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Reproductionresearch REPRODUCTIONRESEARCH b-Microseminoprotein in human spermatozoa and its potential role in male fertility N Anahı´ Franchi, Conrado Avendan˜o, Rosa I Molina1, Andrea D Tissera1, Cristina A Maldonado2, Sergio Oehninger 3 and Carlos E Coronel Laboratorio de Bioquı´mica y Biologı´a Reproductiva, Instituto de Ciencia y Tecnologı´a de Alimentos, Facultad de Ciencias Exactas, Fı´sicas y Naturales, Universidad Nacional de Co´rdoba, Co´rdoba 5000, Argentina, 1Laboratorio de Andrologı´a y Reproduccio´n (LAR), Co´rdoba 5000, Argentina, 2Centro de Microscopı´a Electro´nica, Facultad de Ciencias Me´dicas, Universidad Nacional de Co´rdoba, Co´rdoba 5000, Argentina and 3Department of Obstetrics and Gynecology, Eastern Virginia Medical School, The Jones Institute for Reproductive Medicine, Norfolk, Virginia 23507, USA Correspondence should be addressed to N A Franchi; Email: [email protected] Abstract b-Microseminoprotein (MSMB) is one of the most abundant proteins in human seminal plasma. The objectives of this study were: (1) to purify MSMB from seminal plasma (SP) and generate antibodies against the pure protein; (2) to investigate the interaction of MSMB with ejaculated spermatozoa and its possible effect on the spontaneous acrosome reaction (AR); and (3) to quantify MSMB content in SP and examine its relationship with the clinical sperm parameters. MSMB was purified from SP and its presence on the sperm surface was examined by indirect immunofluorescence using a specific polyclonal antibody. The effect of MSMB on the AR was evaluated using guinea pig epididymal spermatozoa as a model. MSMB quantification assay was performed with a two-site binding ELISA using two polyclonal antibodies against MSMB. MSMB was assessed in semen samples from fertile donors (controls) and subfertile patients according to World Health Organization criteria. MSMB was detected on the sperm surface and mainly localized to the acrosomal region of the head and neck. A significant spontaneous AR inhibition was observed when guinea pig epididymal spermatozoa were preincubated with MSMB. Finally, MSMB was significantly increased in subfertile patientswhen compared with fertile controls (P!0.02). The association of MSMB to the sperm surface, the inhibitoreffectonthe spontaneous ARand the increased MSMB levels found inSPin subfertilemen suggestsa relationshipbetween this protein and semen quality and a possible role in the process of fertilization. Reproduction (2008) 136 157–166 Introduction an immunoglobulin binding factor (Kamada et al.1998) and/or tumor marker for prostate cancer (Sakai et al.1999), b-Microseminoprotein (MSMB), also called prostatic the biological function of MSMB in the male or female secretory protein 94 (PSP94), is one of the most abundant reproductive tract is still unknown. proteins in the secretions produced by the human prostate. Semen evaluation for human male infertility and Originally, MSMB was isolated from human seminal assisted reproduction relies on conventional measures plasma (SP) (Akiyama et al.1985) but has subsequently been identified in several different species, including of light microscopic evaluation of sperm count, baboon (Xuan et al.1997), rhesus monkey (Nolet et al. morphology, and motility (WHO 1999), and provides 1991), rat (Fernlund et al.1996), pig (Fernlund et al. 1994), useful, yet somewhat limited, clinical information in and mouse (Xuan et al.1999). MSMB is a cysteine-rich couples seeking infertility treatment. The semen analysis, nonglycosylated protein with an apparent molecular upon which the diagnosis of male factor infertility is mass of 15 kDa as determined by SDS-PAGE. The human based, is highly subjective (Amann 1989, Coetzee et al. gene for MSMB has been cloned and mapped to 1999). Few objective methods for infertility diagnostic chromosome 10 (q11.2) and there are three glucocorticoid and fertility prediction are currently available, some of response elements and one estrogen response element them based on the detection of DNA damage (Henkel in the promoter region of the first intron. These findings 2007). The correlation between clinical semen para- suggest that the gene may be regulated by hormones meters and fertility is moderate to low (Guzick et al. (Nolet et al.1991, Ochiai et al.1995)asalsoreportedinrat 2001). For instance, sperm with intrinsic defects may lateral prostate (Kwong et al.2000). Although putative appear morphologically normal upon light microscopic biological/clinical roles have been suggested, i.e., acting as evaluation (Nikolettos et al. 1999) and there is substantial q 2008 Society for Reproduction and Fertility DOI: 10.1530/REP-08-0032 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 10/01/2021 07:57:31AM via free access 158 N A Franchi and others inter-laboratory variability in both subjective and auto- mated morphological semen analyses (Neuwinger et al. 1990, Jorgensen et al. 1997, Coetzee et al. 1999). Therefore, additional objective techniques for semen evaluation, not based on conventional measures of semen parameters, are sought (Amann 1989, Douglas-Hamilton 1995, Krause 1995). In this respect, the characterization of semen proteins interacting with the spermatozoa may be criticalin ordertounderstand their relationship with semen quality and sperm functional competence. The aims of the present study were: (1) to purify MSMB protein and to develop specific antibodies against MSMB; (2) to investi- gatewhether MSMB binds tothe human sperm surface on a Figure 1 MSMB protein purified from human seminal plasma and specific manner and to characterize its localization; (3) to MSMB antibody specificity. (A) MSMB purified to homogeneity. generate and characterize an antibody system to develop a Seminal plasma proteins were subjected to SDS-PAGE followed by two-site binding ELISA for MSMB quantification; and (4) to immunoblotting with rabbit anti-MSMB antibody. (B) Coomassie analyze whether the quantity of the antigenic MSMB is Brilliant Blue staining. (C) Immunoblotting with rabbit anti-MSMB. related to fertility. For these purposes, we compared the MWS, molecular weight standards; HSP, human seminal plasma level of MSMB in SP from proved fertile men and from proteins; MSMB, pure MSMB protein. subfertile patients. the IgG fraction by affinity chromatography in a protein Results A-Sepharose column. Purified rabbit IgG were used as capture antibody in the ELISA assay. Rat anti-MSMB was Protein purification and antibodies characterization used as a detection antibody. MSMB was purified from human SP using salt precipi- tation and a combination of chromatographic methods. MSMB immunolocalization on sperm surface After the first step of solid ammonium sulfate precipi- tation (35% saturation), the protein was found in the To evaluate the presence of MSMB binding sites on the supernatant. This material was brought to 70% satu- sperm surface, ejaculated spermatozoa were examined ration, and the protein was present in the precipitate, by indirect immunofluorescence (IIF) using the rabbit which was used as the starting material in the following monospecific polyclonal antibody anti-MSMB. Freshly chromatographic steps. Two rounds of gel filtration ejaculated sperm showed different fluorescence chromatography were used and the fractions containing patterns. As shown in Fig. 2A and B, in most of the MSMB were pooled and loaded onto an anion sperm cells the immunostaining was localized to the interchange column, where the elution was carried out anterior region of the head, indicating MSMB binding applying a continuous NaCl gradient from 0 to 0.5 M sites on the acrosomal region. In a few cases, staining in buffer 25 mM Tris–HCl (pH 7.6). In order to achieve was localized to the equatorial region and neck (Fig. 2C). homogeneity, the fractions containing MSMB were No immunofluorescence was observed when rabbit subjected to a high performance liquid chromato- nonimmune serum was used or the first antibody was graphy (HPLC) step in an Ultraspherogel Sec 2000 avoided. column (0.75!30 cm). MSMB purity was assessed by Samples from the same set of experiments were SDS-PAGE (Fig. 1A). submitted to ultrastructural immunocytochemistry using Polyclonal antibodies against MSMB were generated protein-A colloidal gold complex and then examined by in rabbit and rat by inoculation of pure MSMB as electron microscopy. Different spermatozoa fixed described in the Materials and Methods section. In order immediately after collection showed gold labeling to determine the antibodies specificity, Western corresponding to MSMB in the plasma membrane on immunoblot analysis of human SP proteins was the sperm head (Fig. 3). These results confirmed MSMB performed using rabbit and rat anti-MSMB antiserum as localization observed by immunofluorescence. a primary antibody. Among the protein components of Since MSMB has specific binding sites on the sperm SP, rabbit antiserum reacted only with a 15 kDa band, surface, we investigated whether MSMB could affect corresponding to MSMB protein, showing the mono- some of the processes that sperm undergo after the specificity of the anti-MSMB antibody (Fig. 1B and C). ejaculation and before fertilizing the egg. While the A similar result was obtained with the rat anti-MSMB. ejaculated spermatozoa have MSMB already bound in Thereafter, we used the rabbit anti-MSMB antiserum for their surface, we examined an animal model in order to the immunodetection of MSMB on sperm surface. obtain epididymal spermatozoa to assay the binding of A fraction
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