Abstract
Reactive oxygen species (ROS) play a critical role in defining the functional competence of human spermatozoa. When generated in moderate amounts, ROS promote sperm capacitation by facilitating cholesterol efflux from the plasma membrane, enhancing cAMP generation, inducing cytoplasmic alkalinization, increasing intracellular calcium levels, and stimulating the protein phosphorylation events that drive the attainment of a capacitated state. However, when ROS generation is excessive and/or the antioxidant defences of the reproductive system are compromised, a state of oxidative stress may be induced that disrupts the fertilizing capacity of the spermatozoa and the structural integrity of their DNA. This article focusses on the sources of ROS within this system and examines the circumstances under which the adequacy of antioxidant protection might become a limiting factor. Seminal leukocyte contamination can contribute to oxidative stress in the ejaculate while, in the germ line, the dysregulation of electron transport in the sperm mitochondria, elevated NADPH oxidase activity, or the excessive stimulation of amino acid oxidase action are all potential contributors to oxidative stress. A knowledge of the mechanisms responsible for creating such stress within the human ejaculate is essential in order to develop better antioxidant strategies that avoid the unintentional creation of its reductive counterpart.
Highlights
Publisher’s Note: MDPI stays neutralThe notion that oxidative stress is a major factor in the aetiology of male infertility has a long history stretching back to studies performed in the 1920s, when the impact of vitamin E deficiency on normal testicular function became apparent [1]
They highlighted the ability of fatty acid peroxides to rapidly, and permanently, arrest the motility of human spermatozoa [4], thereby opening the door to a pathophysiological mechanism that is recognized as a major cause of defective sperm function in all species examined, from sea urchins to man [5]
It is clear that such stress can arise via a range of different mechanisms, including the infiltration of leukocytes in response to pro-inflammatory signals generated within the male tract, the generation of Reactive oxygen species (ROS) by the sperm mitochondria, and the aberrant regulation of enzymes (NADPH and amino acid oxidases) that normally serve to provide the redox drive to sperm capacitation (Figure 3)
Summary
The notion that oxidative stress is a major factor in the aetiology of male infertility has a long history stretching back to studies performed in the 1920s, when the impact of vitamin E deficiency on normal testicular function became apparent [1]. Pioneering studies conducted by Thaddeus Mann and colleagues at the University of Cambridge extended this concept when they elegantly demonstrated the damaging impact of lipid peroxidation on normal sperm function [2,3] They were the first to point out the vulnerability of mammalian spermatozoa to peroxidative damage because of their high cellular content of polyunsaturated fatty acids, and the first to identify the particular vulnerability of plasmalogen to this process. They highlighted the ability of fatty acid peroxides to rapidly, and permanently, arrest the motility of human spermatozoa [4], thereby opening the door to a pathophysiological mechanism that is recognized as a major cause of defective sperm function in all species examined, from sea urchins to man [5]. This review is not intended to cover all these aspects, but rather constitutes an in-depth assessment of the causes of oxidative stress in the male germ line and potential strategies for addressing this pathology in a therapeutic context
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