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1 Reproductive Biology and Genetics Group, Division of Reproductive and Child Health, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK, 2 Department of Physiology, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana, 3 School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK, 4 The Center of Reproductive Medicine, Peking University Third Hospital, Beijing 100083, China and 5 Assisted Conception Unit, Birmingham Women’s Hospital, Birmingham B15 2TG, UK
Correspondence should be addressed to C L R Barratt who is now at Division of Reproductive and Child Health, The Medical School, University of Birmingham, Room WX 1.30, West Wing, Birmingham B15 2TT, UK; Email: c.l.barratt{at}bham.ac.uk
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Epidemiological data show that 1:7 couples are classed as sub-fertile (Hull et al. 1985, Templeton et al. 1990). Sperm dysfunction is the single most common cause of infertility and affects approximately 1:15 men (HFEA 2005, www.hfea.gov.uk). Studies using semen assessment as the criteria for sub-fertility (sperm concentration < 20x106/ml) show that 1:5 18-year-olds are classed as sub-fertile (Andersen et al. 2000). This is a high proportion of the population compared with other prevalent diseases such as diabetes (2.8% of the population; Wild et al. 2004). Thus, male sub-fertility is a very significant global problem and, what is most worrying is that the recent reports suggest that its prevalence is increasing (Sharpe & Irvine 2004).
Improving and evaluating the diagnosis of male fertility, in particular, sperm dysfunction
There is an urgent requirement to develop new and robust tests of sperm function to accurately diagnose male infertility. The value of traditional semen parameters (concentration, motility and morphology) in the diagnosis and prognosis of male infertility has been debated for 60 years and, perhaps not surprisingly, the debate intensifies (see Bjorndahl & Barratt 2005 for detailed discussion). There are clear issues over concordance with standardized procedures (Holt 2005, Pacey 2006) with differences undoubtedly leading to uncritical reporting of results and thus precipitous decline in usefulness of the tests. A stark warning presents itself: if the professionals cannot successfully turn around the current low performance in the majority of Andrology laboratories, semen analysis will become undervalued and a redundant procedure. Unquestionably, even with appropriate quality assurance, traditional semen parameters can only provide a limited degree of prognostic and diagnostic information for the infertile couple (Tomlinson et al. 1999), primarily at the lower ranges of the spectrum (Comhaire 2000). The insanity that surrounds perceived absolute values, e.g. 5% ‘normal’ forms is just that – insanity. Continual discussion and generation of putative cut-off values will lead to further irrelevant and misleading information.
It is, therefore, necessary to develop simple, robust and effective tests of sperm function. Yet, despite the plethora of potential assays available, results have been very disappointing (Muller 2000, Aitken 2006). Recent data suggest that only three potential tests of sperm function have sufficient data to support their routine use: penetration into cervical mucus (or e.g. hyaluronate; Ivic et al. 2002), measurement of reactive oxygen species production/lipid peroxidation (Ford 2004, Williams & Ford 2005) and estimate of sperm chromatin/DNA damage (Seli & Sakkas 2005); however, promising initial data for the latter is now being questioned (see Bungum et al. 2004, Gandini et al. 2004, Erenpreiss et al. 2006, Makhlouf & Niederberger 2006).
After decades of research, the primary reason for the paucity of effective and robust estimate of sperm function is our limited basic understanding of the functioning of the spermatozoon (Ford 2001, Conner et al. 2007). Additionally, there has been inappropriate and uncritical use of the current tools (Barratt 1995, Tomlinson et al. 1999, Conner et al. 2007). However, there are a number of new developments which promise to transform our diagnostic and treatment pathways (for examples see Aitken 2006, Jimenez-Gonzalez et al. 2006, Publicover et al. 2007). Two of these are 1) development of at-home testing and 2) biomarkers for sperm function.
A new paradigm in male fertility diagnosis: the development of at-home testing
Many men find the production of a semen sample for infertility investigations an embarrassing, difficult and stressful experience. To add to this, there can be a significant waiting time for an initial appointment at the hospital and an additional time delay before the results are available. All these factors heighten the anxiety associated with infertility investigations, often delaying investigations and subsequent treatment and consequently reducing the chances of success (HFEA 2005, www.hfea.gov.uk). The development of an over-the-counter home sperm test, which would allow the patient to obtain an assessment of fertility potential at their own convenience in the comfort of their home, has a number of benefits including potentially increasing the number of men who are tested and speeding up the diagnosis.
Several putative tests are available but the primary questions regarding home sperm testing are accuracy and reliability. In our laboratories, we have concentrated on developing a test (Fertell; Bjorndahl et al. 2006) based on assessing the concentration of progressively motile sperm, which is one of the most predictive parameters for estimating natural fertility in both sub-fertile (review Tomlinson et al. 1999) and normal couples (Larsen et al. 2000, Zinaman et al. 2000; Fig. 1
). In addition, we wanted an assay that would provide an assessment of the functional capacity of the sperm as a small proportion of men with normal semen parameters (e.g. >10 million progressively motile sperm/ml semen) have dysfunctional sperm (see Barratt et al. 1989). Briefly, we mimicked penetration into human cervical mucus in vitro using hyaluronic acid, a known cervical mucus substitute for sperm function studies (Aitken et al. 1992). Our analysis show that the test is accurate (~95%) and patients find it easy to use (see Bjorndahl et al. 2006 for details).
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Biomarkers for sperm function
Events associated with sperm capacitation
After deposition in the female tract, mammalian sperm undergo a number of functional and structural changes termed ‘capacitation’, which render the cells competent to fertilize. Capacitation can also be induced in vitro by incubation, usually for some hours, in suitable medium. The most widely accepted functional definition of in vitro capacitation is acquisition of ability to undergo acrosome reaction in response to a biological agonist, such as zona pellucida or progesterone. Studies on sperm incubated under capacitating conditions have revealed numerous biochemical and physiological changes that accompany the process including an efflux of plasma membrane cholesterol, an increase in the activity of adenylate cyclase (both soluble and membrane localized), elevated levels of cAMP and protein kinase A (PKA) activity, a rise in intracellular pH, hyper-polarization of membrane potential and increased serine/ threonine and tyrosine phosphorylation of some proteins (Tash & Means 1983, Leclerc et al. 1996, Cross 1998, Osheroff et al. 1999, Lefièvre et al. 2002, Visconti et al. 2002, O’Flaherty et al. 2004, Fraser et al. 2005, Moseley et al. 2005). These observations provide useful indicators of the occurrence of capacitation in spermatozoa in vitro, but it is still far from clear how the various events relate to each other or whether all of them must occur for the acquisition of fertilization competence to occur. It is likely that sperm possess the ability to regulate the signalling pathways involved in capacitation, thus minimizing over-capacitation and premature acrosome reaction (Visconti et al. 2002, Ecroyd et al. 2004, De Jonge 2005, Fraser et al. 2005), but it is not clear to what extent the changes that have been observed in capacitating cells are reversible and whether they are capacitation endpoints or part of the capacitation process (such that reversal does not prevent subsequent induction of acrosome reaction).
We have recently demonstrated that upon transfer of cells from non-capacitating to capacitating media (CM), PKA activity, serine/threonine phosphorylation and [Ca2+]i-signalling ‘switch’ between minimum and maximum rapidly (as fast as detectable; Fig. 3; Bedu-Addo et al. 2005, Moseley et al. 2005). In contrast, the occurrence of tyrosine phosphorylation of tail proteins requires up to 3 h to reach its maximum. Progesterone-induced acrosome reaction also rises much more slowly, possibly because of the latency of tyrosine phosphorylation of head proteins (Fig. 3; Bedu-Addo et al. 2005). We have also shown that different CM vary strikingly in their efficacy as IVF fertilization media was shown to accelerate sperm capacitation where both tyrosine phosphorylation and acrosome reaction reached a maximum after only 90 min (Moseley et al. 2005). This effect did not seem to be associated with enhanced activation of PKA or increased levels of serine/threonine phosphorylation suggesting factor(s) acting through signalling pathways other than the well-characterized activation of soluble adenylyl cyclase/cAMP/PKA (Moseley et al. 2005). Moreover, we have also demonstrated that, in human spermatozoa, progesterone-induced [Ca2+]i signalling, protein serine/ threonine phosphorylation, protein tyrosine phosphorylation and progesterone-induced acrosome reaction are all reversibly regulated by the external environment (Fig. 3; Bedu-Addo et al. 2005). Human spermatozoa are therefore capable of repeated and reversible cycles of many of the events that occur in response to capacitating conditions and have a high degree of plasticity and adaptability in their responses to events which signal ovulation.
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There is little doubt that failure of capacitation is a cause of infertility in a subset of patients. However, the complexity of the process involved is such that it is not yet possible to identify a reliable marker of capacitated (competent to fertilize) sperm. The complexity of ‘capacitation’ may even be such that no single reliable marker exists.
Calcium oscillations in sperm – a new signalling system?
We have recently reviewed and discussed at length the exciting developments in calcium (Ca2+) signalling in the spermatozoon (Harper & Publicover 2005, Jimenez-Gonzalez et al. 2006, Publicover et al. 2007). We believe that sperm intracellular calcium ([Ca2+]i) oscillations are functionally significant, modulating flagellar activity in a way that promotes functional sperm motility changes (Harper & Publicover 2005). Intriguingly, the ability of cells to generate these complex [Ca2+]i signals does not seem to be noticeably related to capacitation. Perhaps, this should not be surprising. The prime marker of capacitation is acrosome reaction, and the Ca2+ store mobilization that occurs during oscillations raises [Ca2+]i in the neck and midpiece regions of the sperm and affects the flagellum but does not induce acrosome reaction (Harper et al. 2004, Bedu-Addo et al. 2007). Similarly, hyperactivation, though often associated with capacitation, can be induced separately and occurs by a separate, Ca2+-dependent, signalling pathway (Marquez & Suarez 2004). Our recent findings suggest that two factors, prior filling of the Ca2+ store in the sperm neck region and nitrosylation of sperm proteins, predispose the sperm to generate [Ca2+]i oscillations and consequent effects on flagellar activity. Thus, the ability of the sperm to generate complex Ca2+ signals is apparently regulated, but by mechanisms separate to those that underlie classical ‘capacitation’. Identification of features that are diagnostic of this regulation may provide a new way to identify sperm that are capable of generating complex patterns of flagellar activity and provide the first step to being able to manipulate these patterns using specific drugs.
The sperm proteome: the potential for new biomarkers of male fertility and a transformation in our understanding of the spermatozoon as a machine
The comprehensive and systematic identification and quantification of proteins expressed in cells and tissues are providing important and fascinating insights into the dynamics of cell function (Chu et al. 2006, Rifai et al. 2006). Yet, although spermatozoa are ideal to study from a proteomic perspective, until very recently, there have been relatively few studies examining the proteome of the spermatozoa (Ainsworth 2005, Conner et al. 2007). By virtue of the rudimentary technology available, initial human sperm proteomic studies were relatively crude. Many studies used antisperm antibody sera in an attempt to detect potential novel (and functional) sperm targets for male contraception. Unfortunately this rational approach met with limited success (Naaby-Hansen et al. 1997, Shetty et al. 1999, Shibahara et al. 2002; review in Conner et al. 2007). Perhaps surprisingly, recent studies employing more sophisticated proteomic profiling have similarly failed to identify interesting targets (Bhande & Naz 2007). It is likely that we need to redefine the nature of immunological infertility before this strategy will yield meaningful results. The more recent experiments have followed four main themes: (1) identification of proteins associated with specific events in sperm function, (2) examination of specific structures and associated signalling complexes, (3) whole proteome investigation and (4) comparison with normal versus abnormal (fertile versus sub-fertile).
Identification of proteins associated with specific events in sperm function.
It has been 12 years since the discovery of tyrosine phosphorylation as a putative marker of capacitation (Visconti et al. 1995a, 1995b; see above), but the role of these proteins and their sequence of activation is still very sketchy with the exception of only a small number of candidate proteins (see Naz & Rajesh 2004). Until recently, we were a long way from obtaining even a minimal ‘picture’ of events. However, several recent proteomic studies have provided a wealth of information which has the capacity to transform our potential understanding of protein changes associatedwith capacitation. For example, examining the phosphoproteome of human sperm during capacitation has provided some interesting novel targets. In addition to A-kinase-anchoring proteins (AKAPs; AKAP3 and AKAP4) and calcium-binding tyrosine-phosphorylation regulated protein, several other interesting proteins: heat shock protein 70 and 90
suggested as being involved in sperm egg interaction andvalosin-containing protein (VCP/p97) a member of the ATPases associated with various cellular activities were detected (Ficarro et al. 2003). Interestingly, tyrosine phosphorylation of VCP/p97 regulates its sub-cellular localization and its localization changes from the neck to the head after capacitation (Ficarro et al. 2003). Several other groups of proteins such as enzymes, structural proteins and channels were also identified. Moreover, with the pivotal role of tyrosine phosphorylation in sperm capacitation it is important to identify the kinases involved. Lalancette et al.(2006) used an affinity chromatography approach combined with proteomic analysis on the cytosolic fraction of bovine sperm to enrich tyrosine kinase activity. Tyrosine kinases from three families were identified: Src (Lyn), Csk and Tec (bmx, Btx). In addition, other important proteins involved in different cellular events associated with sperm, such as capacitation and acrosome reaction were also identified (a total of 126 proteins). These proteins include: actin polymerization, chaperones, proteases, proteases inhibitors, metabolism, vesicle transport/membrane fusion, signal transduction, sperm–egg interaction and structural proteins. Surprisingly, a number of sperm RNA binding/transport proteins were also identified. In view of the recent suggestions of the potential role of RNA in early embryo developed, these could be an important surreptitious finding (Miller et al. 2005).
Stein et al.(2006) performed a selected proteomic analysis of mouse sperm of the regions that are likely to be involved in mediating sperm–egg interactions. Sub-cellular fractionation included enrichment of acrosomal contents and plasma membrane. In the acrosomal contents, 166 proteins were identified and, as expected, two of the largest groups were enzymes and their inhibitors and secretory proteins. Twenty-five percent of the proteins were novel. Two hundred twenty-nine proteins were identified from the vesicle fraction and 171 from biotinylation fraction. Interestingly, a significant number of the biotinylated proteins were ion channels, most of which had unknown function.
Examination of specific structures and associated signalling complexes.
Nomura & Vacquier (2006) performed immunoprecipitation experiments for soluble adenylate cyclase (sAC) to determine the proteins associated with sAC in the sea urchin flagellum. Ten proteins were tightly associated with sAC including guanylyl cyclase and cGMP specific phosphodiesterase (PDE5A). This approach provides a critical starting point demonstrating the potential role in protein phosphorylation and ion channel activities in sperm motility.
There are a number of studies examining the proteomic composition of the 9+2 arrangement of the cilium. For example, Pazour et al.(2005) performed a proteomic analysis of Chlamydomonas reinhardtii flagella documenting the basic building blocks (for updates go to http://labs.umassmed.edu/chlamyfp/index.php). As the 9+2 structure is relatively conserved throughout evolution, you would expect a similar proteome across species. Yet, although there is remarkable conservation across the phyla, detailed proteomic studies on, for example, the flagella of trypanosomes show surprising diversity among the 300 or so proteins forming the axoneme (Broadhead et al. 2006). Interestingly, comparing the proteomes of Trypanosoma brucei with C. reinhardtii classified only 49 proteins to be common. 249 proteins were present but not in C. reinhardtii and 203 proteins present in C. reinhardtii but not in T. brucei. Further studies are required to determine the role of ‘organism specific elaborations’. Sperm proteomic techniques are still refining the composition of the axonemal structures, e.g. outer dynein arms (Hozumi et al. 2006). Such studies, used in comparisons across species, are likely to provide a detailed understanding of the basic molecular motor apparatus. For example, comparisons between mutants of Chlamydomonas can provide a powerful analysis of the defects present in the sperm of sub-fertile men and identify potential interactions of novel signalling complexes (see Zhang et al. 2004). Detailed imaging of the flagella motion (Ohmuro & Ishijima 2006) will allow a clear understanding of how the dynamics of the signalling complexes affect waveform. In addition to the studies on the axoneme, there is also data on the sperm accessory structures (fibrous sheath, outer dense fibres). For example, Cao et al.(2006) identified 50 proteins associated with these structures dramatically enhancing our knowledge of localization of both expected and unexpected complexes. This study confirmed that the fibrous sheath is a dynamic structure having a fundamental role in signalling, metabolism and oxidative stress. A proteomic study of the human fibrous sheath identified a unique ADP/ATP carrier protein and seven glycolytic enzymes previously unreported in the human fibrous sheath confirming that the fibrous sheath is a complex structure intimately involved in energy transduction (Kim et al. 2007). Such studies will lead to a new understanding of sperm metabolism and open exciting avenues for research potentially addressing ‘old’ questions such as the role of glucose in sperm energy metabolism (Ford 2006).
Whole proteome investigation.
So far, there are only two studies addressing the complete human sperm proteome (Johnston et al. 2005, Martinez-Heredia et al. 2006). Using a two-dimensional gel analysis followed by mass spectrometry, Martinez-Heredia et al.(2006) identified 98 different proteins. A significant number was associated with proteosome turnover providing further evidence for the existence of the proteosome in human sperm function (Sutovsky et al. 2004). Interestingly, the second most abundant group of proteins were those involved with transcription, protein synthesis and turnover and protein transport/folding. As the spermatozoon is supposed to be transcriptionally and translationally silent, this may reflect a role for sperm RNA in the egg (see above and Lalancette et al. 2006, Martinez-Heredia et al. 2006). Alternatively, the dogma that the sperm are translationally dormant may need to be reassessed in the light of recent preliminary evidence that they can both synthesize and turnover proteins (Gur & Breitbart 2006).
Johnston et al.(2005) adopted a direct one-dimensional SDS–PAGE approach with liquid chromatography tandem mass spectrometry performed on the various protein bands from detergent soluble and insoluble fractions of human spermatozoa. They identified 1760 proteins with high confidence – representing 76% of the proteins predicted to be in sperm. This represents the most comprehensive sperm proteome to date. Interestingly, the greatest number of proteins characterized was either novel proteins or proteins for which no ontology was available providing a wealth of new information. Of particular interest was the significant number of tissue-specific proteins as these could potentially be used as targets for male contraception. It is likely that a number of studies reporting/refining the whole-sperm proteome will become available in the next 12 months allowing a comprehensive first draft of the mature cell to be available. In addition to studies on the sperm proteome, a number of authors have examined the protein profile of seminal plasma. In the most comprehensive study to date, Pilch & Mann (2006) identified 923 proteins with high confidence. Not surprisingly, the most abundant proteins were those associated with involvement in clot formation, metabolism and protection of the sperm cell. Potentially, this dataset could be used for biomarker discovery for testicular cancer, prostate cancer and for male infertility. Once a subset of protein markers is available, it may be feasible to perform protein chip diagnoses as used for cancer (Ciordia et al. 2006).
Comparison with normal versus abnormal (fertile versus sub-fertile).
In our laboratory, we have been using proteomic strategies to identify defects in sperm function responsible for fertilization (Lefièvre et al. 2003, Pixton et al. 2004, reviewed Conner et al. 2007). Specifically, we are interested in identifying differences in sperm protein expression between control (fertile) men and patients with spermatozoa that failed to fertilize oocytes in vitro. Our initial studies showed, surprisingly, relatively little intra- and inter-donor variation and we have categorized one man (Pixton et al. 2004) where we identified 20 differences from the control that we are confident would represent true differences. Examination of five more men has found several consistent differences in protein expression levels (Conner et al. 2007) but further studies are required to determine if these differences relate to sperm function and where in the pathways these defects are manifested. Interestingly, with the clear need to identify (and improve) the fertility potential of animals in the agricultural industry, there is a concentration of effort to identify factors responsible for high fertility. For example, a study in bulls showed a significant effect of seminal plasma proteins on the function of the sperm, i.e. seminal plasma from high fertility bulls can act to improve the fertilizing potential of low-fertility bulls (Henault et al. 1995). Detailed proteomic studies of accessory gland fluids have shown consistent differences in high-/low-fertility groups, where four interesting proteins were identified: bovine seminal plasma 30 kDa (sperm capacitation), osteopontin (sperm-oolema interaction), phospholipase A2 (acrosome reaction) and spermadhesin Z13 (sperm motility) as contributing to the higher fertility (Moura et al. 2006, 2007a, 2007b). Examination of fertility in bulls is a very powerful approach as it allows in vitro studies to be complemented with data in vivo. Such complementary experiments cannot be performed in humans. The identification of proteins in the accessory glands of bulls contributing to fertility will allow a detailed understanding of how the sperm cell is modified by extrinsic factors.
How can all this detailed information be used to improve diagnosis and treatment of male infertility?
There has been a dramatic increase in our knowledge of the protein composition of the spermatozoon, its structures and the surrounding fluids (epididymal, vesicular, prostate) contributing to its function. Additionally, we have preliminary insight into the signalling complexes involved in key physiological processes, e.g. capacitation and the regulation of sperm motility. The difficulty is that this knowledge represents only but a starting point, somewhat analogous to knowing all the genes in the human genome but uncertain of their role and interactions. Detailed physiological experiments are required to fully understand the biological function of these proteins (and complexes) in the mature cell and its interaction with its functional environment – the female tract and human egg. The data generated by proteomic analysis is leading to a dramatic increase in our understanding (and by its nature re-evaluation) of sperm cell function. As the current methods to assess sperm function are inadequate, a key objective will be to develop more effective biomarkers as has been done in other diseases (reviewed in Rifai et al. 2006). For example, if we can successfully adopt redox proteomics to sperm then we may be better able to identify men who will benefit from antioxidant therapy. If we apply critical validation methods to evaluate these new biomarkers, we can expect a dramatic change in the way we diagnose male fertility.
In addition, knowledge of the cell proteome (combined with metabolomics) will allow us, for the first time, to be able to develop rational therapies for sperm dysfunction. Remarkably, although, male infertility is an important health issue, there are no drug treatments to enhance sperm function that have been shown to be effective in randomized controlled trials (Kamischke & Nieschlag 2002, cf. Greco et al. 2005). The only treatment option for the sub-fertile man is IVF/ICSI. ART is very expensive, invasive, has limited success, a number of side effects, is not widely available, and poses significant concerns about the long-term health of children (Maher 2005; review Hansen et al. 2005). This means that, put simply, as a result of our ignorance of the causes of sperm dysfunction, we are currently subjecting an increasing proportion of women to inappropriate invasive therapy in order to treat their partners. Hopefully, in the near future, perhaps using high throughput screening tools, we will be able to exploit our new knowledge base to develop and test new drug regimes for the enhancement of sperm function and avoid unnecessary ART treatment.
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