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REVIEW |
1 Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland2 Turku Center for Disease Modeling, TCDM, University of Turku, FIN-20520 Turku, Finland3 Department of Reproductive Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, UK
Correspondence should be addressed to M Poutanen; Email: matti.poutanen{at}utu.fi
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Abstract |
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Introduction |
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Epididymal sperm maturation |
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During epididymal transit, the spermatozoa also undergo a change in size, shape, and internal structure of the acrosome (Olson et al. 2002). In addition, the sperm cell membrane is under constant remodeling, with attachment and shedding of molecules in a sequential manner (for review, see Cuasnicu et al. 2002, Jones 2002). It has been postulated, that the factors involved in sperm–egg fusion are produced in the proximal epididymis, whereas proteins involved in the sperm–zona binding as well as the decapacitation factors are produced more distally (Cooper 1999).
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Methods for identifying putative epididymal target genes |
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Gene discovery and analysis in silico has become a powerful tool of modern biotechnology. Libraries of expressed sequence tags (ESTs) have been used successfully to identify genes expressed in the various epididymal segments of the mouse (Penttinen et al. 2003, Jalkanen et al. 2006a) The UniGene database (http://www.ncbi.nlm.nih.gov/unigene) is a collection of sequences of individual clones of the cDNA libraries of various tissues. These sequences are organized into clusters in such a way that each cluster contains ESTs that overlap in their sequence with at least one other EST of the cluster but not with ESTs of other clusters. Thus, each cluster is likely to contain sequence information of a single gene (Pontius et al. 2003). Among various species, the highest number of EST sequences is available for the human and mouse. The number of ESTs of a specific gene in the library is likely to predict the level of its expression. Furthermore, as EST libraries are available from various tissues, developmental, and diseases stages, the EST database also provides valuable information about the putative tissue distribution of gene expression. By using the digital differential display (DDD) tool at the NCBI (http://www.ncbi.nlm.nih.gov/UniGene/ddd.cgi) or on the TIGR database (http://www.jcvi.org/cms/research/software/) one can search genes present exclusively in the EST library of a certain tissue but not among EST libraries of other tissues. For example, DDD has been used recently to identify two novel members of the Cres subgroup of family two cystatins expressed in the mouse testis, epididymis, cerebrum, and pituitary (Xiang et al. 2008). Other useful databases for obtaining gene expression data from tissues of interest include SAGEmap (http://www.ncbi.nml.nih.gov/projects/SAGE/), GUDMAP (http://www.gudmap.org/), and GEO database (http://www.ncbi.nlm.nih.gov/geo/). The strategy used to identify and characterize novel epididymal proteins as putative targets for a male contraceptive is shown in Fig. 1.
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Functional characterization of novel genes |
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In addition to the GM mouse models, immunological techniques have been used to study the role of proteins in sperm–zona pellucida (ZP) binding in vivo. In this approach, the experimental animals are immunized against a protein specifically present on sperm surface, and the antibodies produced are used to block the sperm motility or ability of sperm to bind to the complementary sites of the oocyte. The epididymal genes with role in fertilization that have been studied using the immunological approach include cysteine-rich secretory protein 1 (Crisp1; Ellerman et al. 2008), carbonyl reductase P34H (Sullivan 2004), CD52 (also known as HE5; Koyama et al. 2007), and serine protease inhibitor-like, with Kunitz and whey acidic protein (WAP) domains 1 (Spinlw1, also known as Eppin; O'Rand et al. 2006).
An intriguing option to study the functions of epididymal genes is to apply in vivo electroporation. In that technique, a DNA construct is injected into the interstitium or lumen of the epididymis using electric pulses that are provided by electric tweezers. After a recovery period, tissue is analyzed. This method has been applied successfully in promoter analysis in vivo (Kirby et al. 2004), and in studying the Ets variant 4 (ETV4, also known as PEA3) transcription factor family and fibroblast growth factor receptor 1 (FGFR1) pathways (Yang et al. 2006). An apparent problem in identifying putative contraceptive drug targets is that many genes have important functions in a variety of different tissues which makes them unattractive drug targets. However, when a signaling pathway necessary for male fertility is identified, this technique in a combination with short hairpin RNA (shRNA) techniques could well provide an efficient strategy to screen epididymal pathway members that would be more suitable drug targets to be further validated in studies in GM animals.
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Putative epididymal target genes |
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The beta-defensin family
Beta-defensins belong to a large family (a total of 52 in the mouse) of small antimicrobial peptides. In mammals, beta-defensins are organized into four to five dense clusters on the genome (Patil et al. 2005), and the organization of the clusters is highly similar between the mouse, rat, dog, and human. Furthermore, almost all mouse beta-defensins have been reported to have a human homologue. Recent studies have revealed that many of the beta-defensins are mainly expressed in the male reproductive track, particularly in the epididymis and testis (Patil et al. 2005). In addition to antimicrobial and host defense activities, a role in sperm maturation has been suggested for them on the basis of the localization of several defensins on sperm surface (Liu et al. 2001, Rao et al. 2003). However, only the rat SPAG11e and macaque DEFB126 have been reported to be involved in reproductive function. The rat SPAG11e induces progressive sperm motility by increasing the uptake of calcium by spermatozoa (Zhou et al. 2004) and the macaque DEFB126 has been reported to be involved in sperm penetration through the cervical mucus (Tollner et al. 2008), and sperm-ZP recognition and binding (Tollner et al. 2004). However, more studies are needed to confirm the role of this gene family in sperm maturation.
Carbonyl reductase
Human carbonyl reductase P34H is a member of the short chain dehydrogenase/reductase superfamily, and it is expressed in the epididymis with the highest level in the corpus region. During the epididymal transit P34H progressively accumulates in the sperm acrosomal region (reviewed by Sullivan 2004). It has been suggested that P34H is involved in sperm-ZP binding. This is supported by the results indicating that immunization against P34H inhibits sperm-zona binding in vitro (Boué et al. 1994). Furthermore, the loss of P34H from sperm surface has been associated with idiopathic infertility in men (Boué & Sullivan 1996, Moskovtsev et al. 2007), and human spermatozoa lacking P34H have been shown to be unable to bind to the extracellular matrix of oocyte (Boué & Sullivan 1996). However, the usefulness of P34H as a contraceptive target should be critically considered owing to the wide tissue distribution (Felsted & Bachur 1980) of its expression and the general metabolic role of carbonyl reductases in converting various carbonyl compounds to corresponding alcohols (Wermuth 1981).
CD52 (also known as HE5)
Human CD52 is a small, highly glycosylated, glycosyl-phosphatidyl inositol (GPI) -anchored cell membrane glycopeptide expressed in the lymphocytes, distal epididymidis, and vas deferens. Detailed structural analysis of the CD52 protein in the lymphocytes and genital tract revealed that these two populations are distinct in the attached N-linked glycans and GPI-anchor domains (reviewed in Kirchhoff 2002). CD52 is incorporated into the sperm membrane with a GPI-anchor, but the function of this protein in sperm surface remains unknown. Antibodies directed against CD52 yielded in sperm immobilization and inhibition of zona binding when applied in IVF conditions (Mahony et al. 1991, Koyama et al. 2007), and further, antibodies against CD52 occur naturally in some women (Koyama et al. 2007), which leads to difficulties in conceiving. Disappointingly, it was recently shown that CD52 KO male mice are fully fertile both in vivo and in vitro (Yamaguchi et al. 2008). Whether this reflects a species difference between mouse and human remains to be solved.
Gpr64 (also known as HE6)
Gpr64 is an efferent duct and IS specific member of the LNB-7TM subfamily of G-protein coupled receptors (Osterhoff et al. 1997). Disruption of the gene in mice results in dysregulation of fluid reabsorption within the efferent ductules, leading to fluid accumulation in the testis, subsequent stasis of spermatozoa within the efferent ducts, and finally to infertility (Davies et al. 2004). Currently, Gpr64 is one of the most promising targets for a post-testicular male contraceptive. It remains to be assured that long-term inhibition of Gpr64 action does not lead to complete atrophy of the germinal epithelium due to fluid accumulation and back pressure in the testis. However, the studies so far carried out with the Gpr64 KO mouse model do not indicate such effects (Davies et al. 2004).
Proteases
The modification of sperm surface proteins is important for epididymal sperm maturation. These modifications lead to complete removal of proteins or redistribution of modified proteins in the sperm membranes. Examples of such proteolytically processed proteins include the germinal form of angiotensin I converting enzyme (gACE) and the disintegrin and metallopeptidase domain 2 (Adam2). gACE is released from the surface of spermatozoa during their transit through caput epididymidis, whereas Adam2 is degraded by two successive cleavages during the caput transit, leaving the protein to the post-acrosomal domain of spermatozoa (Gatti et al. 2004). Other sperm membrane proteins known to be modified during epididymal transit include sperm adhesion molecule 1 (Spam1, also known as PH-20 hyaluronidase), basigin (Bsg, also known as CE9, CD147, EMMPRIN, gp42, HT-7, neurothelin), and mannosidase 2 alpha B2 (Man2b2, also known as 
-D-mannosidase; Gatti et al. 2004). However, to date none of the protease(s) responsible for these modifications is known.
The ADAM family
One of the most studied proteinase families in the epididymis is the disintegrin and metalloprotease (ADAM) gene family, which currently contains about 40 members (http://people.virginia.edu/~jw7g/Table_of_the_ADAMs.html). The ADAM proteins are considered to have two distinct functions, while some of them act as cell adhesion molecules, and some act as proteases (Primakoff & Myles 2000). At least 16 ADAM family members are expressed in the testis, and the expression of five has been reported in the epididymis. Of the epididymal ADAM proteins, Adam7 is expressed uniformly in the all epididymal regions and it has been shown to bind to sperm surface, and to be redistributed in the sperm head during acrosome reaction (Oh et al. 2005). Furthermore, on the basis of Adam KO mouse models, it has been suggested that ADAM1a and ADAM2 form a protein complex, which in turn is involved in maintaining the stability of other sperm surface proteins including ADAM3 (Nishimura et al. 2004). Studies on the Adam2 and Adam3 KO spermatozoa led to the hypothesis that ADAM7 also associates with the ADAM1a/2-ADAM3 heterodimers on the sperm membrane. On the basis of these results, a putative role for ADAM7 in sperm – oocyte binding was suggested (Kim et al. 2006b). Furthermore, ADAM7 does not seem to contain the enzymatically active metalloprotease domain (Lin et al. 2001), and thus it probably acts only as a cell adhesion molecule.
The other epididymal ADAM family member, Adam28, is expressed in the IS and is regulated by testicular factors other than testosterone (Sipilä et al. 2006). There are two splice variants of Adam28 in the epididymis, a membrane bound and a secreted form. Unlike ADAM7, ADAM28 possesses an active metalloprotease domain, and is therefore, suggested to perform proteolytic functions within the epididymis (Jury et al. 1999). In conclusion, the putative role of these epididymal ADAM proteins in sperm maturation process and fertility is yet to be resolved.
KO mice are available for Adam1a (Nishimura et al. 2004) and -1b (also known as fertilin , Kim et al. 2006a), Adam2 (also known as fertilin β, Cho et al. 1998) and Adam3 (also known as cyritestin, Shamsadin et al. 1999, Nishimura et al. 2001). Interestingly, males of all these mouse models are infertile owing to either defects in the ability of sperm to migrate from the uterus into the oviduct (Adam1 and -2), and/or to defects in ZP binding (Adam2 and -3). These findings provide strong evidence for the importance of the ADAM family proteins for fertility.
Protease inhibitors
It has been reported that the loss of certain ADAM proteins from the sperm surface results in the concomitant disappearance of the other ADAMs (Nishimura et al. 2004, 2007). This suggests that the sperm surface architecture depends on correct localization of its components, and highlights the importance of the sequence of the proteolytic processing of the sperm surface in the epididymal duct. Proteolysis in the epididymal lumen thus needs to be well controlled, and several protease inhibitors expressed in the certain epididymal regions are expected to be responsible for this control. There are several protease inhibitor families present in the epididymis including cystatin (Cornwall & Hsia 2003), Kunitz (Richardson et al. 2001, Penttinen et al. 2003), Kazal (Moritz et al. 1991, Jalkanen et al. 2006b) and (WAP, (Jalkanen et al. 2006b), and serpin families (Laurell et al. 1992, Hu et al. 2002).
From the cystatin family of cysteine protease inhibitors, Cst8 (also known as Cres) and Cst12 (also known as Cres3) are expressed mainly in the epididymis (Cornwall & Hsia 2003), whereas Cst11 (also known as Cres2) has been reported to be epididymis-specific (Cornwall & Hsia 2003). Classical cystatins are potent cysteine protease inhibitors. However, studies in vitro have shown that Cst8 inhibits the serine protease (prohormone convertase 2) instead of cysteine proteases (Cornwall & Hsia 2003).
Kazal protease inhibitors also belong to the group of serine protease inhibitors, and they inhibit trypsin-, chymotrypsin-, and elastase-like proteases, including acrosin (for review, see Rawlings et al. 2004). Five members of the Kazal family have been detected in the epididymis, namely Spink2 (serine protease inhibitor, Kazal type 2; Moritz et al. 1991), Spink8, Spink10, Spink11, and Spink12 (Jalkanen et al. 2006b). Analyses of the testicular gene expression of azoospermic infertile men revealed that they were characterized by a 4.2-fold decrease in Spink2 (previously known as human acrosin-trypsin inhibitor HUSI-II) expression compared with fertile men (Rockett et al. 2004). Nevertheless, further studies are required to investigate the significance of this finding, as well as the functions of SPINKs in the epididymis.
The Kunitz protease inhibitors are a large protein family whose members are able to inhibit serine proteases (Pritchard & Dufton 1999). To our knowledge, Spint4 (Penttinen et al. 2003) is the only pure Kunitz protease inhibitor so far identified in the epididymis. In addition, there are some protease inhibitors with Kunitz and WAP domains present in the epididymis, those including serine protease inhibitor-like, with Kunitz and WAP domains 1 (Spinlw1, also known as Eppin) and (WAP)-type four sulfide core (WFDC) genes –8 and 10 (Jalkanen et al. 2006b, O'Rand et al. 2006). A role in male fertility has been suggested for Spinlw1, since active immunization against Spinlw1 resulted in reversible contraception in five out of nine male monkeys (O'Rand et al. 2004). Because Spinlw1 belongs to the large group of genes expressed both in the testis and epididymis, the role of the epididymal expression in the maintenance of fertility remains unclear. However, the data on Spinlw1 emphasize the role of protease inhibitors in male fertility.
The presence of several proteinase inhibitors from different families is consistent with the hypothesis that correctly timed epididymal proprotein processing is essential for proper sperm maturation. Furthermore, the fact that many of these enzymes have a human homologue, and are highly epididymis-specific (Table 2), indicates that they are putative targets for post-testicular male contraception.
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From epididymal genes to contraceptives |
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The presence of the blood-epididymis barrier (Cyr et al. 2002) presents a major challenge in delivering potential contraceptive drugs to the epididymis. Drug delivery through the blood-brain and blood-testis barriers have been studied in more detail, and solutions from those systems are expected to apply for the epididymis as well. For example, there are already potential contraceptive drugs (for example Miglustat, N-butyldeoxynojirimycin, NB-DNJ, Amory et al. 2007) that appear to traverse through the blood-testis barrier by passive diffusion. Another strategy to cross the blood-epididymis barrier could be the use of endogenous transport systems including glucose, amino acid carriers, and receptor-mediated transcytosis. For example, another putative non-hormonal contraceptive, Adjudin (1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide), was found to be unacceptable as a male contraceptive in humans owing to liver inflammation and muscle atrophy (Mruk et al. 2006). To circumvent the systemic side effects adjuvin was conjugated to a modified FSH mutant protein, which lacked hormonal activity but retained its receptor-binding ability (Mruk et al. 2006). Thus, the use of such shuttle molecules would enable both drug delivery through the blood-epididymis barrier as well as to target drug molecules to specific tissues/cells. However, possible epididymal shuttle molecules are yet to be discovered. Over the past few years, considerable effort has been put to developing nanoparticles loaded with liposomes for delivery of drugs into the brain. For example, doxorubicin bound to polysorbate-coated nanoparticles crosses the blood-brain barrier and results in better treatment response than doxorubicin alone (Steiniger et al. 2004). However, nanoparticles are given as injections, which is one of the least accepted contraceptive methods among men (Martin et al. 2000), and they have to be coated with suitable surfactant, which makes them expensive. These disadvantages are acceptable for cancer drugs, but not for contraceptives meant for every day use.
In addition to epididymal protein targets, there are several other aspects in epididymal functions that could serve as contraceptive targets. They have been reviewed recently by Cooper (2002) and will not be discussed in this review.
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Conclusions |
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Declaration of interest |
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Funding |
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Acknowledgements |
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Received March 20, 2008
First decision May 14, 2008
Revised manuscript received December 2, 2008
Accepted January 8, 2009
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Abstract
Introduction