Introduction

The clinical significance of oxidative stress in the etiology of defective sperm function was first indicated by Thaddeus Mann and colleagues at the University of Cambridge, recognizing the ability of the antioxidant catalase to prevent motility loss

Department of Anatomy and Developmental Biology, Monash University, Wellington Road, Clayton, VIC 3800, Australia e-mail: [email protected]

A. Agarwal et al. (eds.), Studies on Men's Health and Fertility, Oxidative Stress 21

in Applied Basic Research and Clinical Practice, DOI 10.1007/978-1-61779-776-7_2, © Springer Science+Business Media, LLC 2012

in human sperm [1]. The role of oxidative stress in male infertility has since been well documented over the last few decades [2-5]. This phenomenon is not restricted to humans, but is also evident in a number of other species including boar [ 6], mouse [7], rabbit [8], rat [9], and horse [10].

Unlike somatic cells, spermatozoa are unique in that they are no longer capable of gene transcription [11]. This is compounded by the lack of cytoplasmic space to house antioxidant enzymes, leaving the spermatozoon in a precarious position. However, the male reproductive tract compensates for the lack of internal antioxi-dant capacity by saturating spermatozoa in a complex mixture of reactive oxygen species (ROS)-scavenging enzymes and small molecular mass antioxidants. This is evident when spermatozoa are traversing the epididymis, a process that may take 12 days [12], and after they are ejaculated into seminal plasma. Therefore, a significant increase in ROS generation and/or severe decrease in antioxidants over a chronic time frame are needed to shift the balance and cause a state of oxidative stress within spermatozoa.

The principal sources of endogenous ROS in semen are spermatozoa themselves (intrinsic) [13] and leukocytes (extrinsic) [14-16] Every human semen sample contains differential levels of contaminating leukocytes, the majority being neutro-phils and macrophages. Upon stimulation, neutrophils are extremely efficient generators of ROS particularly superoxide anion ( O-) and hydrogen peroxide (H2O2). The importance of oxidative stress due to leukocyte contamination has been shown to be critical during chronic infection [17] or when of epididymal origin [18], as both have been associated with the induction of significant sperm DNA damage

[19]. Leukocytospermia and oxidative stress will be discussed in greater detail in Chap. 26.

Often considered a likely source of ROS in spermatozoa, the presence of NADPH oxidase in spermatozoa has been inconclusive. There is data indicating that the addition of NADPH can elicit a ROS response when measured by chemiluminescence

[20]. However, Richer and Ford [21] were unable to confirm NADP-dependent ROS generation using electron paramagnetic resonance spectroscopy. Since then, a number of studies have shown the presence of a calcium-dependant NADPH oxidase, NOX 5, to be present within sperm [22-24]. The identified NOX 5 appears to be a unique form, as it is not controlled by protein kinase C as occurs in the leukocyte form of NADPH oxidase [24]. Subsequently, evidence for a NOX 2 was also reported by Shukla et al. [25] within the head region of mouse spermatozoa. No definitive conclusion on the role of NADPH oxidase in mammalian spermatozoa has yet been reached, and as such, highlights the importance of research into other sources of ROS.

Novel understandings on the subcellular source of aberrant ROS generation in spermatozoa have been developed in recent years. Although the generation of mito-chondrial ROS by spermatozoa was already known in rabbit [26] and rat [9], the study by Koppers et al. [27] highlighted its importance in human sperm by showing a correlation between low sperm motility and increased mitochondrial ROS production.

This chapter will present evidence for the role the mitochondria play in the generation of excessive ROS production within mammalian spermatozoa and the importance of mitochondrial antioxidants. Links to intrinsic and external factors and subsequent consequences will then be discussed.

Pregnancy Guide

Pregnancy Guide

A Beginner's Guide to Healthy Pregnancy. If you suspect, or know, that you are pregnant, we ho pe you have already visited your doctor. Presuming that you have confirmed your suspicions and that this is your first child, or that you wish to take better care of yourself d uring pregnancy than you did during your other pregnancies; you have come to the right place.

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