Hum. Reprod. Advance Access originally published online on February 27, 2008
Human Reproduction 2008 23(6):1240-1241; doi:10.1093/humrep/den019
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The human sperm proteome: the potential for new biomarkers of male fertility and a transformation in our understanding of the spermatozoon as a machine
Commentary on the article ‘Identification of proteomic differences in asthenozoospermic sperm samples’ by Martinez et al.
Reproductive and Developmental Biology, Division of Maternal and Child Health Sciences, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, Scotland
Correspondence address. Tel: +44-1382-740170; Fax: +44-1382-425554; E-mail: c.barratt{at}dundee.ac.uk
The comprehensive and systematic identification and quantification of proteins expressed in cells and tissues are providing fascinating insights into the dynamics of cell function in a plethora of areas, for example, cancer—the blood peptidome (Petricoin et al., 2006
). With no physiologically active transcription and translation, spermatozoa are ideal cells to study from a proteomic perspective. As such, proteomics has the potential to transform our understanding of the workings of the mature cell. Such a leap in knowledge is necessary as spermatozoa are very specialized cells that have jettisoned superfluous machinery, and thus, applying our knowledge from what happens in other cells is of limited value. Following a slow start, rapid progress is now being made (Lefièvre et al., 2007a) and the study by Oliva and colleagues in this issue of the journal (Martínez-Heredia et al., 2008) complements these developments allowing, for example, the development of putative new biomarkers in diagnostic andrology. So what now needs to be done and how can all this information be utilized?
The first essential step is to determine the complete sperm toolkit—the human sperm proteome. Several studies have provided preliminary information (Johnston et al. 2005, Baker et al., 2007), with the latter identifying 1053 proteins with some notable discoveries e.g. NADPH oxidase. Although there are likely to be many more proteins to be discovered, particularly those associated with the insoluble fraction, this is an essential and impressive starting point. A number of reports refining the whole sperm proteome e.g. tail proteins, membrane proteins, will be available in the next 12 months allowing a comprehensive first draft of the mature cell. This will complement studies on the protein profile of seminal plasma (Pilch and Mann, 2006) and allow an insight into the proteome of the complete human ejaculate. Using this as a comparison to the proteome of other species e.g. Drosophila (Dorus et al., 2006) will answer fundamental questions such as: what is the basic machinery necessary to make a functionally mature male gamete? Secondly, there is the opportunity of examining key dynamic processes involving post translational protein modifications (PTM), e.g. capacitation, about which we know relatively little. Although the key pathways in sperm capacitation—the identification of the kinases (Lalancette et al., 2006)—are just emerging, there has been relatively little information, since the seminal work of Visconti and colleagues, as to the identity and dynamics of protein phosphorylation during human sperm capacitation (Ficarro et al., 2003). This is likely to dramatically change with a more comprehensive and robust documentation of the dynamic protein modifications becoming available in the very near future. Such studies will not be confined to phosphorylation, as the first draft of the human sperm S-nitroso proteome is now available, with over 240 proteins undergoing PTM (S nitrosylation) in response to agonist (nitric oxide) stimulation (Lefièvre et al., 2007b).
Thirdly, we will be able to have a comprehensive and non-biased comparison between the normal spermatozoon and abnormal/dysfunctional cells. Previous case reports represent the tip of the iceberg, and more detailed studies are now appearing. For example, Zhao and colleagues (Zhao et al., 2007) compared 8 men with asthenozoospermia to controls. In this study, 17 proteins were either increased or decreased compared to normal, 10 of which were identified. Half of the differences were in enzymes associated with sperm metabolism. Whilst these are preliminary studies they highlight the potential power of this approach and combined with detailed functional studies this will accelerate (i) putative biomarkers to be identified, as has been the case in other diseases (Rifai et al., 2006), and (ii) provide a clearer understanding into the nature of the pathology. It is these arenas that the study of Oliva and colleagues is important as they provide preliminary evidence of differences in the protein profiles between men with asthenozoospermia (Martínez-Heredia et al., 2008). However, it is essential that we use critical validation methods to evaluate these new tools (Bossuyt et al., 2006) if we are to correctly determine where in the pathways putative new biomarkers appropriately fit.
Using the information from the above, a fourth area that is likely to receive a dramatic boost is the development and assessment of novel therapeutic drugs that will enhance sperm function when applied either in vivo or in vitro. To date, there is minimal preliminary data but proteomics is likely to lead to a number of novel receptors (and pathway interactions) being identified and thus the screening of drugs to improve sperm function can begin in earnest. There is an absolute and urgent requirement to develop rational therapies for sperm dysfunction. Initial promising data is often not repeated in larger data sets and consistently, authors who review this subject, e.g. use of carnitines, conclude that large comprehensive ‘well designed studies are necessary’ (e.g. Agarwal and Said, 2004). Currently, the only realistic treatment option for the sub-fertile man with sperm dysfunction is IVF/ICSI. This is expensive, invasive, of limited success [overwhelming majority of EU countries having deliveries/cycle <25% - (Andersen et al., 2007)] and not widely available.
Currently, andrology is immersed in a very exciting phase with significant developments presenting themselves with increasing frequency, e.g. the role of RNAs. Proteomics can now be added to this list. As long as we learn our lessons from the past and critically evaluate these new opportunities we will produce more effective biomarkers and non-invasive therapeutic regimes.
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Submitted on January 10, 2008; accepted on January 11, 2008.
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