The Positive Impact of Lipid Peroxidation The Induction of Sperm Capacitation

We have known since the excellent studies published by Claude Gagnon and Eve de Lamirande in the early 1990s that sperm capacitation is an oxidative process that is heavily dependent on the active generation of ROS [9]. While several independent laboratories have confirmed the oxidative drive to capacitation [10-12], the way in which changes in the redox status of human spermatozoa allows these cells to attain a capacitated state has remained largely unresolved. To date, there is evidence that both primary cAMP production and the resultant stimulation of tyrosine phosphorylation are oxidatively induced by as a consequence of ROSmediated changes in soluble adenylyl cyclase and tyrosine phosphatase activities respectively [6, 13-15]. In addition, exciting data has recently come to light, suggesting that oxidative changes to cholesterol in the sperm plasma membrane may also facilitate capacitation [16].

It has been known for some time that one of the key changes driving sperm capac-itation is a loss of cholesterol from the sperm plasma membrane under the absorptive influence of albumin [17] . Such a change is thought to enhance the fluidity of the plasma membrane, promoting critical intermolecular interactions that promote the development of a capacitated state. However, the mechanisms by which cholesterol is induced to leave the plasmalemma and bind to albumin have never been satisfactorily explained. Brouwers et al. [16] have provided a possible answer to this question by revealing that cholesterol becomes oxidized in response to the ROS generated during capacitation. The oxysterols generated as a consequence of this process are more hydrophilic than the parent molecule and can therefore move more freely out of the plasma membrane to bind acceptor proteins, such as albumin.

Paradoxically, the redox mechanisms that drive capacitation through the oxidation and subsequent depletion of cholesterol from the sperm plasma membrane may also ultimately damage these cells. Thus oxysterol accumulation has been widely linked with the activation of apoptosis and cell death in other cell types [ 18]. Of particular interest is the fact that mitochondria appear to be key mediators of oxysterol-induced pathology via mechanisms involving stimulation of the intrinsic apoptotic cascade and activation of excessive ROS generation [19-21]. If this is the case, then we might postulate a dual role for cholesterol oxidation during the life history of a sperm cell [22]. Thus, during capacitation ROS-induced cholesterol oxidation can be considered biologically useful because it facilitates the removal of cholesterol from the sperm plasma membrane and the attainment of a capacitated state. However, if the spermatozoa do not manage to find and fertilize an egg, then the continued generation of ROS will result in an accumulation of oxysterols in the mitochondrial as well as the plasma membrane. The presence of oxysterols in the mitochondrial membranes might then precipitate enhanced mitochondrial ROS generation and induction of the intrinsic apoptotic cascade. This sedate progression from a state of capacitation to apoptotic cell death is probably an adaptive response that ensures the efficient removal of moribund, postmature spermatozoa from the female reproductive tract. Under these circumstances, the presence of apoptotic markers such as phosphatidylserine on the sperm surface would be expected to inform the infiltrating phagocyte population that the consumption of these cells should be "silent," i.e., should not be accompanied by an oxidative burst or the production of proinflammatory cytokines [ 22] . These beautifully orchestrated biochemical changes illustrate the important, complex role that oxidized lipid products have in regulating the physiological function of spermatozoa in terms of their competence for fertilization and efficiency with which these cells can be removed from the female tract once they are beyond their "sell-by" date. However, in cases of male infertility, this carefully choreographed sequence of events becomes disrupted and the focus of interest shifts from the oxysterol content of these cells to the oxidation status of the fatty acids in the sperm plasma membrane [23-25].

Pregnancy Nutrition

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