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W2020602183 abstract "Human seminal plasma is a complex mixture of proteins, glycoproteins, peptides, glycopeptides, and prostaglandins secreted by organs of the male reproductive tract. The components of this fluid have been implicated in the suppression of immune response, agonistic effects on sperm-egg binding, and promotion of successful implantation of the human embryo. Fractionation followed by biophysical analyses revealed that free oligosaccharides constitute a major component of the total glycoconjugates within seminal plasma. Significant findings of our analyses include the following: (i) the concentration of free oligosaccharides is 0.3–0.4 mg/ml; (ii) mono- and difucosylated forms of the disaccharide lactose are major components; (iii) many of the remaining oligosaccharides are also rich in fucose and carry Lewisx and/or Lewisyepitopes; (iv) a subset of the oligosaccharides express the reducing end sequence (GlcNAcβ1–3/4Glc) not reported in human milk oligosaccharides; (v) oligosaccharides in seminal plasma exclusively express type 2 (Galβ1–4GlcNAc) but not the type 1 sequences (Galβ1–3GlcNAc) that predominate in human milk glycans; and (vi) the structural diversity of seminal plasma oligosaccharides is far less than human milk oligosaccharides. The agonistic effect of both fucose and fucosylated glycoconjugates on human sperm-egg binding in vitro suggests that fucosylated oligosaccharides may also promote fertilization in the female reproductive tract. Human seminal plasma is a complex mixture of proteins, glycoproteins, peptides, glycopeptides, and prostaglandins secreted by organs of the male reproductive tract. The components of this fluid have been implicated in the suppression of immune response, agonistic effects on sperm-egg binding, and promotion of successful implantation of the human embryo. Fractionation followed by biophysical analyses revealed that free oligosaccharides constitute a major component of the total glycoconjugates within seminal plasma. Significant findings of our analyses include the following: (i) the concentration of free oligosaccharides is 0.3–0.4 mg/ml; (ii) mono- and difucosylated forms of the disaccharide lactose are major components; (iii) many of the remaining oligosaccharides are also rich in fucose and carry Lewisx and/or Lewisyepitopes; (iv) a subset of the oligosaccharides express the reducing end sequence (GlcNAcβ1–3/4Glc) not reported in human milk oligosaccharides; (v) oligosaccharides in seminal plasma exclusively express type 2 (Galβ1–4GlcNAc) but not the type 1 sequences (Galβ1–3GlcNAc) that predominate in human milk glycans; and (vi) the structural diversity of seminal plasma oligosaccharides is far less than human milk oligosaccharides. The agonistic effect of both fucose and fucosylated glycoconjugates on human sperm-egg binding in vitro suggests that fucosylated oligosaccharides may also promote fertilization in the female reproductive tract. human seminal plasma fast atom bombardment mass spectrometry electrospray gas chromatography mass spectrometry quadrupole orthogonal acceleration time of flight mass spectrometer collisionally activated decomposition prostaglandin Human semen contains a variety of different cell types including sperm, neutrophils, monocytes, and lymphocytes (reviewed in Ref. 1Setchell B.P. Brooks D.E. Knobil E. Neill J.D. Perspectives in Male Reproduction. Raven Press, Ltd., New York1980: 753-856Google Scholar). If incubated for a brief period of time, semen undergoes a process known as liquefaction that leads to clearing of this fluid and a partial loss of its viscosity (2Sobrero A.J. MacLeod J.K. Fertil. Steril. 1962; 13: 184-189Abstract Full Text PDF PubMed Google Scholar). Centrifugation of partially liquefied semen leads to the separation of the cellular components from the viscous acellular fluid known as human seminal plasma (HSP).1HSP is more than simply a liquid medium for transporting sperm into the vagina. It is an extremely complex mixture of proteins, glycoproteins, peptides, glycopeptides, and prostaglandins secreted by the organs of the male reproductive tract (reviewed in Ref. 1Setchell B.P. Brooks D.E. Knobil E. Neill J.D. Perspectives in Male Reproduction. Raven Press, Ltd., New York1980: 753-856Google Scholar). A plethora of different studies indicate that HSP supports sperm function, modulates maternal immune responses directed against sperm, and promotes successful implantation of the human embryo (reviewed in Refs. 1Setchell B.P. Brooks D.E. Knobil E. Neill J.D. Perspectives in Male Reproduction. Raven Press, Ltd., New York1980: 753-856Google Scholar, 3Kelly R.W. Critchley H.O. Hum. Reprod. 1997; 12: 2200-2207Crossref PubMed Scopus (81) Google Scholar, and 4Robertson S.A. Sharkey D.J. Semin. Immunol. 2001; 13: 243-254Crossref PubMed Scopus (140) Google Scholar). The components of HSP may therefore profoundly impact male fertility in the female reproductive tract.Previous studies confirm that HSP contains a specific glycoprotein with immunomodulatory activities (5Bolton A.E. Pockley A.G. Clough K.J. Mowles E.A. Stoker R.J. Westwood O.M. Chapman M.G. Lancet. 1987; 1: 593-595Abstract PubMed Scopus (204) Google Scholar) now known as glycodelin-S (6Morris H.R. Dell A. Easton R.L. Panico M. Koistinen H. Koistinen R. Oehninger S. Patankar M.S. Seppala M. Clark G.F. J. Biol. Chem. 1996; 271: 32159-32167Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Glycodelin-S also promotes human sperm binding to homologous zona pellucida in the hemizona assay system (6Morris H.R. Dell A. Easton R.L. Panico M. Koistinen H. Koistinen R. Oehninger S. Patankar M.S. Seppala M. Clark G.F. J. Biol. Chem. 1996; 271: 32159-32167Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). This intriguing combination of biological activities led us to investigate further the glycosylation of other components associated with HSP. By using fast atom bombardment (FAB) and electrospray (ES) mass spectrometry to screen HSP for novel glycoconjugates (7Dell A. Khoo K.-H. Panico M. McDowell R.A. Etienne A.T. Reason A.J. Morris H.R. Fukuda M. Kobata A. Glycobiology: A Practical Approach. Oxford University Press, Oxford1993: 187-222Google Scholar), we have made the surprising discovery that this fluid is also rich in free oligosaccharides. The only other human secretion known to contain a significant amount of free oligosaccharides is human milk (reviewed in Refs. 8Newburg D.S. Neubauer S.H. Jenson R.G. Handbook of Milk Composition. Academic Press, San Diego1995: 273-349Google Scholar and 9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar). More than 90 distinct human milk oligosaccharides have been identified. Their structural heterogeneity is derived primarily from differential sialylation, fucosylation, branching, and polylactosamine chain extension (8Newburg D.S. Neubauer S.H. Jenson R.G. Handbook of Milk Composition. Academic Press, San Diego1995: 273-349Google Scholar, 9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar).Several significant biological activities have been ascribed to human milk oligosaccharides. For example, many pathogens and bacterial toxins recognize terminal carbohydrate sequences associated with these glycans (reviewed in Ref. 10Newburg D.S. Curr. Med. Chem. 1999; 6: 117-127PubMed Google Scholar). Thus human milk oligosaccharides may block infection in infants by interfering with crucial adhesion and binding events essential for bacterial colonization and infection. A more recent study suggests that human milk oligosaccharides inhibit the binding of neutrophils activated with tumor necrosis factor to endothelial cells in vitro (9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar) and thus may modulate inflammatory events in vivo.In this paper, we report the structural characterization of several families of free oligosaccharides present in HSP and show that they share some of the structural characteristics of human milk oligosaccharides, as well as having a number of unique features. The great majority are heavily fucosylated and contain structural motifs also present in the antennae of the N-linked oligosaccharides of glycodelin-S. The potential impact of these unusual free oligosaccharides on male reproductive function is discussed.DISCUSSIONTo our knowledge this study is the first revealing the existence of free oligosaccharides in HSP. Thus both human milk and HSP are secretions that contain free oligosaccharides. However, there are several significant differences between milk and HSP oligosaccharides revealed by the current structural analyses: (i) the concentration of free oligosaccharides is greater in human milk than HSP (5–8versus 0.3–0.4 mg/ml) (9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar); (ii) sialylated oligosaccharides are very minor components in HSP (data not shown) but represent 25–30% of the total human milk glycans (15Smith D.F. Zopf D.A. Ginsburg V. Anal. Biochem. 1978; 85: 602-608Crossref PubMed Scopus (34) Google Scholar); (iii) the majority of complex HSP oligosaccharides are fucosylated; (iv) a subset of HSP oligosaccharides express the reducing end sequence (GlcNAcβ1–3/4Glc) not reported in human milk oligosaccharides; (v) HSP oligosaccharides exclusively express type 2 (Galβ1–4GlcNAc) but not the type 1 sequences (Galβ1–3GlcNAc) that predominate in human milk oligosaccharides (9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar); and (vi) the structural diversity of human milk oligosaccharides greatly exceeds that of HSP oligosaccharides (16Stahl B. Thurl S. Zeng J. Karas M. Hillenkamp F. Steup M. Sawatzki G. Anal. Biochem. 1994; 223: 218-226Crossref PubMed Scopus (251) Google Scholar).The pathway for the synthesis of HSP and human milk oligosaccharides may share some common features, however. β-Galactosyltransferase and α-fucosyltransferase activities associated with free oligosaccharide synthesis are present in human milk (17Nagasawa T. Kiyosawa I. Tanahashi N. J. Dairy Sci. 1971; 54: 835-841Abstract Full Text PDF PubMed Scopus (6) Google Scholar, 18Grollman E.F. Kobata A. Ginsburg V. J. Clin. Invest. 1969; 48: 1489-1494Crossref PubMed Scopus (79) Google Scholar). Similar enzymatic activities are also present in HSP (19Tadolini B. Wilson T.J. Reddy P.R. Williams-Ashman H.G. Adv. Enzyme Regul. 1976; 15: 319-336Crossref PubMed Scopus (15) Google Scholar, 20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar). The properties of the HSP-associated galactosyltransferase include the following: (i) sensitivity to α-lactalbumin (20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar), a modifier protein in mammalian milk (21Brodbeck U. Ebner K.E. J. Biol. Chem. 1966; 241: 762-764Abstract Full Text PDF PubMed Google Scholar) that shifts the substrate acceptor specificity of breast milk galactosyltransferase from GlcNAc to Glc (22Brew K. Vanaman T.C. Hill R.L. Proc. Natl. Acad. Sci. U. S. A. 1968; 59: 491-497Crossref PubMed Scopus (373) Google Scholar); (ii) origin primarily in the prostate and epididymis (19Tadolini B. Wilson T.J. Reddy P.R. Williams-Ashman H.G. Adv. Enzyme Regul. 1976; 15: 319-336Crossref PubMed Scopus (15) Google Scholar, 20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar); and (iii) androgen dependence (20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar). A possible functional linkage is the observation that human sperm penetration through cervical mucus is positively correlated with this HSP-associated β-galactosyltransferase activity (23Ronquist G. Stegmayr B. Andren C. Wikstrom K. Urol. Int. 1985; 40: 269-273Crossref PubMed Scopus (1) Google Scholar).Another interesting finding is that the level of HSP-associated α-fucosyltransferase activity greatly exceeds the β-galactosyltransferase activity in vitro (24Ronquist G. Urol. Int. 1987; 42: 143-147Crossref PubMed Scopus (3) Google Scholar). This observation is consistent with the content of fucosylated oligosaccharides present in HSP. This α-fucosyltransferase activity originates primarily in the prostate and is also androgen-dependent (25Ronquist G. Stegmayr B. Urol. Res. 1984; 12: 243-247Crossref PubMed Scopus (15) Google Scholar).There is currently no evidence suggesting that other mammalian species express free oligosaccharides in their seminal plasma. However, there are data supporting the existence of glycosyltransferases and associated biosynthetic proteins in rat seminal plasma. Both a substantial β-galactosyltransferase activity and an α-lactalbumin homologue are present in rat seminal plasma (26Hamilton D.W. Biol. Reprod. 1981; 25: 385-392Crossref PubMed Scopus (39) Google Scholar). Rat seminal plasma also contains very substantial amounts of α-fucosyltransferase activity (27Tulsiani D.R. Orgebin-Crist M.C. Skudlarek M.D. J. Reprod. Fertil. 1998; 53 (suppl.): 85-97Google Scholar). These enzymes are postulated to function in the modification of sperm-surface glycoproteins (27Tulsiani D.R. Orgebin-Crist M.C. Skudlarek M.D. J. Reprod. Fertil. 1998; 53 (suppl.): 85-97Google Scholar), but based on the current evidence such enzymes could be involved in free oligosaccharide synthesis.The function of HSP oligosaccharides in the male and/or the female reproductive systems is unknown. Because humans do not inject semen directly into the uterus, sperm and other seminal plasma components must traverse the cervical mucin plug to enter this organ (reviewed in Ref. 28Gipson I.K. Front. Biosci. 2001; 6: D1245-D1255Crossref PubMed Google Scholar). It may be easier for smaller components like free oligosaccharides to move through this plug at midcycle to influence events within the uterus and the oviduct. Support of sperm function in the uterus and oviduct would certainly be physiologically relevant. Of the several million sperm present in human semen, at most a few hundred arrive in the ampulla of the oviduct where fertilization takes place (reviewed in Ref. 1Setchell B.P. Brooks D.E. Knobil E. Neill J.D. Perspectives in Male Reproduction. Raven Press, Ltd., New York1980: 753-856Google Scholar). Indeed, a very great mystery is how natural fertilization occurs in the presence of such low concentrations of sperm compared with those required for successful in vitro fertilization or sperm binding assays. The logical reason is that male and female factors operating within the vagina and oviduct facilitate this process.Possible supportive effects of free oligosaccharides on sperm function include the following: (i) increasing sperm longevity by delaying hyperactivation; (ii) modifying sperm motion parameters that increase fertility, especially progressive motility; and (iii) promoting sperm binding to eggs.Human sperm display decreased hyperactivation and increased progressive motility following exposure to human cervical mucinsin vitro (29Eriksen G.V. Carlstedt I. Uldbjerg N. Ernst E. Fertil. Steril. 1998; 70: 350-354Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). The major O-glycans associated with human midcycle cervical mucins are terminated with Lewisx and Lewisy sequences (30Yurewicz E.C. Matsuura F. Moghissi K.S. J. Biol. Chem. 1982; 257: 2314-2322Abstract Full Text PDF PubMed Google Scholar), as are HSP oligosaccharides. Human sperm binding to the zona pellucida is increased by 20% in the hemizona assay in the presence of fucose (1 mg/ml) but not other monosaccharides (31Oehninger S. Acosta A. Hodgen G.D. Fertil. Steril. 1990; 53: 143-149Abstract Full Text PDF PubMed Google Scholar). Similarly, glycodelin-S, a HSP glycoprotein also terminated with Lewisx and Lewisy sequences, increases sperm binding in the hemizona assay by 50% at physiological concentrations (6Morris H.R. Dell A. Easton R.L. Panico M. Koistinen H. Koistinen R. Oehninger S. Patankar M.S. Seppala M. Clark G.F. J. Biol. Chem. 1996; 271: 32159-32167Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). The expression of fucosylated sequences on free oligosaccharides, mucins, and glycoproteins may promote sperm-egg binding in the human oviduct.The oligosaccharides associated with HSP could also play a pivotal role in blocking immune/inflammatory cell reactions in the male and female reproductive systems. Except for sperm, leukocytes are the most prevalent cell type present in HSP from fertile males. These leukocytes are primarily neutrophils, with lower numbers of monocytes and T cells (reviewed in Ref. 32Wolff H. Fertil. Steril. 1995; 63: 1143-1157Abstract Full Text PDF PubMed Google Scholar). Leukocytospermia is a condition characterized by excessive numbers of leukocytes in semen (reviewed in Ref. 33Aitken R.J. Baker H.W. Hum. Reprod. 1995; 10: 1736-1739Crossref PubMed Scopus (160) Google Scholar). Elevation in leukocytes above a certain threshold is associated with male infertility (32Wolff H. Fertil. Steril. 1995; 63: 1143-1157Abstract Full Text PDF PubMed Google Scholar). There is also a very profound influx of leukocytes into the vagina and cervix following intercourse, an event referred to as the leukocyte reaction (34Thompson L.A. Barratt C.L. Bolton A.E. Cooke I.D. Am. J. Reprod. Immunol. 1992; 28: 85-89Crossref PubMed Scopus (96) Google Scholar). The majority of the invasive cells are neutrophils, with minor amounts of natural killer cells and monocytes (34Thompson L.A. Barratt C.L. Bolton A.E. Cooke I.D. Am. J. Reprod. Immunol. 1992; 28: 85-89Crossref PubMed Scopus (96) Google Scholar). Human sperm express carbohydrate sequences that are recognized by natural killer cells (35Patankar M.S. Ozgur K. Oehninger S. Dell A. Morris H. Seppala M. Clark G.F. Mol. Hum. Reprod. 1997; 3: 501-505Crossref PubMed Scopus (23) Google Scholar), so they are likely protected from this type of lymphocyte. However, the factors protecting sperm from other immune and inflammatory cell types in semen and the uterus are not very well defined.There is some good evidence that prostate vesicles (prostasomes) present in HSP scavenge reactive oxygen species produced by neutrophils and monocytes (36Saez F. Motta C. Boucher D. Grizard G. Mol. Hum. Reprod. 1998; 4: 667-672Crossref PubMed Scopus (87) Google Scholar). Therefore, prostasomes may protect sperm from the toxic by-products of neutrophil metabolism. Other investigators suggest that prostaglandins (PGE2 and 19-hydroxy-PGE) present in HSP play a crucial role in the suppression of leukocytes (3Kelly R.W. Critchley H.O. Hum. Reprod. 1997; 12: 2200-2207Crossref PubMed Scopus (81) Google Scholar). However, incubation of the neutrophil model cell line U937 with a seminal plasma fraction enriched in PGE2 and 19-hydroxy-PGE had no effect on the release of the immunosuppressive cytokine interleukin-10 at the highest concentration tested (0.1% of the seminal plasma concentration) (37Denison F.C. Grant V.E. Calder A.A. Kelly R.W. Mol. Hum. Reprod. 1999; 5: 220-226Crossref PubMed Scopus (78) Google Scholar). By contrast, incubation of U937 cells with media containing HSP diluted to the same extent induces substantial interleukin-10 release from U937 cells (37Denison F.C. Grant V.E. Calder A.A. Kelly R.W. Mol. Hum. Reprod. 1999; 5: 220-226Crossref PubMed Scopus (78) Google Scholar). This result implies that other components within HSP are likely responsible for the major suppressive effect of this secretion. One factor implicated in this immunomodulation is glycodelin-S, a glycoprotein that shares terminal Lewisx and Lewisy sequences with the HSP oligosaccharides (6Morris H.R. Dell A. Easton R.L. Panico M. Koistinen H. Koistinen R. Oehninger S. Patankar M.S. Seppala M. Clark G.F. J. Biol. Chem. 1996; 271: 32159-32167Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar).Human milk oligosaccharides block the binding of many pathogens or their toxins to colonic epithelial cells in vitro (reviewed in Refs. 9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar and 10Newburg D.S. Curr. Med. Chem. 1999; 6: 117-127PubMed Google Scholar). Several of these crucial interactions are inhibited by fucosylated oligosaccharides present in this secretion. HSP oligosaccharides could also block infection with pathogens responsible for urogenital tract infections. Fucosylated glycans have been implicated in infection with human T-cell lymphotrophic virus, type I, and human immunodeficiency virus (38Zacharopoulos V.R. Phillips D.M. Microb. Pathog. 1997; 23: 225-233Crossref PubMed Scopus (19) Google Scholar, 39Ushijima H. Schroder H.C. Poznanovic S. Matthes E. Muller W.E. Res. Virol. 1992; 143: 97-99Crossref PubMed Scopus (2) Google Scholar). Additional study will be required to determine whether HSP oligosaccharides confer any protective effect against pathogens in the male and/or female reproductive systems.In summary, free oligosaccharides of highly restricted sequence heterogeneity are expressed in the HSP of fertile men. The presence of a predominant modification of the complex glycans (fucosylation) suggests potential functional significance especially when linked to previous data collected in the human model. Further investigation will be required to define the precise physiological roles of these free oligosaccharides in human reproduction. Human semen contains a variety of different cell types including sperm, neutrophils, monocytes, and lymphocytes (reviewed in Ref. 1Setchell B.P. Brooks D.E. Knobil E. Neill J.D. Perspectives in Male Reproduction. Raven Press, Ltd., New York1980: 753-856Google Scholar). If incubated for a brief period of time, semen undergoes a process known as liquefaction that leads to clearing of this fluid and a partial loss of its viscosity (2Sobrero A.J. MacLeod J.K. Fertil. Steril. 1962; 13: 184-189Abstract Full Text PDF PubMed Google Scholar). Centrifugation of partially liquefied semen leads to the separation of the cellular components from the viscous acellular fluid known as human seminal plasma (HSP).1 HSP is more than simply a liquid medium for transporting sperm into the vagina. It is an extremely complex mixture of proteins, glycoproteins, peptides, glycopeptides, and prostaglandins secreted by the organs of the male reproductive tract (reviewed in Ref. 1Setchell B.P. Brooks D.E. Knobil E. Neill J.D. Perspectives in Male Reproduction. Raven Press, Ltd., New York1980: 753-856Google Scholar). A plethora of different studies indicate that HSP supports sperm function, modulates maternal immune responses directed against sperm, and promotes successful implantation of the human embryo (reviewed in Refs. 1Setchell B.P. Brooks D.E. Knobil E. Neill J.D. Perspectives in Male Reproduction. Raven Press, Ltd., New York1980: 753-856Google Scholar, 3Kelly R.W. Critchley H.O. Hum. Reprod. 1997; 12: 2200-2207Crossref PubMed Scopus (81) Google Scholar, and 4Robertson S.A. Sharkey D.J. Semin. Immunol. 2001; 13: 243-254Crossref PubMed Scopus (140) Google Scholar). The components of HSP may therefore profoundly impact male fertility in the female reproductive tract. Previous studies confirm that HSP contains a specific glycoprotein with immunomodulatory activities (5Bolton A.E. Pockley A.G. Clough K.J. Mowles E.A. Stoker R.J. Westwood O.M. Chapman M.G. Lancet. 1987; 1: 593-595Abstract PubMed Scopus (204) Google Scholar) now known as glycodelin-S (6Morris H.R. Dell A. Easton R.L. Panico M. Koistinen H. Koistinen R. Oehninger S. Patankar M.S. Seppala M. Clark G.F. J. Biol. Chem. 1996; 271: 32159-32167Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Glycodelin-S also promotes human sperm binding to homologous zona pellucida in the hemizona assay system (6Morris H.R. Dell A. Easton R.L. Panico M. Koistinen H. Koistinen R. Oehninger S. Patankar M.S. Seppala M. Clark G.F. J. Biol. Chem. 1996; 271: 32159-32167Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). This intriguing combination of biological activities led us to investigate further the glycosylation of other components associated with HSP. By using fast atom bombardment (FAB) and electrospray (ES) mass spectrometry to screen HSP for novel glycoconjugates (7Dell A. Khoo K.-H. Panico M. McDowell R.A. Etienne A.T. Reason A.J. Morris H.R. Fukuda M. Kobata A. Glycobiology: A Practical Approach. Oxford University Press, Oxford1993: 187-222Google Scholar), we have made the surprising discovery that this fluid is also rich in free oligosaccharides. The only other human secretion known to contain a significant amount of free oligosaccharides is human milk (reviewed in Refs. 8Newburg D.S. Neubauer S.H. Jenson R.G. Handbook of Milk Composition. Academic Press, San Diego1995: 273-349Google Scholar and 9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar). More than 90 distinct human milk oligosaccharides have been identified. Their structural heterogeneity is derived primarily from differential sialylation, fucosylation, branching, and polylactosamine chain extension (8Newburg D.S. Neubauer S.H. Jenson R.G. Handbook of Milk Composition. Academic Press, San Diego1995: 273-349Google Scholar, 9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar). Several significant biological activities have been ascribed to human milk oligosaccharides. For example, many pathogens and bacterial toxins recognize terminal carbohydrate sequences associated with these glycans (reviewed in Ref. 10Newburg D.S. Curr. Med. Chem. 1999; 6: 117-127PubMed Google Scholar). Thus human milk oligosaccharides may block infection in infants by interfering with crucial adhesion and binding events essential for bacterial colonization and infection. A more recent study suggests that human milk oligosaccharides inhibit the binding of neutrophils activated with tumor necrosis factor to endothelial cells in vitro (9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar) and thus may modulate inflammatory events in vivo. In this paper, we report the structural characterization of several families of free oligosaccharides present in HSP and show that they share some of the structural characteristics of human milk oligosaccharides, as well as having a number of unique features. The great majority are heavily fucosylated and contain structural motifs also present in the antennae of the N-linked oligosaccharides of glycodelin-S. The potential impact of these unusual free oligosaccharides on male reproductive function is discussed. DISCUSSIONTo our knowledge this study is the first revealing the existence of free oligosaccharides in HSP. Thus both human milk and HSP are secretions that contain free oligosaccharides. However, there are several significant differences between milk and HSP oligosaccharides revealed by the current structural analyses: (i) the concentration of free oligosaccharides is greater in human milk than HSP (5–8versus 0.3–0.4 mg/ml) (9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar); (ii) sialylated oligosaccharides are very minor components in HSP (data not shown) but represent 25–30% of the total human milk glycans (15Smith D.F. Zopf D.A. Ginsburg V. Anal. Biochem. 1978; 85: 602-608Crossref PubMed Scopus (34) Google Scholar); (iii) the majority of complex HSP oligosaccharides are fucosylated; (iv) a subset of HSP oligosaccharides express the reducing end sequence (GlcNAcβ1–3/4Glc) not reported in human milk oligosaccharides; (v) HSP oligosaccharides exclusively express type 2 (Galβ1–4GlcNAc) but not the type 1 sequences (Galβ1–3GlcNAc) that predominate in human milk oligosaccharides (9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar); and (vi) the structural diversity of human milk oligosaccharides greatly exceeds that of HSP oligosaccharides (16Stahl B. Thurl S. Zeng J. Karas M. Hillenkamp F. Steup M. Sawatzki G. Anal. Biochem. 1994; 223: 218-226Crossref PubMed Scopus (251) Google Scholar).The pathway for the synthesis of HSP and human milk oligosaccharides may share some common features, however. β-Galactosyltransferase and α-fucosyltransferase activities associated with free oligosaccharide synthesis are present in human milk (17Nagasawa T. Kiyosawa I. Tanahashi N. J. Dairy Sci. 1971; 54: 835-841Abstract Full Text PDF PubMed Scopus (6) Google Scholar, 18Grollman E.F. Kobata A. Ginsburg V. J. Clin. Invest. 1969; 48: 1489-1494Crossref PubMed Scopus (79) Google Scholar). Similar enzymatic activities are also present in HSP (19Tadolini B. Wilson T.J. Reddy P.R. Williams-Ashman H.G. Adv. Enzyme Regul. 1976; 15: 319-336Crossref PubMed Scopus (15) Google Scholar, 20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar). The properties of the HSP-associated galactosyltransferase include the following: (i) sensitivity to α-lactalbumin (20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar), a modifier protein in mammalian milk (21Brodbeck U. Ebner K.E. J. Biol. Chem. 1966; 241: 762-764Abstract Full Text PDF PubMed Google Scholar) that shifts the substrate acceptor specificity of breast milk galactosyltransferase from GlcNAc to Glc (22Brew K. Vanaman T.C. Hill R.L. Proc. Natl. Acad. Sci. U. S. A. 1968; 59: 491-497Crossref PubMed Scopus (373) Google Scholar); (ii) origin primarily in the prostate and epididymis (19Tadolini B. Wilson T.J. Reddy P.R. Williams-Ashman H.G. Adv. Enzyme Regul. 1976; 15: 319-336Crossref PubMed Scopus (15) Google Scholar, 20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar); and (iii) androgen dependence (20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar). A possible functional linkage is the observation that human sperm penetration through cervical mucus is positively correlated with this HSP-associated β-galactosyltransferase activity (23Ronquist G. Stegmayr B. Andren C. Wikstrom K. Urol. Int. 1985; 40: 269-273Crossref PubMed Scopus (1) Google Scholar).Another interesting finding is that the level of HSP-associated α-fucosyltransferase activity greatly exceeds the β-galactosyltransferase activity in vitro (24Ronquist G. Urol. Int. 1987; 42: 143-147Crossref PubMed Scopus (3) Google Scholar). This observation is consistent with the content of fucosylated oligosaccharides present in HSP. This α-fucosyltransferase activity originates primarily in the prostate and is also androgen-dependent (25Ronquist G. Stegmayr B. Urol. Res. 1984; 12: 243-247Crossref PubMed Scopus (15) Google Scholar).There is currently no evidence suggesting that other mammalian species express free oligosaccharides in their seminal plasma. However, there are data supporting the existence of glycosyltransferases and associated biosynthetic proteins in rat seminal plasma. Both a substantial β-galactosyltransferase activity and an α-lactalbumin homologue are present in rat seminal plasma (26Hamilton D.W. Biol. Reprod. 1981; 25: 385-392Crossref PubMed Scopus (39) Google Scholar). Rat seminal plasma also contains very substantial amounts of α-fucosyltransferase activity (27Tulsiani D.R. Orgebin-Crist M.C. Skudlarek M.D. J. Reprod. Fertil. 1998; 53 (suppl.): 85-97Google Scholar). These enzymes are postulated to function in the modification of sperm-surface glycoproteins (27Tulsiani D.R. Orgebin-Crist M.C. Skudlarek M.D. J. Reprod. Fertil. 1998; 53 (suppl.): 85-97Google Scholar), but based on the current evidence such enzymes could be involved in free oligosaccharide synthesis.The function of HSP oligosaccharides in the male and/or the female reproductive systems is unknown. Because humans do not inject semen directly into the uterus, sperm and other seminal plasma components must traverse the cervical mucin plug to enter this organ (reviewed in Ref. 28Gipson I.K. Front. Biosci. 2001; 6: D1245-D1255Crossref PubMed Google Scholar). It may be easier for smaller components like free oligosaccharides to move through this plug at midcycle to influence events within the uterus and the oviduct. Support of sperm function in the uterus and oviduct would certainly be physiologically relevant. Of the several million sperm present in human semen, at most a few hundred arrive in the ampulla of the oviduct where fertilization takes place (reviewed in Ref. 1Setchell B.P. Brooks D.E. Knobil E. Neill J.D. Perspectives in Male Reproduction. Raven Press, Ltd., New York1980: 753-856Google Scholar). Indeed, a very great mystery is how natural fertilization occurs in the presence of such low concentrations of sperm compared with those required for successful in vitro fertilization or sperm binding assays. The logical reason is that male and female factors operating within the vagina and oviduct facilitate this process.Possible supportive effects of free oligosaccharides on sperm function include the following: (i) increasing sperm longevity by delaying hyperactivation; (ii) modifying sperm motion parameters that increase fertility, especially progressive motility; and (iii) promoting sperm binding to eggs.Human sperm display decreased hyperactivation and increased progressive motility following exposure to human cervical mucinsin vitro (29Eriksen G.V. Carlstedt I. Uldbjerg N. Ernst E. Fertil. Steril. 1998; 70: 350-354Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). The major O-glycans associated with human midcycle cervical mucins are terminated with Lewisx and Lewisy sequences (30Yurewicz E.C. Matsuura F. Moghissi K.S. J. Biol. Chem. 1982; 257: 2314-2322Abstract Full Text PDF PubMed Google Scholar), as are HSP oligosaccharides. Human sperm binding to the zona pellucida is increased by 20% in the hemizona assay in the presence of fucose (1 mg/ml) but not other monosaccharides (31Oehninger S. Acosta A. Hodgen G.D. Fertil. Steril. 1990; 53: 143-149Abstract Full Text PDF PubMed Google Scholar). Similarly, glycodelin-S, a HSP glycoprotein also terminated with Lewisx and Lewisy sequences, increases sperm binding in the hemizona assay by 50% at physiological concentrations (6Morris H.R. Dell A. Easton R.L. Panico M. Koistinen H. Koistinen R. Oehninger S. Patankar M.S. Seppala M. Clark G.F. J. Biol. Chem. 1996; 271: 32159-32167Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). The expression of fucosylated sequences on free oligosaccharides, mucins, and glycoproteins may promote sperm-egg binding in the human oviduct.The oligosaccharides associated with HSP could also play a pivotal role in blocking immune/inflammatory cell reactions in the male and female reproductive systems. Except for sperm, leukocytes are the most prevalent cell type present in HSP from fertile males. These leukocytes are primarily neutrophils, with lower numbers of monocytes and T cells (reviewed in Ref. 32Wolff H. Fertil. Steril. 1995; 63: 1143-1157Abstract Full Text PDF PubMed Google Scholar). Leukocytospermia is a condition characterized by excessive numbers of leukocytes in semen (reviewed in Ref. 33Aitken R.J. Baker H.W. Hum. Reprod. 1995; 10: 1736-1739Crossref PubMed Scopus (160) Google Scholar). Elevation in leukocytes above a certain threshold is associated with male infertility (32Wolff H. Fertil. Steril. 1995; 63: 1143-1157Abstract Full Text PDF PubMed Google Scholar). There is also a very profound influx of leukocytes into the vagina and cervix following intercourse, an event referred to as the leukocyte reaction (34Thompson L.A. Barratt C.L. Bolton A.E. Cooke I.D. Am. J. Reprod. Immunol. 1992; 28: 85-89Crossref PubMed Scopus (96) Google Scholar). The majority of the invasive cells are neutrophils, with minor amounts of natural killer cells and monocytes (34Thompson L.A. Barratt C.L. Bolton A.E. Cooke I.D. Am. J. Reprod. Immunol. 1992; 28: 85-89Crossref PubMed Scopus (96) Google Scholar). Human sperm express carbohydrate sequences that are recognized by natural killer cells (35Patankar M.S. Ozgur K. Oehninger S. Dell A. Morris H. Seppala M. Clark G.F. Mol. Hum. Reprod. 1997; 3: 501-505Crossref PubMed Scopus (23) Google Scholar), so they are likely protected from this type of lymphocyte. However, the factors protecting sperm from other immune and inflammatory cell types in semen and the uterus are not very well defined.There is some good evidence that prostate vesicles (prostasomes) present in HSP scavenge reactive oxygen species produced by neutrophils and monocytes (36Saez F. Motta C. Boucher D. Grizard G. Mol. Hum. Reprod. 1998; 4: 667-672Crossref PubMed Scopus (87) Google Scholar). Therefore, prostasomes may protect sperm from the toxic by-products of neutrophil metabolism. Other investigators suggest that prostaglandins (PGE2 and 19-hydroxy-PGE) present in HSP play a crucial role in the suppression of leukocytes (3Kelly R.W. Critchley H.O. Hum. Reprod. 1997; 12: 2200-2207Crossref PubMed Scopus (81) Google Scholar). However, incubation of the neutrophil model cell line U937 with a seminal plasma fraction enriched in PGE2 and 19-hydroxy-PGE had no effect on the release of the immunosuppressive cytokine interleukin-10 at the highest concentration tested (0.1% of the seminal plasma concentration) (37Denison F.C. Grant V.E. Calder A.A. Kelly R.W. Mol. Hum. Reprod. 1999; 5: 220-226Crossref PubMed Scopus (78) Google Scholar). By contrast, incubation of U937 cells with media containing HSP diluted to the same extent induces substantial interleukin-10 release from U937 cells (37Denison F.C. Grant V.E. Calder A.A. Kelly R.W. Mol. Hum. Reprod. 1999; 5: 220-226Crossref PubMed Scopus (78) Google Scholar). This result implies that other components within HSP are likely responsible for the major suppressive effect of this secretion. One factor implicated in this immunomodulation is glycodelin-S, a glycoprotein that shares terminal Lewisx and Lewisy sequences with the HSP oligosaccharides (6Morris H.R. Dell A. Easton R.L. Panico M. Koistinen H. Koistinen R. Oehninger S. Patankar M.S. Seppala M. Clark G.F. J. Biol. Chem. 1996; 271: 32159-32167Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar).Human milk oligosaccharides block the binding of many pathogens or their toxins to colonic epithelial cells in vitro (reviewed in Refs. 9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar and 10Newburg D.S. Curr. Med. Chem. 1999; 6: 117-127PubMed Google Scholar). Several of these crucial interactions are inhibited by fucosylated oligosaccharides present in this secretion. HSP oligosaccharides could also block infection with pathogens responsible for urogenital tract infections. Fucosylated glycans have been implicated in infection with human T-cell lymphotrophic virus, type I, and human immunodeficiency virus (38Zacharopoulos V.R. Phillips D.M. Microb. Pathog. 1997; 23: 225-233Crossref PubMed Scopus (19) Google Scholar, 39Ushijima H. Schroder H.C. Poznanovic S. Matthes E. Muller W.E. Res. Virol. 1992; 143: 97-99Crossref PubMed Scopus (2) Google Scholar). Additional study will be required to determine whether HSP oligosaccharides confer any protective effect against pathogens in the male and/or female reproductive systems.In summary, free oligosaccharides of highly restricted sequence heterogeneity are expressed in the HSP of fertile men. The presence of a predominant modification of the complex glycans (fucosylation) suggests potential functional significance especially when linked to previous data collected in the human model. Further investigation will be required to define the precise physiological roles of these free oligosaccharides in human reproduction. To our knowledge this study is the first revealing the existence of free oligosaccharides in HSP. Thus both human milk and HSP are secretions that contain free oligosaccharides. However, there are several significant differences between milk and HSP oligosaccharides revealed by the current structural analyses: (i) the concentration of free oligosaccharides is greater in human milk than HSP (5–8versus 0.3–0.4 mg/ml) (9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar); (ii) sialylated oligosaccharides are very minor components in HSP (data not shown) but represent 25–30% of the total human milk glycans (15Smith D.F. Zopf D.A. Ginsburg V. Anal. Biochem. 1978; 85: 602-608Crossref PubMed Scopus (34) Google Scholar); (iii) the majority of complex HSP oligosaccharides are fucosylated; (iv) a subset of HSP oligosaccharides express the reducing end sequence (GlcNAcβ1–3/4Glc) not reported in human milk oligosaccharides; (v) HSP oligosaccharides exclusively express type 2 (Galβ1–4GlcNAc) but not the type 1 sequences (Galβ1–3GlcNAc) that predominate in human milk oligosaccharides (9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar); and (vi) the structural diversity of human milk oligosaccharides greatly exceeds that of HSP oligosaccharides (16Stahl B. Thurl S. Zeng J. Karas M. Hillenkamp F. Steup M. Sawatzki G. Anal. Biochem. 1994; 223: 218-226Crossref PubMed Scopus (251) Google Scholar). The pathway for the synthesis of HSP and human milk oligosaccharides may share some common features, however. β-Galactosyltransferase and α-fucosyltransferase activities associated with free oligosaccharide synthesis are present in human milk (17Nagasawa T. Kiyosawa I. Tanahashi N. J. Dairy Sci. 1971; 54: 835-841Abstract Full Text PDF PubMed Scopus (6) Google Scholar, 18Grollman E.F. Kobata A. Ginsburg V. J. Clin. Invest. 1969; 48: 1489-1494Crossref PubMed Scopus (79) Google Scholar). Similar enzymatic activities are also present in HSP (19Tadolini B. Wilson T.J. Reddy P.R. Williams-Ashman H.G. Adv. Enzyme Regul. 1976; 15: 319-336Crossref PubMed Scopus (15) Google Scholar, 20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar). The properties of the HSP-associated galactosyltransferase include the following: (i) sensitivity to α-lactalbumin (20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar), a modifier protein in mammalian milk (21Brodbeck U. Ebner K.E. J. Biol. Chem. 1966; 241: 762-764Abstract Full Text PDF PubMed Google Scholar) that shifts the substrate acceptor specificity of breast milk galactosyltransferase from GlcNAc to Glc (22Brew K. Vanaman T.C. Hill R.L. Proc. Natl. Acad. Sci. U. S. A. 1968; 59: 491-497Crossref PubMed Scopus (373) Google Scholar); (ii) origin primarily in the prostate and epididymis (19Tadolini B. Wilson T.J. Reddy P.R. Williams-Ashman H.G. Adv. Enzyme Regul. 1976; 15: 319-336Crossref PubMed Scopus (15) Google Scholar, 20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar); and (iii) androgen dependence (20Ross P. Vigneault N. Provencher S. Potier M. Roberts K.D. J. Reprod. Fertil. 1993; 98: 129-137Crossref PubMed Scopus (14) Google Scholar). A possible functional linkage is the observation that human sperm penetration through cervical mucus is positively correlated with this HSP-associated β-galactosyltransferase activity (23Ronquist G. Stegmayr B. Andren C. Wikstrom K. Urol. Int. 1985; 40: 269-273Crossref PubMed Scopus (1) Google Scholar). Another interesting finding is that the level of HSP-associated α-fucosyltransferase activity greatly exceeds the β-galactosyltransferase activity in vitro (24Ronquist G. Urol. Int. 1987; 42: 143-147Crossref PubMed Scopus (3) Google Scholar). This observation is consistent with the content of fucosylated oligosaccharides present in HSP. This α-fucosyltransferase activity originates primarily in the prostate and is also androgen-dependent (25Ronquist G. Stegmayr B. Urol. Res. 1984; 12: 243-247Crossref PubMed Scopus (15) Google Scholar). There is currently no evidence suggesting that other mammalian species express free oligosaccharides in their seminal plasma. However, there are data supporting the existence of glycosyltransferases and associated biosynthetic proteins in rat seminal plasma. Both a substantial β-galactosyltransferase activity and an α-lactalbumin homologue are present in rat seminal plasma (26Hamilton D.W. Biol. Reprod. 1981; 25: 385-392Crossref PubMed Scopus (39) Google Scholar). Rat seminal plasma also contains very substantial amounts of α-fucosyltransferase activity (27Tulsiani D.R. Orgebin-Crist M.C. Skudlarek M.D. J. Reprod. Fertil. 1998; 53 (suppl.): 85-97Google Scholar). These enzymes are postulated to function in the modification of sperm-surface glycoproteins (27Tulsiani D.R. Orgebin-Crist M.C. Skudlarek M.D. J. Reprod. Fertil. 1998; 53 (suppl.): 85-97Google Scholar), but based on the current evidence such enzymes could be involved in free oligosaccharide synthesis. The function of HSP oligosaccharides in the male and/or the female reproductive systems is unknown. Because humans do not inject semen directly into the uterus, sperm and other seminal plasma components must traverse the cervical mucin plug to enter this organ (reviewed in Ref. 28Gipson I.K. Front. Biosci. 2001; 6: D1245-D1255Crossref PubMed Google Scholar). It may be easier for smaller components like free oligosaccharides to move through this plug at midcycle to influence events within the uterus and the oviduct. Support of sperm function in the uterus and oviduct would certainly be physiologically relevant. Of the several million sperm present in human semen, at most a few hundred arrive in the ampulla of the oviduct where fertilization takes place (reviewed in Ref. 1Setchell B.P. Brooks D.E. Knobil E. Neill J.D. Perspectives in Male Reproduction. Raven Press, Ltd., New York1980: 753-856Google Scholar). Indeed, a very great mystery is how natural fertilization occurs in the presence of such low concentrations of sperm compared with those required for successful in vitro fertilization or sperm binding assays. The logical reason is that male and female factors operating within the vagina and oviduct facilitate this process. Possible supportive effects of free oligosaccharides on sperm function include the following: (i) increasing sperm longevity by delaying hyperactivation; (ii) modifying sperm motion parameters that increase fertility, especially progressive motility; and (iii) promoting sperm binding to eggs. Human sperm display decreased hyperactivation and increased progressive motility following exposure to human cervical mucinsin vitro (29Eriksen G.V. Carlstedt I. Uldbjerg N. Ernst E. Fertil. Steril. 1998; 70: 350-354Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). The major O-glycans associated with human midcycle cervical mucins are terminated with Lewisx and Lewisy sequences (30Yurewicz E.C. Matsuura F. Moghissi K.S. J. Biol. Chem. 1982; 257: 2314-2322Abstract Full Text PDF PubMed Google Scholar), as are HSP oligosaccharides. Human sperm binding to the zona pellucida is increased by 20% in the hemizona assay in the presence of fucose (1 mg/ml) but not other monosaccharides (31Oehninger S. Acosta A. Hodgen G.D. Fertil. Steril. 1990; 53: 143-149Abstract Full Text PDF PubMed Google Scholar). Similarly, glycodelin-S, a HSP glycoprotein also terminated with Lewisx and Lewisy sequences, increases sperm binding in the hemizona assay by 50% at physiological concentrations (6Morris H.R. Dell A. Easton R.L. Panico M. Koistinen H. Koistinen R. Oehninger S. Patankar M.S. Seppala M. Clark G.F. J. Biol. Chem. 1996; 271: 32159-32167Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). The expression of fucosylated sequences on free oligosaccharides, mucins, and glycoproteins may promote sperm-egg binding in the human oviduct. The oligosaccharides associated with HSP could also play a pivotal role in blocking immune/inflammatory cell reactions in the male and female reproductive systems. Except for sperm, leukocytes are the most prevalent cell type present in HSP from fertile males. These leukocytes are primarily neutrophils, with lower numbers of monocytes and T cells (reviewed in Ref. 32Wolff H. Fertil. Steril. 1995; 63: 1143-1157Abstract Full Text PDF PubMed Google Scholar). Leukocytospermia is a condition characterized by excessive numbers of leukocytes in semen (reviewed in Ref. 33Aitken R.J. Baker H.W. Hum. Reprod. 1995; 10: 1736-1739Crossref PubMed Scopus (160) Google Scholar). Elevation in leukocytes above a certain threshold is associated with male infertility (32Wolff H. Fertil. Steril. 1995; 63: 1143-1157Abstract Full Text PDF PubMed Google Scholar). There is also a very profound influx of leukocytes into the vagina and cervix following intercourse, an event referred to as the leukocyte reaction (34Thompson L.A. Barratt C.L. Bolton A.E. Cooke I.D. Am. J. Reprod. Immunol. 1992; 28: 85-89Crossref PubMed Scopus (96) Google Scholar). The majority of the invasive cells are neutrophils, with minor amounts of natural killer cells and monocytes (34Thompson L.A. Barratt C.L. Bolton A.E. Cooke I.D. Am. J. Reprod. Immunol. 1992; 28: 85-89Crossref PubMed Scopus (96) Google Scholar). Human sperm express carbohydrate sequences that are recognized by natural killer cells (35Patankar M.S. Ozgur K. Oehninger S. Dell A. Morris H. Seppala M. Clark G.F. Mol. Hum. Reprod. 1997; 3: 501-505Crossref PubMed Scopus (23) Google Scholar), so they are likely protected from this type of lymphocyte. However, the factors protecting sperm from other immune and inflammatory cell types in semen and the uterus are not very well defined. There is some good evidence that prostate vesicles (prostasomes) present in HSP scavenge reactive oxygen species produced by neutrophils and monocytes (36Saez F. Motta C. Boucher D. Grizard G. Mol. Hum. Reprod. 1998; 4: 667-672Crossref PubMed Scopus (87) Google Scholar). Therefore, prostasomes may protect sperm from the toxic by-products of neutrophil metabolism. Other investigators suggest that prostaglandins (PGE2 and 19-hydroxy-PGE) present in HSP play a crucial role in the suppression of leukocytes (3Kelly R.W. Critchley H.O. Hum. Reprod. 1997; 12: 2200-2207Crossref PubMed Scopus (81) Google Scholar). However, incubation of the neutrophil model cell line U937 with a seminal plasma fraction enriched in PGE2 and 19-hydroxy-PGE had no effect on the release of the immunosuppressive cytokine interleukin-10 at the highest concentration tested (0.1% of the seminal plasma concentration) (37Denison F.C. Grant V.E. Calder A.A. Kelly R.W. Mol. Hum. Reprod. 1999; 5: 220-226Crossref PubMed Scopus (78) Google Scholar). By contrast, incubation of U937 cells with media containing HSP diluted to the same extent induces substantial interleukin-10 release from U937 cells (37Denison F.C. Grant V.E. Calder A.A. Kelly R.W. Mol. Hum. Reprod. 1999; 5: 220-226Crossref PubMed Scopus (78) Google Scholar). This result implies that other components within HSP are likely responsible for the major suppressive effect of this secretion. One factor implicated in this immunomodulation is glycodelin-S, a glycoprotein that shares terminal Lewisx and Lewisy sequences with the HSP oligosaccharides (6Morris H.R. Dell A. Easton R.L. Panico M. Koistinen H. Koistinen R. Oehninger S. Patankar M.S. Seppala M. Clark G.F. J. Biol. Chem. 1996; 271: 32159-32167Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Human milk oligosaccharides block the binding of many pathogens or their toxins to colonic epithelial cells in vitro (reviewed in Refs. 9Kunz C. Rudloff S. Baier W. Klein N. Strobel S. Annu. Rev. Nutr. 2000; 20: 699-722Crossref PubMed Scopus (824) Google Scholar and 10Newburg D.S. Curr. Med. Chem. 1999; 6: 117-127PubMed Google Scholar). Several of these crucial interactions are inhibited by fucosylated oligosaccharides present in this secretion. HSP oligosaccharides could also block infection with pathogens responsible for urogenital tract infections. Fucosylated glycans have been implicated in infection with human T-cell lymphotrophic virus, type I, and human immunodeficiency virus (38Zacharopoulos V.R. Phillips D.M. Microb. Pathog. 1997; 23: 225-233Crossref PubMed Scopus (19) Google Scholar, 39Ushijima H. Schroder H.C. Poznanovic S. Matthes E. Muller W.E. Res. Virol. 1992; 143: 97-99Crossref PubMed Scopus (2) Google Scholar). Additional study will be required to determine whether HSP oligosaccharides confer any protective effect against pathogens in the male and/or female reproductive systems. In summary, free oligosaccharides of highly restricted sequence heterogeneity are expressed in the HSP of fertile men. The presence of a predominant modification of the complex glycans (fucosylation) suggests potential functional significance especially when linked to previous data collected in the human model. Further investigation will be required to define the precise physiological roles of these free oligosaccharides in human reproduction." @default.
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W2020602183 title "The Expression of Free Oligosaccharides in Human Seminal Plasma" @default.
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