Spermatozoa are complex and compartmentalized cells subjected to sequential mat-urational steps in the testis, the epididymis, and finally the female genital tract [1]. This latter step is associated with a series of timely and finely regulated changes,

E. de Lamirande, PhD (*) ♦ C. O'Flaherty, DVM, PhD

Urology Research Laboratory, McGill University Health Center, Royal Victoria Hospital, Montréal, QC, Canada H3A 1A1 e-mail: [email protected]

A. Agarwal et al. (eds.), Studies on Men's Health and Fertility, Oxidative Stress 57

in Applied Basic Research and Clinical Practice, DOI 10.1007/978-1-61779-776-7_4, © Springer Science+Business Media, LLC 2012

collectively called capacitation, that are essential for the acquisition of fertilizing ability [1-6]. Various events occur during capacitation, such as increases in intracellular pH and calcium (Ca2+), production of low and controlled levels of reactive oxygen species (ROS), increase in membrane fluidity due to loss of cholesterol, and activation of several signal transduction cascades and related protein kinases resulting in the subsequent phosphorylation of numerous proteins on serine (Ser), threonine (Thr), and tyrosine (Tyr) residues [1-10] . In parallel, spermatozoa develop a very specific type of movement, called hyperactivation, which is characterized by high speed, low linearity, and high amplitude of lateral head displacement [1, 3, 6]. Hyperactivation involves higher force, which allows spermatozoa to detach from the oviductal epithelium after capacitation is completed, swim through media of higher viscosity and elasticity as can be found in the female genital tract and around the oocytes, and finally penetrate through the zona pellucida [1, 3, 6].

Once capacitated spermatozoa can attach to the zona pellucida that surrounds the eggs; as a result, they undergo the acrosome reaction, which is an exocytotic event involving the release of enzymes (acrosin, hyaluronidase, etc.) that hydrolyze proteins of the zona pellucida, thus helping their progression toward the egg [1, 3, 7, 11, 12] . The acrosome reaction is a complex and irreversible process that occurs over a short period of time (within minutes); it is also associated with ROS generation as well as specific ion fluxes, activation of signal transduction cascades, and phosphorylation of proteins [1-3, 7, 9, 13, 14].

Sperm activation normally occurs in the female genital tract and its physiological inducers are presently not all known; we can expect that they are many and also that they may interact with each other. Sperm capacitation, hyperactivation, and acrosome reaction can be studied in vitro using defined media and various inducers, but it should always be remembered that all these are models and that their use has to be established with more than one inducer or conditions.

Numerous cellular processes, including acquisition of fertilizing ability by spermatozoa, are regulated by ROS [1, 3, 13, 15-18]. Some of the best-studied ROS for their positive role in cell biology are the superoxide anion (O2'-), its dismutation product, hydrogen peroxide (H2O2), nitric oxide (NO'), and the peroxynitrite anion (ONOO-) (Table 4.1). The effect of these ROS is limited not only by the action of enzymes, such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX), thioredoxin (TRX), and peroxiredoxin (PRDX), but also by small molecules, such as vitamins (E, C, etc.) and sulfhydryl (SH)-containing substances (glutathione, protein cysteine residues, Cys) that dispose of ROS [19-23]. We are aware that the ROS and ROS scavengers listed above represent only few players in a very complex scheme of ROS reactions, but they appear as the most important for their actions in cell physiology. The reader is referred to very-well-written books for more extensive data on ROS chemistry and biology [19, 24].

In this chapter, we summarize the present knowledge on the positive role of ROS during sperm activation. We center our attention mainly on studies performed on human spermatozoa and use data reported on other species as supplement, or complement, when needed for the benefit of the discussion. The deleterious effects of serious oxidative stresses in which ROS production far exceeds cell defenses and

4 Sperm Capacitation as an Oxidative Event Table 4.1 Main ROS involved in cell physiology.

Origin (best recognized)

Half-life Reactivity

Cell Specific scavenger permeant (best recognized)




One electron reduction of O2 (metabolism, specific oxidases) O2'- dismutation

1 ms Low No Superoxide dismutase

Minutes to Low to hours medium l-Arg conversion to 1-7 s l-citrulline by nitric oxide synthase

Yes Catalase, glutathione peroxidase, thioredoxin, peroxiredoxin Low Yes None

Reaction of O2" with NO'

Minutes High No Glutathione peroxidase, peroxiredoxin causes loss of motility and viability, DNA damage, lipid peroxidation, etc. are emphasized in other chapters of this book.

We first introduce the physiology of ROS and present the first evidences for a positive action of ROS in human spermatozoa as well as relevance to clinical situations. We then report on the sperm production of ROS and more specifically on the methods of measurement, time course during capacitation, and natural modulators (zinc and semenogelin) and generators (oxidases, NOX; nitric oxide synthase, NOS). The study of ROS effects on signal transduction cascades, protein phosphorylation events, and the sulfhydryl/disulfide (SH/SS) couple on sperm proteins follows. We then briefly report on what is known of ROS involvement in other sperm activation events, namely, hyperactivation and acrosome reaction, and finally offer some conclusions, main points to remember, as well as a general outlook on what future research could aim for.

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