Mol. Hum. Reprod. Advance Access originally published online on May 18, 2008
Molecular Human Reproduction 2008 14(7):387-391; doi:10.1093/molehr/gan031
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RANTES and human sperm fertilizing ability: effect on acrosome reaction and sperm/oocyte fusion
1Andrologic Unit, Department of Internal Medicine, University of L’Aquila, Blocco 11, Coppito 67100, Coppito, L’Aquila, Italy 2Department of Basic and Applied Biology, University of L’Aquila, Blocco 11, Coppito 67100, Coppito, L’Aquila, Italy
3 Correspondence address: Tel: +39-0862-368338; Fax: +39-0862-368342; E-mail: sandrof{at}univaq.it
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Abstract |
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β-Chemokine, regulated on activation and normally T-cell expressed and presumably secreted (RANTES), is present in both the male and female genital tract fluids where its levels increase in diseases related to infertility, such as endometriosis and male genital tract infections. β-Chemokine receptors (CCR3 and CCR5) are expressed on freshly ejaculated human sperm cells and a sperm chemoattractant effect for RANTES has been reported. No information exists on other possible roles of RANTES on sperm functions involved in the fertilization process. In the present study, the exposure of sperm suspensions to high concentrations of the chemokine, comparable to those observed in inflammatory diseases, significantly decreased the stimulatory effect exerted by progesterone on sperm/oocyte fusion, evaluated by means of the hamster egg penetration test. Accordingly, a large proportion of spermatozoa preincubated under capacitating conditions with high concentrations of RANTES underwent a premature acrosome reaction (AR) that prevented subsequent progesterone-induced AR. Finally, sperm samples exposed to the same high levels of chemokine showed a significant increase in the intracellular levels of cAMP, which is involved in capacitation and AR dynamics. These results indicate a negative interference of high levels of RANTES on the sperm fertilizing ability, thereby suggesting a potential contribution of this chemokine to subfertility associated with endometriosis and genital tract inflammatory diseases.
Key words: RANTES/fertilization/human spermatozoa/acrosome reaction/sperm/oocyte fusion
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Introduction |
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Chemokines are a large superfamily of molecules with physiological and pathological chemotactic activity for a specific leukocyte subset. These molecules are classified in subfamilies based on the relative position of their cysteine (Cys) residues: in the β-chemokine structure, the first two Cys residues are continuous (CCs). β-Chemokine regulated on activation and normally T-cell expressed and presumably secreted (RANTES) is a 68-aminoacid peptide (Nelson et al., 1993) of 8 kDa (Schall et al., 1990), which binds the CC-chemokine receptors (CCR) 1, 3 and 5 (Wells et al., 1992). CCR5 is the main HIV-1 co-receptor (Berger, 1997; Dragic, 2001), whereas CCR3 is described to facilitate infection by a subset of primary HIV-1 (Choe et al., 1996; He et al., 1997). RANTES, mainly produced by activated T lymphocytes, is a selective and very potent eosinophil, monocyte, macrophage and T-lymphocyte chemoattractant both in vitro and in vivo (Schall et al., 1990; Alam et al., 1993).
The chemokine RANTES is present in seminal plasma (Naz and Leslie, 2000; Penna et al., 2007; Politch et al., 2007), uterine (Hornung et al., 1997), peritoneal (Khorram et al., 1993; Hornung et al., 2001) and follicular fluid, where its physiological concentration has been reported to be 
200 pg/ml (Karstrom-Encrantz et al., 1998; Machelon et al., 2000; Xu et al., 2006). Therefore, human spermatozoa are exposed to RANTES in both the male and female genital tract before they reach the site of fertilization.
The level of RANTES in the genital tract fluid is elevated in diseases related to subfertility (Khorram et al., 1993; Hornung et al., 2001; Xu et al., 2006; Penna et al., 2007). Levels of the chemokine as high as 10 ng/ml have been reported in peritoneal fluid from women affected by endometriosis, and they correlated with the severity of the disease (Khorram et al., 1993). Increased levels of RANTES (as high as 5 ng/ml) were also observed in seminal plasma from patients with chronic prostatitis/chronic pelvic pain syndrome or benign prostatic hyperplasia (Penna et al., 2007).
Interestingly, human spermatozoa contain mRNA coding for RANTES receptors CCR1 and CCR5 (Isobe et al., 2002; Januchowski et al., 2004) and express CCR3 and CCR5 protein (Muciaccia et al., 2005a,b). Therefore, during their transit through the female genital tract, spermatozoa could be responsive to RANTES, and a possible role of this chemokine in the modulation of sperm functions has been hypothesized.
Mammalian spermatozoa must undergo a series of biochemical and functional changes called capacitation before they can fertilize oocytes (Yanagimachi, 1994). The cascade of controlled physiological events occurring during capacitation confers to spermatozoa the ability to gain hyperactive motility, adhere to the zona pellucida, respond to physiological inducers of acrosome reaction (AR) and initiate oocyte fusion (Yanagimachi, 1994). A key role of the female genital tract microenvironment is to support and regulate this process, but the nature of the complex and dynamic signalling between female reproductive tract, oocyte and spermatozoon remains poorly defined. Furthermore, cellular factors and chemical mediators, abnormally secreted into the female genital tract in pathological conditions, could affect the capacitation-dependent acquisition of the sperm fertilizing ability. An effect of RANTES on human sperm chemotaxis has been recently reported (Isobe et al., 2002), but no information exists on other possible effects on sperm fertilizing ability exerted by this chemokine, either in physiological or in abnormally high concentrations revealed in pathological conditions. The aim of the present study was to evaluate the possible effects of increasing levels of RANTES on the capacitation-dependent acquisition of sperm fertilizing ability.
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The study was approved by the Ethic Committee of the Azienda Sanitaria Locale no. 4 of L’Aquila.
Chemicals
Recombinant human RANTES was purchased from R&D Systems (Minneapolis, MN, USA). All the other reagents were purchased from Sigma Chemical Co. (St Louis, MO, USA). Progesterone was prepared daily as stock solutions in dimethyl sulfoxide (DMSO) and was diluted in Biggers, Whitten and Whittingham (BWW) medium to obtain the working concentrations before use.
Sperm processing
Semen samples were collected according to the World Health Organization (WHO)-recommended procedure (WHO, 1999) by masturbation, from healthy normozoospermic donors. All samples were produced into sterile containers and left for at least 30 min to liquefy before processing. Motile sperm suspensions were obtained by swim-up procedure. Briefly, spermatozoa were washed twice (700xg for 7 min) in BWW medium containing 0.1% human serum albumin (HSA), fraction V, no. 1653. After the second centrifugation, supernatants were removed by aspiration, leaving 0.5 ml on the pellet, and, after an incubation time of 30 min, supernatants, containing highly concentrated motile sperm, were carefully aspirated. Capacitated suspensions were obtained by incubation of motile spermatozoa in BWW with the addition of 1% HSA, fraction V, no. 1653, at 37°C in an atmosphere of 5% CO2/95% air.
Hamster egg penetration test
The effect of RANTES on sperm/oocyte fusion was evaluated by means of the progesterone-enhanced hamster egg penetration test (HEPT), performed as previously described (Barbonetti et al., 2006). Briefly, motile sperm suspensions were divided into aliquots before capacitation, and exposed to scalar concentrations (0.2, 1 and 10 ng/ml) of RANTES or to BWW as control. At the end of 5 h capacitation, sperm suspensions were exposed to progesterone (5 µM) or to proper dilution (1:2000) of DMSO, as control, for 15 min before a 3 h coincubation with oocytes. Spermatozoa were washed before the incubation with oocytes, in order to exclude a possible direct effect of reagents on oocytes.
Standard procedures were utilized for the recruitment of hamster oocytes (WHO, 1999). A total of 10–15 zona-free oocytes were added to each droplet of 100 µl containing 0.7 x 106 motile spermatozoa. After 3 h coincubation at 37°C in an atmosphere of 5% CO2/95% air, oocytes were recovered from the droplets, washed free of loosely adherent spermatozoa and coloured with SYBR 14 (1:500). SYBR 14 is a nuclear membrane permeant, DNA-specific fluorochrome. It stains nuclei of living spermatozoa fluorescing bright green. Ova were examined for evidence of swollen sperm heads, as the criterion of sperm penetration, under a microscope equipped with epifluorescence (Leica DMLB, Wetzlar, Germany). The number of spermatozoa penetrating each oocyte was assessed and expressed as total number of penetrations/total number of oocytes (Penetration Index, PI).
AR assessment
A set of experiments was carried out in order to evaluate the effect of RANTES on spontaneous and progesterone-induced ARs. Motile sperm suspensions were divided into aliquots and exposed to scalar concentrations (0.2, 1 and 10 ng/ml) of RANTES or to BWW as control. After a 5 h incubation in capacitating conditions, sperm suspensions were divided into two aliquots each containing 0.7 x 106 motile spermatozoa: an aliquot was exposed to progesterone (15 µM) and the other one to a proper dilution of DMSO for 30 min. Sperm suspensions were centrifuged and then resuspended in hypo-osmotic solution for 1 h according to Aitken et al. (1993). After centrifugation spermatozoa were smeared, fixed in methanol, incubated with fluoresceinated Pisum sativum agglutinin at 100 µg/ml in phosphate-buffered saline for 2 h, washed and observed under a fluorescent microscope (Leica DMLB, Wetzlar, Germany). At least 200 spermatozoa were counted in each smear, and the percentage of spermatozoa not uniformly fluorescing at the anterior region of the head (reacted spermatozoa) was evaluated. According to Aitken et al. (1993), only curly-tailed spermatozoa were considered viable and thus scored as true ARs. The true progesterone-induced AR rate was calculated by subtracting the true AR rate observed in samples non-exposed to progesterone (spontaneous AR rate) from the true AR rate observed in samples exposed to progesterone.
Cyclic AMP measurement
Motile sperm suspensions were divided into aliquots containing at least 10 x 106 spermatozoa and were incubated in the absence or in the presence of increasing concentrations (0.2, 1 and 10 ng/ml) of RANTES under capacitating conditions. After 5 h incubation, spermatozoa were separated from the medium by centrifugation at 3000xg for 10 min and the pellets were homogenized in 0.1 M HCl. The homogenates were centrifuged at 10 000xg at room temperature for 30 min, and the supernatants were acetylated before determining the cAMP concentrations according to the instructions of the commercial kit manufacturer (Direct EIA kit, Assay Designs, Inc. Ann Arbor, MI, USA). cAMP levels were calculated in femtomole of cAMP per 106 spermatozoa.
Computer-aided semen analysis
Motility exhibited by sperm suspensions incubated for 5 h in the absence or in the presence of scalar concentrations of RANTES was evaluated with computer-aided semen analysis (CASA), using ATS20 (JCD, Gauville, France). Determinations were performed on the same sperm suspensions used to evaluate the dose–response effect of RANTES on the progesterone-enhanced HEPT in four different settings. All analyses were performed at 37°C.
Statistical analysis
Statistical analysis was performed by the SAS statistical software (version 9.1, 2003; SAS Institute, Inc., Cary, NC, USA). The HEPT results were subjected to the two-way analysis of variance to separate replicate from treatment variations (general linear model procedure, PROC GLM). Data from CASA, AR assessment and cAMP measurement were analysed by ANOVA. Post hoc comparisons between pairs of groups were performed by the Tukey’s studentized range—honestly significant difference—test and statistical significance was accepted when P 
0.05. Results were expressed as mean ± SEM.
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Effects of RANTES on HEPT
The brief exposure of capacitated human spermatozoa to progesterone (5 µM) exerted, as expected, a stimulatory effect on the sperm/oocyte fusion (PI = 6.0 ± 0.4 versus 1.0 ± 0.2; P < 0.05) (Fig. 1).
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Low concentrations of RANTES (0.2 ng/ml), added to the sperm samples from the onset of capacitation, did not produce any significant interference on the progesterone-stimulated sperm/oocyte fusion (PI = 4.9 ± 0.5, Fig. 1). Conversely, the exposure of sperm suspensions to 1 ng/ml RANTES produced a significant reduction of the progesterone-stimulated PI (PI = 2.8 ± 0.6; P < 0.05); this inhibitory effect was similar to that produced by higher levels (10 ng/ml) of the chemokine (PI = 2.7 ± 0.5, Fig. 1). No change in the percentage of motile spermatozoa, as well as in the quality of motility, evaluated with CASA, was observed with any treatment (Fig. 1).
Effect of RANTES on AR
A low concentration (0.2 ng/ml) of RANTES did not exert a significant effect on the spontaneous AR rate (13 ± 2.2 versus 11 ± 0.9% observed in controls; Fig. 2). Conversely, a significantly higher incidence (2-fold) of spontaneous AR was observed in the presence of 1 ng/ml RANTES (25 ± 1.9%; P < 0.05, Fig. 2). A similar effect was produced by higher levels (10 ng/ml) of the chemokine (26 ± 1.9%; P < 0.05, Fig. 2). When the progesterone-induced AR rate was evaluated, the increase of the AR rate above the spontaneous rate was significantly lower in spermatozoa exposed to high levels (1 and 10 ng/ml) of RANTES (8 ± 0.7 and 9 ± 1%, respectively) than in controls and in those exposed to low level (0.2 ng/ml) of RANTES (21 ± 1.4 and 20 ± 1.6%, respectively; P < 0.05, Fig. 2).
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Effect of exposure to RANTES on intracellular cAMP levels during capacitation
In cell types different from spermatozoa, RANTES is involved in the regulation of adenylate cyclase activity by means of CCRs-dependent signalling pathways (Zhao et al., 1998; Zhang et al., 2003), and cAMP plays pivotal roles in molecular events leading to mammalian capacitation (Visconti et al., 1995; Leclerc et al., 1996; De Jonge, 2005) and AR (De Jonge et al., 1991; Anderson et al., 1992; Doherty et al., 1995). This prompted us to measure cAMP in spermatozoa capacitated for 5 h in the presence of scalar concentrations of RANTES to analyse the potential involvement of this secondary messenger in the observed effects of the chemokine on the AR.
As evaluated in three independent duplicate experiments, the exposure of spermatozoa to low concentrations of RANTES (0.2 ng/ml) produced only a slight, not significant increase in the intracellular cAMP levels during capacitation with respect to control (180 ± 20 versus 110 ± 26.4 fmol/106 spermatozoa; P > 0.05, Fig. 3). The treatment of spermatozoa with high concentrations of RANTES (1 and 10 ng/ml) produced a significant (2.5-fold) increase in intracellular cAMP levels with respect to control samples: values from samples exposed to 1 and 10 ng/ml RANTES were 286.6 ± 13.4 and 276.6 ± 30.3 fmol/106 spermatozoa (P < 0.05), respectively (Fig. 3).
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Discussion |
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The female genital tract microenvironment exerts a key role in supporting and regulating the capacitation process, which makes mammalian spermatozoa able to fertilize oocytes. However, the signalling mechanisms of the complex interaction between female reproductive tract, oocyte and spermatozoon are still largely unknown. Furthermore, the acquisition of sperm fertilizing ability during capacitation could be hindered by the abnormal secretion of chemical mediators into the female genital tract in pathological conditions.
We investigated the effect of RANTES on sperm/oocyte fusion, a relevant biological endpoint of the fertilization process, evaluated with the progesterone-enhanced HEPT. In proximity to oocyte, capacitated spermatozoa are exposed to progesterone, a well-characterized physiological inducer of AR (Baldi et al., 1991; Meizel et al., 1997), which is secreted at micromolar levels by oocyte and steroidogenic cumulus cells (Hartshorne, 1989; Osman et al., 1989). Therefore, progesterone-enhanced HEPT evaluates the sperm ability to capacitate and to respond to progesterone, by exhibiting a functional AR. This is accompanied by the generation of a fusogenic equatorial segment of the sperm head, which makes spermatozoa able to recognize and to fuse with the vitelline membrane of the oocyte (Irvine and Aitken, 1994). Here, we show a negative interference of high levels of RANTES on the capacitation-dependent acquisition of sperm responsiveness to progesterone. The exposure of sperm suspensions to high concentrations of RANTES, comparable to those observed in inflammatory diseases such as endometriosis (Khorram et al., 1993; Hornung et al., 2001; Xu et al., 2006), significantly decreased the stimulatory effect exerted by progesterone on the sperm/oocyte fusion, whereas no effect was exerted by low, physiological concentrations of the chemokine (Fig. 1). As an explanation, a large proportion of spermatozoa preincubated under capacitating conditions with high concentrations of RANTES underwent a premature acrosome exocytosis, whereas the proportion of those undergoing progesterone-induced AR was significantly reduced (Fig. 2). The AR is a prerequisite to successful fertilization. However, it must occur at the appropriate time and in proximity to the oocyte. Spermatozoa that have prematurely lost their acrosome are unable to fertilize oocytes (Jones, 1990; Brucker and Lipford, 1995; de Lamirande et al., 1997; Herrero and Gagnon, 2001). Therefore, it may be speculated that the induction of premature spontaneous acrosomal exocytosis by high levels of RANTES could reduce the proportion of fully capacitated spermatozoa able to respond to physiological inducers of functional (i.e. relevant to fertilization) AR, when they approach the oocyte. The increased intracellular cAMP levels registered in sperm samples incubated with 1 and 10 ng/ml of RANTES (Fig. 3) likely represent the pathway by which high levels of this chemokine induce a premature acrosome exocytosis. It is known that cAMP is involved in the dynamics of AR (Zaneveld et al., 1991), and the adenylate-cyclase agonist forskolin, as well as cAMP analogues, induce AR in a dose-dependent manner both in capacitated (De Jonge et al., 1991; Doherty et al., 1995) and non-capacitated (Anderson et al., 1992) human spermatozoa.
Although cAMP is also involved in the regulation of mammalian sperm motility (Tash and Means, 1983; Luconi and Baldi, 2003; Luconi et al., 2005) and hyperactivated motility (Tesarik et al., 1992; Calogero et al., 1998; Nassar et al., 1999a), the increased levels of cAMP induced by RANTES did not produce a detectable effect on sperm motility. This is not surprising, considering the subcellular sperm compartmentalization of cAMP generation, which appears to be localized at the points where it is needed and does not stimulate other nearby pathways (Travis and Kopf, 2002). Furthermore, although a number of pharmacological agents can stimulate sperm motility via a cAMP-dependent pathway, this effect is widely variable in human spermatozoa, with a higher responsiveness exhibited by asthenozoospermic samples than by sperm samples with good motility (Kay et al., 1993; Krausz et al., 1994; Nassar et al., 1999b), as those used in the present study.
Scanty data exist claiming a possible effect of RANTES on human sperm fertilizing ability. The demonstration of an in vitro dose-dependent chemotactic effect of RANTES on human sperm suggested that this chemokine could be one of the physiological chemoattractants of human spermatozoa in follicular fluid (Isobe et al., 2002). The high concentrations of RANTES in genital tract fluids, observed in endometriosis and inflammatory diseases, might disturb the transfer of sperm to the fertilization site (Isobe et al., 2002). We demonstrated, for the first time, that high levels of RANTES, comparable to those reported in inflammatory diseases of the female and male genital tract (Khorram et al., 1993; Machelon et al., 2000; Hornung et al., 2001; Xu et al., 2006; Penna et al., 2007), exert a negative interference on sperm functions involved in the interaction with oocyte. This strongly suggests a potential contribution of RANTES to subfertility associated with endometriosis and genital tract inflammatory diseases.
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Funding |
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This work was supported by MIUR, COFIN 2005 and COFIN 2006, Italy.
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References |
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Submitted on February 13, 2008; resubmitted on May 9, 2008; accepted on May 13, 2008.
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