driven by ROS. This hypothesis was corroborated as subsequent experiments clearly showed that exogenous addition of ROS (O2'- from xanthine + xanthine oxidase; H2O2 by direct addition or from glucose+glucose oxidase; NO' from spontaneous degradation of chemicals, such as sodium nitroprusside or NONOates) promotes capacitation [8, 37-45]. Conversely, ROS scavengers, such as SOD and catalase, as well as NOS inhibitors (l-NAME, l-NMMA, 7-nitroindazole), prevented capacitation triggered by agents as diverse as bovine serum albumin (BSA), progesterone, l-arginine (l-Arg), ultrafiltrate from fetal cord serum (FCSu), etc. [8, 37-46], further strengthening the concept that ROS are essential for capacitation. The importance of ROS is further evidenced as they appear to control several events of the capacitation process, including the late Tyr phosphorylation of two fibrous sheath proteins of 80 and 105 kDa (p80 and p105) [8, 39, 40, 42-44, 46] which is often considered as a hallmark of capacitation.

Clinical data also support a role for ROS in sperm activation. First, we observed over the years that about 16% of men presenting at the infertility clinic and having normal sperm parameters according to the World Health Organization [47] have recurrent spontaneous sperm hyperactivation in whole semen; this appears linked to a lower SOD-like activity (O2'- scavenging capacity) in seminal plasma (by 37%) and spermatozoa (by 45%) as compared to what is found in samples from nor-mospermic men [48, 49] . On the other side, we have seen two cases in which an excessively high (2-2.5-fold) O2'- scavenging capacity in seminal plasma was associated with complete failure at capacitation, hyperactivation, and in vitro fertilization (unpublished data). Therefore, imbalance in the scavenging of O2'- seems to lead to fertility problems. Furthermore, the concentration of ROS in the medium after sperm washing correlates positively with success in in vitro fertilization and there is then even a positive trend between sperm ROS formation and the four cell stage formation [50] . The sharp increase in oxygen (O. ) pressure, from 5 ± 1 to 41 ± 4 mmHg, in fluids from the female genital tract (golden hamster) around the time of ovulation [51] may be a promoting factor for the increased synthesis of ROS in vivo.

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