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Published-Ahead-of-Print November 8, 2005, DOI:10.2164/jandrol.05108
Journal of Andrology, Vol. 27, No. 2, March/April 2006
Copyright © American Society of Andrology
DOI: 10.2164/jandrol.05108

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Polyol Pathway in Human Epididymis and Semen

GILLES FRENETTE*, MICHEL THABET{dagger} AND ROBERT SULLIVAN*

From the * Centre de Recherche en Biologie de la Reproduction and the Département d'Obstétrique-Gynécologie et {dagger} chirurgie, Faculté de Médecine, Université Laval, Ste-Foy, Québec, Canada.

Correspondence to: Robert Sullivan, Unité d'Ontogénie-Reproduction, Centre de Recherche, Centre Hospitalier de l'Université Laval, 2705 Blvd Laurier, Ste-Foy, PQ, Canada, G1V 4G2 (e-mail: robert.sullivan{at}crchul.ulaval.ca).
Received for publication June 2, 2005; accepted for publication August 30, 2005.

   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Two enzymes are involved in the polyol pathway: an aldose reductase that reduces glucose in sorbitol followed by its oxidation in fructose by sorbitol dehydrogenase. It has been previously shown that both enzymes are presented in the bovine epididymis, where they are associated with membranous vesicles called epididymosomes. Based on the distribution of these enzymes, it has been hypothesized that the polyol pathway can modulate sperm motility during the epididymal transit. In the present study, polyol pathway was investigated in semen and along the epididymis in humans in order to determine if sperm maturation can be associated with this sugar pathway. Western blot analysis shows that both aldose reductase and sorbitol dehydrogenase are associated with ejaculated spermatozoa and prostasomes in humans. These enzymes are also associated with epididymosomes collected during surgical vasectomy reversal. Western blot, Northern blot, and reverse transcription–polymerase chain reaction analysis show that aldose reductase and sorbitol dehydrogenase are expressed at the transcriptional and translational levels along the human epididymis. Unlike what occurs in the bovine model, distribution of these enzymes is rather uniform along the human excurrent duct. Immunohistological studies together with Western blot analysis performed on epididymosomes preparations indicate that the polyol pathway enzymes are secreted by the epididymal epithelium. These results indicate that the polyol pathway plays a role in human sperm physiology.

     Key words: Spermatozoa, sperm maturation, sperm motility


Leaving the testis, the mammalian spermatozoon has to transit along the epididymis. This long convoluted tubule is involved in the remodeling of the sperm surface and in modifications of macromolecular constituents, culminating in the storage of fully functional male gametes. This process, called sperm maturation, includes the acquisition of flagellar forward motility and the ability to efficiently encounter the oocytes and their investments (Robaire and Hinton, 2002; Ecroyd et al, 2004).

We have previously shown that the epididymal epithelium secretes in an apocrine mode small membranous vesicles that interact with the spermatozoa during epididymal transit (Sullivan et al, 2001, 2003; Saez et al, 2003). Complex patterns of proteins are associated with these vesicles, called epididymosomes (Légaré et al, 1999a; Frenette and Sullivan, 2001). Prostasomes are similar vesicles secreted by the prostate and present in semen. Within the epididymal intraluminal compartment, selected proteins of epididymosomes are transferred to define sperm surface domains (Frenette et al, 2002). Using a proteomic approach, we showed in bovine that aldose reductase is one of the major proteins associated with epididymosomes (Frenette et al, 2003). Aldose reductase uses NADPH as an electron donor to reduce aldoses and ketoses. This enzyme is involved in the reduction of glucose in sorbitol in the polyol pathway. The second step of this sugar pathway involved sorbitol dehydrogenase, which oxidizes sorbitol using NAD+ as an electron acceptor to produce fructose (Oates, 2002) (Figure 1). Using the bovine as a model, we showed that both enzymes of the polyol pathway are synthesized by the epididymal epithelium and that aldose reductase is highly expressed in the proximal portion in the epididymis, while sorbitol dehydrogenase has a maximum activity in the distal portion (Frenette et al, 2004). We thus proposed that sorbitol is accumulating along the bovine epididymis and is oxidized in the distal portion of the epididymis to produce fructose. Based on this concept, we hypothesized that the polyol pathway can modulate the flagellar motility of the transiting epididymal spermatozoa.


Figure 1
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  		Figure 1. Polyol pathway. AR indicates aldose reductase; SODH, sorbitol dehydrogenase; NAD+, nicotinamide adenine dinucleotide; and NADPH, nicotinamide adenine dinucleotide phosphate. Note that sorbitol is a linear sugar.

 
Epididymal physiology is poorly understood in humans and shows characteristics when compared to usual animal models (Légaré and Sullivan, 2004). In this context, factors modulating the metabolism and flagellar motility of epididymal spermatozoa have to be revisited in humans. The objective of the present work was to investigate the existence of the polyol pathway along the epididymis of normal men.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Biological Material

Human epididymides were obtained with the collaboration of our local transplantation program after we obtained informed consent from relatives. Donors ranged in age from 18 to 55 years and had no previous history that would affect the reproductive function. Donors had experienced accidental death, and tissues were dissected while artificial circulation was maintained to preserve those tissues destined for transplantation. Epididymides were dissected on ice in caput, corpus, and cauda segments (Légaré et al, 1999b). Some tissue pieces were fixed in 4% paraformaldehyde for immunohistochemistry or were snap-frozen in liquid nitrogen for protein and RNA extraction. Vas deferens intraluminal fluid was obtained during surgical vasectomy reversal, and semen samples were obtained from the andrology laboratory of our hospital. All procedures were approved by the ethics committee at our institution.

Epididymosomes/Prostasomes

Epididymosomes were prepared from fluids collected from the vas deferens during vasectomy reversal surgery. Prostasomes were prepared from semen samples obtained by masturbation. Only normospermic samples, according to World Health Organization criteria, were used in this study (World Health Organization, 1999). Vas deferens fluids and semen samples were diluted with 2 volumes of Tris (30 mM) NaCl (130 mM) (TN; pH 7.5) and centrifuged twice at 3000 x g for 10 minutes. Supernatants of vas deferens were centrifuged at 120 000 x g for 2 hours; pellets were resuspended in TN and ultracentrifuged a second time. Pellets from vas deferens fluid containing epididymosomes were frozen until used. Prostasomes from semen samples were prepared using the same protocol, with the exception that pellets obtained after the first centrifugation were chromatographed on a Sephacryl S-500 HR (Pharmacia, Baie d'Urfé, Québec, Canada). The void volume containing prostasomes was than ultracentrifuged a second time at 120 000 x g for 2 hours (Ronquist and Brody, 1985). The quantity of epididymosomes present in seminal fluid is negligible when compared to the quantity of prostasomes.

Western Blots

Epididymal tissues were homogenized in water containing 1% sodium dodecyl sulfate (SDS) and centrifuged at 16 000 x g for 20 minutes. Supernatants were precipitated with MeOH/CHCl 3, and proteins were resuspended in sample buffer and submitted to SDS-polyacrylamide gel electrophoresis (PAGE) (Laemmli, 1970). Protein concentrations were determined by amido black staining of dot blots (Chapdelaine et al, 2001).

Semen samples were diluted with 2 volumes of TN, and spermatozoa were peletted at 1200 x g for 10 minutes. After 2 washings by centrifugation, sperm proteins were extracted with 1% SDS and submitted to SDS-PAGE. Pellets of epididymosomes and prostasomes were resuspended in sample buffer for Western blot analysis.

Electrophoretic protein patterns were transferred on nitrocellulose and probed with antibodies against enzymes of the polyol pathway. The anti-aldose reductase antiserum was raised in rabbit immunized against a recombinant human aldose reductase (AKR1B1) encoded by a cDNA cloned from a human endometrium biopsies cDNA library (generous gift of Dr MA Fortier from Univ Laval, Québec, Canada). The anti-sorbitol dehydrogenase rabbit antiserum was produced against a peptide derived from the sorbitol dehydrogenase–deduced amino acid sequence (Ng et al, 1998) (gift from SK Chung, Hong Kong University). Blots were incubated with the anti-aldose reductase antiserum diluted 1:5000 or with 3.5 µg/mL of rabbit immunoglobulin G (IgG) anti-sorbitol dehydrogenase. Enzymes were detected with a goat anti-rabbit IgG coupled to peroxidase and revealed using enhanced chemiluminescence (ECL) substrate (Amersham, Buckinghamshire, United Kingdom).

Aldose Reductase and Sorbitol Dehydrogenase mRNAs

Epididymal tissues were homogenized in 4 M guanidine thyocyanate, 25 mM sodium citrate, 0.5% sarcosyl, and 0.1 M mercaptoethanol; extracted with phenol-chloroform; and RNAs were precipitated with ethanol (Chomczynski and Sacchi, 1987). RNAs were separated on agarose gels and transferred on a nylon membrane. A probe corresponding to the first 690 nucleotides of the aldose reductase cDNA was random primed with Ready Prime II kit (Amersham Pharmacia Biotech, Buckinghamshire, United Kingdom) and used to probe the nylon membrane. Prehybridization was performed in "Express hyb" (Clontech, Calif) and hybridization was done in the same solution containing 3–4 x 106 dpm/mL labeled probe. The ubiquitous expressed gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used to probe the same membrane.

Northern blot analysis was not sensitive enough to detect sorbitol dehydrogenase mRNA in epididymal tissue homogenates. Reverse-transcribed cDNAs from different epididymal segments were amplified using 5'-ATC-TTC-TTC-TGT-GCC-ACG-CC3' and 5'-GGC-CAC-GTG-TTG-CAG-TAT-CG-3' probes. Reaction conditions were as follows: initial denaturation for 5 minutes at 95°C followed by 32 cycles of denaturation at 94°C for 1 minute, annealing for 1 minute at 55°C, and elongation at 72°C for 1 minute. A 566-bp cDNA fragment was amplified from RNA extracted from each epididymal segment and directly sequenced by the core facilities at our institution.


Figure 2
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  		Figure 2. Western blot of protein from human epididymosomes (E), prostasomes (P), and ejaculated spermatozoa (SP) probed with an anti-aldose reductase (Panel A) or an anti-sorbitol dehydrogenase (Panel B). The quantities of protein or the number of spermatozoa used to perform the Western blots are indicated under each lane. Aldose reductase and sorbitol dehydrogenase are indicated by arrows and molecular weight standards (x103) are indicated on the left.

 
Immunohistological Localization of Aldose Reductase and Sorbitol Dehydrogenase in the Epididymal Tissues

Paraformaldehyde epididymal tissues were embedded in optimal cutting temperature (OCT) immediately after dissection and kept at -80°C until use. Cryosections were washed in phosphate-buffered saline (PBS) and treated for 30 minutes in 3% H2O2 in methanol to inhibit endogenous peroxidases. Histological sections were saturated in 10% goat serum in PBS and incubated with the rabbit anti-aldose reductase antiserum diluted 1:1000 in PBS supplemented with 0.5% goat serum or with 5 µg/mL of rabbit anti-sorbitol dehydrogenase IgG prepared in the same solution. Following incubation with a biotinylated goat anti-rabbit IgG antiserum, the immune complexes were revealed with avidin-peroxidase preformed complex (Vectastain ABC reagent, Vector, Burlingame, Calif). Negative controls were performed with normal rabbit serum diluted 1:1000 in PBS. Histological sections were counterstained with Harris hematoxylin. All tissue sections were processed in parallel to allow for comparison.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Polyol Pathway in Semen

Presence of the polyol pathway enzymes in epididymosomes and prostasomes as well as in proteins extracted from ejaculated spermatozoa was investigated (n = 7). Aldose reductase was detectable in protein extracted from epididymosomes, but at a much lower level than the signal associated with the same amount of protein extracted from prostasomes (Figure 2A). A high signal was obtained when proteins extracted from prostasomes were probed with an anti-sorbitol dehydrogenase. This enzyme was almost undetectable on Western blots of the same amount of protein extracted from epididymosomes (Figure 2B). Both aldose reductase and sorbitol dehydrogenase were associated with ejaculated spermatozoa and showed similar levels of detection on a given semen sample. Both enzymes, however, showed some variability from one semen sample to the other (Figure 2).


Figure 3
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  		Figure 3. Western blot of protein from caput (Ca), corpus (Co), and cauda (Cd) human epididymidis probed with an anti-aldose reductase (Panel A) or an anti-sorbitol dehydrogenase (Panel B). Aldose reductase and sorbitol dehydrogenase are indicated by arrows and molecular weight standards (x103) are indicated on the left.

 
Polyol Pathway in the Epididymis

Western blots performed 4 times on human epididymal protein extracts revealed that both aldose reductase and sorbitol dehydrogenase are immunodetectable (Figure 3). Aldose reductase was detectable at a similar level of expression in the caput and corpus epididymidis, whereas a slightly more intense signal was revealed at the cauda epididymal segment (Figure 3A). Sorbitol dehydrogenase was immunodetectable as a band corresponding to a molecular weight of 39–40 kd in the 3 epididymal segments. A very faint signal was detectable in the corpus when compared to the caput and cauda epididymidis (Figure 3B). Additional bands were associated with high background due to poor antibody titer.

At the immunohistological level, both aldose reductase and sorbitol dehydrogenase were detected in the 3 segments of the human epididymis. The signal was less intense in the caput epididymidis, especially when it was probed with aldose reductase antiserum. The signal was mainly detected in the epididymal epithelium, with a higher labeling at the apical portion of the epithelial cells (Figure 4). Small intraluminal structures are labeled and are thought to be the result of fixation artifact.


Figure 4
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  		Figure 4. Immunohistological localization of aldose reductase (AR) (Panel A) and sorbitol dehydrogenase (SODH) (Panel B) in human caput (Ca), corpus (Co), and cauda (Cd) epididymidis. Presence of antigen is revealed by red staining. Tissue sections were counterstained in blue. Small insertions (Co') are negative controls using preimmune serum.

 

At the transcriptional level, both aldose reductase and sorbitol dehydrogenase mRNAs were detectable in human epididymal tissues. Aldose reductase transcript was detected as a single band of the expected size of 1.5 kb on Northern blots of epididymal RNA (Figure 5). Sorbitol dehydrogenase transcript was undetectable using standard Northern blot protocol but was amplified at the expected size by reverse transcription–polymerase chain reaction nonquantitative assay (Figure 6). Thus, sorbitol dehydrogenase gene was expressed at a much lower level compared to aldose reductase. For both mRNAs, the amount detected was comparable from one epididymal segment to the other (Figures 5 and 6).


Figure 5
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  		Figure 5. (Panel A) Northern blot analysis of aldose reductase (AR) mRNA in the human caput (Ca), corpus (Co), and cauda (Cd) epididymidis. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is used as a housekeeping gene. (Panel B) Densitometric determination of the relative amounts of AR mRNA expressed as ratios of GAPDH.

 

Figure 6
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  		Figure 6. Detection of sorbitol dehydrogenase transcripts by reverse transcription–polymerase chain reaction (RT-PCR) on human caput (Ca), corpus (Co), and cauda (Cd) epididymidis.

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Both aldose reductase and sorbitol dehydrogenase are immunodetectable on protein extracts of ejaculated human spermatozoa. The cellular compartment distribution of these enzymes in spermatozoa, however, remains to be determined, thus limiting the understanding of the role of the polyol pathway in sperm physiology. In human semen, aldose reductase and sorbitol dehydrogenase are not restricted to spermatozoa; they are detectable as components of prostasomes and epididymosomes. Prostasomes are abundant in human seminal plasma and have been shown to play many functions in sperm physiology and modulation of the female reproductive tract (Saez et al, 2003; Ronquist and Nilsson, 2004). The 2 polyol pathway enzymes have also been identified in bovine (Frenette et al, 2004) epididymosomes. Although it is well demonstrated that exosomes from the epididymis intraluminal compartment transfer selected proteins to the sperm surface, the involvement of exosomes from the epididymis or the prostates in the acquisition by spermatozoa of the polyol pathway enzymes remains to be determined. Both sorbitol and fructose are constituents of seminal plasma, and all accessory glands of the rat male reproductive tracts can synthesize these carbohydrates (Kobayashi et al, 2002). In humans, both exosomes and spermatozoa have the enzymes necessary to produce both fructose and sorbitol. Both of these sugars can be used as energy sources by ram (O'Shea and Wales, 1965) and human (Murdoch and White, 1968) spermatozoa. In human semen, involvement of exosomes vs sperm-associated polyol pathways remains to be determined.

The polyol pathway is believed to be involved in the etiology of diabetic complications. It has thus been extensively studied in kidney, retina, and peripheral neurons, the main tissues affected by diabetes (Yabe-Nishimura, 1998; Oates, 2002). Whereas aldose reductase is present in all tissues examined (Markus et al, 1983), sorbitol dehydrogenase tissue distribution shows great interspecies variability (Vaca et al, 1984). As shown in bovine (Frenette et al, 2004) and rat (Kobayashi et al, 2002) models, both aldose reductase and sorbitol dehydrogenase are expressed at the transcriptional and translational levels in human epididymal tissues. Localization of both enzymes in the epididymal epithelium together with their association with human epididymosomes indicate that these enzymes are secreted in the intraluminal compartment. In fact, epididymosomes present in the intraluminal compartment of the excurrent duct are secretory products of the epididymal epithelium that follow an apocrine mode of secretion that has been described in different mammalian species, such as rat (Hermo and Jacks, 2002), mouse (Rejraji et al, 2002), ram (Ecroyd et al, 2004; Gatti et al, 2004), bovine (Frenette and Sullivan, 2001; Frenette et al, 2002), and hamster (Yanagimachi et al, 1985; Légaré et al, 1999a). Association of aldose reductase and sorbitol dehydrogenase with epididymosomes has been shown in bovine (Frenette et al, 2003, 2004) and ram (Ecroyd et al, 2004; Gatti et al, 2004).

In bovine, aldose reductase protein and enzymatic activity is high all along the excurrent duct, except in the distal portion of the cauda epididymidis and vas deferens. Considering that aldose reductase is the limiting enzyme of the polyol pathway (Hers, 1956) and that reduction of glucose in sorbitol is optimum at a slightly acidic pH corresponding the epididymal fluid pH, production of sorbitol is expected to be favored in the epididymis. Sorbitol is a linear sugar and is thus poorly permeable through biological membrane. Thus, sorbitol in the epididymal fluid is not accessible to sperm glycolysis. The high activity of aldose reductase along the epididymis can thus contribute to maintaining sperm motility in a repressive state. A decrease in the aldose reductase activity in the distal cauda epididymidis and vas deferens together with an increase in sorbitol dehydrogenase will favor formation of fructose, a product of sorbitol oxidation that will be more accessible for sperm glycolysis and production of the energy necessary for sperm motility. In bovine, the polyol pathway may thus modulate sperm motility during the epididymal transit (Frenette et al, 2004). The situation appears different in the human excurrent duct. Even though both enzymes of the polyol pathway are expressed at both the transcriptional and translational levels, their distribution along the epididymis seems quite homogeneous. We can thus predict that there is no modulation of sorbitol along the excurrent duct in humans. For obvious reasons, intraluminal concentrations of polyols along the human excurrent duct are, however, unknown.

The need for maintaining sperm motility in a quiescent status within the epididymis may be different in human compared to other mammalian species. Compared to domestic animals and usual laboratory species, morphology of the human epididymis shows many peculiarities. The human caput epididymidis is mainly formed by multiple branched efferent ducts (Yeung et al, 1991), and there is no differentiated initial segment. The cauda epididymidis in human is poorly developed, indicating a poor sperm storage capacity. Whereas the bovine cauda epididymis stores a number of sperm equivalent to 10 to 12 ejaculates (Curtis and Amann, 1981), in humans the epididymis storage capacity is less than 3 ejaculates (Johnson and Varner, 1988; Bedford, 1994). These morphological characteristics of human epididymis reflect the poor development of this single convoluted tubule, which reaches 6 m in length when uncoiled in rat, more than 50 m in large domestic animals, and a modest 5 to 6 m in humans (Bedford, 1994). The sperm transit along the human epididymis is rapid, 2 to 4 days (Bedford, 1994), when compared to the 10- to 12-day journey in other mammalian species (Robaire and Hermo, 1988). In light of these observations, it is obvious that the mechanisms maintaining spermatozoa in a quiescent state during the epididymal transit will not be as critical in humans as they are in animals with more developed excurrent ducts. While the polyol pathway is present in human, it is not differentially expressed along the epididymis as it is in bovine (Frenette et al, 2004) and may thus perform functions other than modulating epididymal sperm motility. Obviously, in humans as in other mammals, mechanisms other than the polyol pathway are involved in the regulation of epididymal sperm motility and metabolism. In many animal models, many genes have been shown to be expressed in specific segments of the epididymis. This appears to not be the case for the polyol pathway enzymes, as has been shown for other gene products (Légaré and Sullivan, 2004). Extrapolation of results from animal models to human epididymal physiology should be handled with caution.


   Acknowledgments
 
We wish to thank Drs MA Fortier and E Madore (Université Laval) for providing us with recombinant aldose reductase and antibodies as well as Dr SK Chung (Hong Kong) for the generous gift of anti-sorbitol dehydrogenase. Mrs C Légaré is acknowledged for technical help and stimulating discussion.


   Footnotes
 
Supported by a Canadian Institutes for Health Research grant to R.S.


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