Apoptosis and Oxidative Stress

Apoptosis is a mode of programmed cellular death based on a genetic mechanism that induces a series of cellular, morphological, and biochemical alterations, leading the cell to suicide without eliciting an inflammatory response. Mature sperm cells have been reported to express distinct markers of apoptosis-related cell damage [28-30],

Infertile males were reported to have relatively high rates of apoptosis in their testicular biopsies [31]. In addition, the percentage of apoptotic sperm is higher in ejaculated semen samples from infertile men compared with healthy men [ 32]. Moreover, sperm caspases become more activated in patients with infertility than in healthy donors during cryopreservation [ 33] . Nevertheless, it has not been confirmed if the apoptotic markers detected in spermatozoa are due to an abortive apop-totic process started before ejaculation or whether they result from apoptosis started in the postejaculation [34, 35].

20.1.3.1 Abortive Apoptosis

During spermatogenesis, Sertoli cells are responsible for the induction of apoptosis in about 50-60% of all germ cells that enter meiosis I. These cells are determined by apoptotic markers of the Fas type [36]. However, this mechanism may not always occur efficiently and a proportion of these defective germ cells enter the process of sperm remodeling during spermiogenesis, appearing later in the ejaculate. It has been proposed that apoptosis is responsible for the process of stripping the cytoplasm in the final stages of sperm maturation. In men with oligozoospermia, the possibility that a spermatozoon with normal morphology to be aneuploid is much higher than in normozoospermic men [37].

High levels of ROS can disrupt the mitochondrial membranes, inducing the release of the cytochrome c and activating caspases and subsequently apoptosis. Apoptosis in spermatozoa may also include the activation of caspases 1, 3, 8, and 9, annexin-V binding, and the mitochondrial generation of ROS [38]. Moreover, production of the mitochondrial ROS is increased in defective spermatozoa leading to the induction of DNA damage, possibly as a component of apoptosis [ 39]. The exposure of mitochondria to ROS ends by releasing apoptosis-inducing factor (AIF), which directly interacts with the DNA and leads to DNA fragmentation [40, 41] . Since ROS are important in mediating apoptosis by inducing caspases 3 and 9 and cytochrome c resulting in single and double DNA strand breaks [42], a significant portion of sperm DNA damage is oxidative in nature [43, 44].

Other proteins are required to initiate apoptotic response such as caspase-activated DNase that is responsible for DNA fragmentation [45]. These protein families include Bcl-2 family (Bcl-xs, Bcl-w, Bax, Bak, Bid, Bad), the tumor suppressor p53, the nuclear factor kB (NF-kB), and the heat shock proteins (HSPs) [46], Moreover in spermatozoa, apoptosis may be initiated by ROS-independent pathways involving the cell surface protein Fas [47] , In contrast is the inhibitor gene of apoptosis, bcl-2, which protects the cell, most likely by decreasing ROS production [48],

Wang et al. [49] reported a positive correlation between the presence of apopto-sis markers, due to OS-induced apoptosis, and sperm DNA damage. It has been shown that infertile patients with higher ROS levels in their seminal plasma had a higher percentage of sperm apoptosis than normal healthy donors [50]. Oxidative stress-induced apoptosis in ejaculated spermatozoa has been recently reviewed [51, 52], Therefore, in the context of male infertility, seminal plasma OS level, sperm DNA damage, and apoptosis are interlinked and constitute a unified pathogenic molecular mechanism.

20.1.3.2 The BCL-2 Family

The BCL-2 family members of proteins reside upstream of irreversible cellular damage and focus much of their efforts at the level of mitochondria; they play a main role in deciding whether a cell will live or die. The BCL-2 proto-oncogene was discovered at the chromosomal breakpoint oft (14;18) bearing human B-cell lymphomas. The BCL-2 family of proteins has expanded significantly and includes both pro- as well as antiapoptotic molecules. Actually, the ratio between these two component helps to determine, in part, the susceptibility of cells to a death signal [53],

This family is characterized by their ability to form homo- as well as heterodim-ers, suggesting neutralizing competition between these proteins. A further characteristic of probable functional significance is their ability to become integral membrane proteins. BCL-2 family members possess up to four conserved BCL-2 homology (BH) domains designated BH1, BH2, BH3, and BH4, which correspond to a-helical segments [54, 55] .

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