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Gpx5 protects the family jewels
R. John Aitken
ARC Centre of Excellence in Biotechnology and Development, Discipline of Biological Sciences, University of Newcastle, Newcastle, New South Wales, Australia.
Address correspondence to: R. John Aitken, ARC Centre of Excellence in Biotechnology and Development, Discipline of Biological Sciences, Room LS4.32, University of Newcastle, Callaghan, New South Wales, Australia. Phone: 61-2-4921-2082; Fax: 61-2-4921-6308; E-mail: john.aitken@newcastle.edu.au.
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Published June 22, 2009 - More info
J Clin Invest. 2009;119(7):1849–1851. https://doi.org/10.1172/JCI39688.
© 2009 The American Society for Clinical Investigation
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Abstract
The mammalian epididymis provides sperm with an environment that promotes their maturation and protects them from external stresses. For example, it harbors an array of antioxidants, including non-conventional glutathione peroxidase 5 (GPX5), to protect them from oxidative stress. To explore the role of GPX5 in the epididymis, we generated mice that lack epididymal expression of the enzyme. Histological analyses of Gpx5–/– epididymides and sperm cells revealed no obvious defects. Furthermore, there were no apparent differences in the fertilization rate of sexually mature Gpx5–/– male mice compared with WT male mice. However, a higher incidence of miscarriages and developmental defects were observed when WT female mice were mated with Gpx5-deficient males over 1 year old compared with WT males of the same age. Flow cytometric analysis of spermatozoa recovered from Gpx5-null and WT male mice revealed that sperm DNA compaction was substantially lower in the cauda epididymides of Gpx5-null animals and that they suffered from DNA oxidative attacks. Real-time PCR analysis of enzymatic scavengers expressed in the mouse epididymis indicated that the cauda epididymidis epithelium of Gpx5-null male mice mounted an antioxidant response to cope with an excess of ROS. These observations suggest that GPX5 is a potent antioxidant scavenger in the luminal compartment of the mouse cauda epididymidis that protects spermatozoa from oxidative injuries that could compromise their integrity and, consequently, embryo viability.
Authors
Eléonore Chabory, Christelle Damon, Alain Lenoir, Gary Kauselmann, Hedrun Kern, Branko Zevnik, Catherine Garrel, Fabrice Saez, Rémi Cadet, Joelle Henry-Berger, Michael Schoor, Ulrich Gottwald, Ursula Habenicht, Joël R. Drevet, Patrick Vernet
Imagine you are a spermatozoon. As an immature germ cell, you lived your life within the seminiferous tubules of the testes, in cytoplasmic communion with your brothers and sisters, nourished and nurtured by Sertoli cells (Figure 1). Then, just when you had completed the complexities of meiosis and your gene transcription machinery had closed down, you were forced to undergo one of the most dramatic morphological transformations in biology — the metamorphosis of a small, spherical haploid cell, the round spermatid, into the epitome of specialized cell types, the spermatozoon. Once created, you were then cast free from the germinal epithelium in a carefully regulated process known as spermiation. At this point in your life history you have, apart from a little too much cytoplasm around your waist, the outward appearance of a mature, functional spermatozoon. However, in reality, you are neither of these things. You may look like a spermatozoon, but you have none of the functional attributes of this cell; you cannot swim, cannot recognize the egg, and cannot engage in the complex array of cell-cell interactions that lead to fertilization. You have virtually no cytoplasm, no capacity for DNA repair, and little facility for apoptosis. And from now on, you are on your own.
Figure 1A simplified life history of mammalian spermatozoa. Male germ cells differentiate in the germinal epithelium, nourished and protected by the nurse cells of the testes, Sertoli cells. Spermatozoa emerge from meiosis as a syncytium of small round spermatids that, in the absence of de novo gene transcription, undergo one of the most dramatic transformations in biology, as they engage in a process known as spermiogenesis and transform into spermatozoa. Once spermiogenesis has been completed, spermatozoa leave the germinal epithelium structurally complete (apart from a cytoplasmic droplet in the sperm midpiece) but lacking in functional competence. The potential to express movement and fertilize the oocyte is acquired during epididymal transit. Spermatozoa are then stored in a quiescent state in the cauda epididymis, ready for ejaculation and subsequent capacitation in the female tract. As a result of capacitation, spermatozoa realize the range of functions acquired as a result of epididymal maturation, including (i) hyperactivated motility, (ii) zona recognition, (iii) the acrosome reaction, (iv) zona penetration, and (v) sperm-oocyte fusion. Throughout their maturation in the epididymis, the spermatozoa exist as isolated cells that are vulnerable to oxidative attack. Because they lack substantial intrinsic defense mechanisms, these cells are highly dependent on extracellular antioxidants released into the epididymal lumen. Prominent among the complex array of antioxidant enzymes present in epididymal plasma is Gpx5. In this issue of the JCI, Chabory et al. (7) report that deletion of Gpx5 in male mice generates a state of oxidative stress within the epididymis that becomes particularly marked with age and is associated with both miscarriage and developmental defects in the embryos. ZP, zona pellucida.
Spermatozoon functionality is acquired during two major phases of post-testicular maturation. The first phase involves passage through a complex, convoluted, regionally differentiated organ known as the epididymis (Figure 1). Within this organ, spermatozoa acquire the potential for progressive movement and fertilization. However, as long as they remain within the epididymal lumen, this potential is never realized. Instead, these cells are stored in a potentially functional but quiescent state, exhibiting little, if any, movement, until the moment of ejaculation. At this point spermatozoa suddenly explode into a state of vigorous progressive motility that allows these cells to begin their ascent of the female reproductive tract to the site of fertilization, high in the fallopian tubes. During this journey spermatozoa undergo the second phase of their maturation known as capacitation, which allows these cells to express the range of potential functions acquired during epididymal maturation. These functional attributes are illustrated in Figure 1 and include: (a) a specialized form of movement known as hyperactivation that facilitates the final stages of sperm transport and penetration of the zona pellucida, a thick shell surrounding the oocyte; (b) an exquisitely specific cell-cell recognition event that allows the spermatozoon to recognize a single cell, the oocyte, while ignoring the hundreds of thousands of other cells encountered on their journey through the female tract; (c) a secretory event, known as the acrosome reaction that releases enzymes to further facilitate zona penetration; (d) penetration of the zona matrix; and (e) remodeling of a specific region of the plasma membrane in the equatorial segment of the sperm head so that it will recognize, and fuse with, the surface of the oocyte (Figure 1).
Remarkably, the highly complex series of changes depicted in Figure 1 occur in a cell that is transcriptionally and translationally silent and driven entirely by posttranslational protein modifications. Furthermore, this maturation process involves a week or more of isolated existence for the spermatozoa as they transit the epididymis, followed by a further period of isolation in the female reproductive tract as the cells capacitate (a process by which the spermatozoon becomes capable of fertilizing an egg) and wait for an egg to arrive.
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