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From the Departments of * Pharmacology &
Therapeutics and Obstetrics & Gynecology,
McGill University, Montréal, Québec, Canada.
| Correspondence to: Dr Bernard Robaire, McIntyre Medical Sciences Building, 3655 Promenade Sir-William-Osler, Room 104, Montréal, Québec, Canada H3G 1Y6 (e-mail: bernard.robaire{at}mcgill.ca). |
| Received for publication July 2, 2008; accepted for publication October 7, 2008. |
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Abstract |
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Key words: Orchidectomy, regression, cell division
Using tritiated thymidine autoradiographic studies, cell turnover in the epididymal epithelium of rodents has been investigated (Sun and Flickinger, 1982). In the epididymis of the adult rat and hamster, cell proliferation and DNA synthesis are extremely low; among all the cell types, principal cells have the highest proliferative activity (Clermont and Flannery, 1970; Nagy and Edmonds, 1975; Majumder and Turkington, 1976). Principal and basal cells of young adult rats have relatively higher mitotic activity than those of fully mature animals (Clermont and Flannery, 1970). Furthermore, after androgen withdrawal, the incidence of cells undergoing apoptosis is very low, and these cells appear to be primarily principal cells; apoptosis is seen in the epithelium of the initial segment of the epididymis 18 hours after orchidectomy and after 2, 4, and 5 days in caput, corpus, and cauda, respectively, and becomes undetectable by 8 days postorchidectomy (Fan and Robaire, 1998).
The purpose of the present study was to investigate, in all regions of the
epididymis, whether testosterone triggers an enhancement of the proliferative
activity of the regressed epithelial cells over time, leading to
reestablishment of the epithelial cell structure. First, we determined the
morphological changes in the regressed epididymal epithelium after
testosterone administration. Second, we assessed mitotic activity of
epididymal cells by using 2 different mitotic markers, bromodeoxyuridine
(BrdU) and proliferating nuclear antigen (PCNA)
(Muskhelishvili et al, 2003).
BrdU, a halogenated derivative of thymidine, is incorporated into nuclei
during the DNA synthetic phase of the cell cycle
(Gratzner, 1982;
Alison, 1995). PCNA is an
auxiliary protein of DNA polymerases 
and 
, enzymes necessary for
DNA synthesis (Kurki et al,
1986; Bravo et al,
1987; Foley et al,
1993); it is also involved in DNA repair. Using specific markers
for each cell type, we identified whether the proportion of each cell type was
changed upon readministration of testosterone in the regressed epididymis. We
found that principal cells were the major cell type showing mitotic activity
in the regressed epididymis in the presence of testosterone and that
testosterone triggers a restoration of the morphological changes induced by
orchidectomy.
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Materials and Methods |
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Tissue Preparation
Male Sprague-Dawley rats (n = 4–5) were anesthetized with an IP
injection of anesthetic cocktail of Vetalar (ketamine HCL 115.4 mg/mL;
Bioniche, Belleville, Canada), Anased (xylazine HCL 20 mg/mL; Novopharm,
Toronto, Canada), normal saline, and Atravet (acepromazine maleate 10 mg/mL;
Ayerst, Montréal, Canada) 20:10:10:1. The epididymides of each rat were
fixed with Bouin solution via perfusion through the abdominal aorta for 10
minutes. After perfusion, epididymides were removed and cut along their long
axis. The tissues were then immersed overnight in Bouin fixative, dehydrated,
and embedded in paraffin. Sections (6 µm) were cut on a microtome and
mounted on glass slides.
Morphometric Observations
Thirty-five to forty cross sections of each epididymal region (8–10
each from 4 separate rats) were measured to obtain mean values for tubule
diameter and epithelial height. Microvilli were not included in measuring
epithelial height.
Immunohistochemistry for PCNA and BrdU
Immunostaining was done as described previously
(Carroll et al, 2006). Mouse
anti-PCNA (1:3000) and BrdU (1:500 [3 µg/mL; Sigma]) affinity-purified
monoclonal antibodies were used. Negative controls were processed in parallel,
but without the primary antibodies. Using a light microscope, we analyzed the
number of immunoreactive cells, as determined from the observation of 100
tubules from 3 cross sections of each epididymal region (n = 4–5).
Immunohistochemical Staining of Epididymal Cell Types
Sections were prepared and immunostained as described above, using a
Vectastain Elite ABC Kit (Vector Laboratories, Burlingame, California). Rabbit
anti-GSTpi (GSTP1) antibody (1:250 [20 µg/mL]; MBL International, Woburn,
Massachusetts) was used to identify basal cells; GSTP1 is localized in
principal and basal cells of the initial segment and caput and in basal cells
of the corpus and cauda epididymidis; its expression is independent of
testicular fluid (Hermo and Papp,
1996). Rabbit anti-V-ATPase B1/2 (vacuolar proton
adenosinetriphosphatase, ATP6V1B1) polyclonal antibody (1:250 [0.8 µg/mL];
Santa Cruz Biotechnology, Inc, Santa Cruz, California) was used for clear
cells; ATP6V1B1 pumps were immunolocalized in the narrow cells and clear cells
of the epididymis (Hermo et al,
2000). Goat anti-CD4 polyclonal antibody (1:50 [4 µg/mL]; Santa
Cruz) was used for halo cells (Serre and
Robaire, 1999). Rabbit anti-clusterin (CLU)-alpha/beta polyclonal
antibody (1:50 [4 µg/mL]; Santa Cruz) was used for principal cells
(Hermo et al, 1991). For each
rat (n = 4/group), 5 or 6 cross sections of corpus epididymidis from the
control and 3 days postimplantation groups were stained and measured to obtain
the proportion of each cell type.
Serum Testosterone Analysis
At the time of sacrifice, blood was collected and serum was obtained by
centrifuging the blood for 2 minutes at 12 000 x g.
Supernatants were collected and frozen at –20°C for further
analysis. A commercially available testosterone enzyme-linked immunosorbent
assay kit (Research Diagnostics, Flanders, New Jersey) was used to measure the
total serum testosterone concentration in each group, according to the
manufacturer's instructions. Sensitivity of the assay was 0.1 ng/mL, and the
intra-assay coefficient of variation was less than 10%. Serum testosterone
values were 2.6 ± 0.8 ng/mL in the sham control, undetectable in the
orchidectomized group with empty implants, and 8.4 ± 2.7 ng/mL in the
orchidectomized group with testosterone implants (n = 5/group).
Statistical Analysis
Statistical analysis was done using 1-way ANOVA followed by the multiple
comparisons Dunnett's test or unprotected t test. Data were expressed
as 
± SEM. Values of
P 
0.05 were regarded as statistically significant.
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Results |
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Because of the similarity of the results observed, we show BrdU and PCNA immunostaining in the initial segment and corpus regions only at 3 and 28 days. After orchidectomy, immunoreactivity for BrdU was undetectable at all time points (Figure 4a, c, e, and g), whereas after testosterone replacement the number of cells that immunostained positively for BrdU had clearly increased after 3 days. A similar pattern was observed for PCNA immunostaining, with the exception that a few cells were stained in the regressed epididymis after 3 days (Figure 5a and e); however, the number decreased to an undetectable level by 28 days (Figure 5c and g). After testosterone replacement, PCNA-positive cells were detected after 1 day and increased over time (Figure 5b, d, f, and h). The corpus epididymidis at 3 days appeared to show maximal staining (Figure 5f). Tubules were deformed after orchidectomy, but they attained their normal shape after testosterone replacement.
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Quantitative Study of Cell Proliferation
BrdU incorporation and PCNA expression were seen in control rat
epididymides in all regions (Figures
6 and
7). BrdU incorporation was not
seen at any time after orchidectomy (Figure
6). A constant level of PCNA expression was seen in regressed
epididymides; the relative number of PCNA-positive cells had not changed by
day 7, but had decreased sharply by day 28 in all segments
(Figure 7). After testosterone
administration, BrdU incorporation and PCNA expression increased in a
segment-specific and time-dependent manner. Neither marker was significantly
increased in any region of the regressed epididymis 1 day after testosterone
replacement. The incorporation of BrdU and expression of PCNA were relatively
constant in the initial segment and were lower than those in controls (Figure
6A and
7A). In the caput epididymidis,
testosterone treatment returned the degree of incorporation of BrdU to control
levels by 7 days and was not further exceeded
(Figure 6B), whereas the
expression of PCNA reached control levels as early as 3 days and kept on
rising to nearly 3 times that level by 28 days. The corpus epididymidis showed
the highest levels for both markers, and this was reached at the 3-day
treatment time point (Figures
6C and
7C); after that time, the
relative number of positive cells decreased, suggesting that there is a limit
to the number of new cells despite the constant level of testosterone. By 3
days after testosterone replacement, the number of BrdU- and PCNA-positive
cells in the cauda epididymidis had returned to that of the control; the
number of BrdU-positive cells peaked at 7 days, whereas that of PCNA-positive
cells was highest at 28 days.
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The highest relative incorporation of BrdU in the regressed epididymides after testosterone replacement vs control was approximately 0.3 in the initial segment, 1 in the caput at 28 days, 5 in the corpus at 3 days, and 2.5 in the cauda at 7 days. Relative to BrdU, expression of PCNA was always higher in all regions at all time points; this may be because of an increase in the number of cells involved in repair.
Immunohistochemical Analysis for Different Cell Types
In order to determine whether cells undergoing division were of a specific
cell type(s), we used selective markers for each cell type to identify the
proportion of each cell type at 3 days after replacement with either empty
implants or testosterone-filled implants in the regressed corpus epididymidis;
the 3-day postimplantation time point was selected because of the large number
of labeled nuclei observed at this time point in this region. Using GSTP1 as a
basal cell marker for this region, we noted intense staining in the nuclei of
these cells in all groups of animals; they made up nearly 20% of the total
cells. The shape of basal cells was changed after orchidectomy; testosterone
replacement could not restore the shape, as anticipated because of the lack of
internal luminal pressure (Figure 8a, c,
and e). Intense staining in apical regions of clear cells of the
corpus epididymidis was seen in all groups of animals. The proportion of clear
cells, as identified by ATP6V1B1 staining, seen in the control and
orchidectomized rats, with empty or testosterone implants, was nearly
identical and represented approximately 7% of all cells
(Figure 8b, d, and f). The
relative contribution of halo cells, identified as CD-4–positive cells,
was 4% in the control and was slightly increased by 10% to 4.4% in
orchidectomized rats with either empty or testosterone implants (data not
shown). Sulfated glycoprotein-2 (clusterin) is localized in the cytoplasm of
all principal cells along the epididymal duct (data not shown). No significant
change was observed in the proportion of principal cells in treated animals
compared with the control. These results suggest that all the cell types can
be divided in control groups. Although orchidectomy decreases the
proliferating activity, testosterone replacement induces cell proliferation in
all cell types. Thus, dividing cells have no impact on the relative cell
populations in the epididymal epithelium.
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Discussion |
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Although there is general agreement in the literature that orchidectomy results in a reduction in epididymal weight, tubule diameter, epithelial height, and enzyme activities (Fawcett and Hoffer, 1979; Moore and Bedford, 1979a), previous studies have not clarified the role of androgen action in maintaining the epithelial cell height and the number of new cells in the regressed epididymis and after testosterone replacement. In this study, we found that orchidectomy resulted in a major decrease in tubular diameter in all regions; even after treatment with testosterone for 28 days, this decrease in tubule diameter was not reversed; presumably, this is because of the removal of the fluid that moves continuously from the testis to the epididymis in the intact animals. However, the tubule diameter is significantly increased in treated animals compared with those receiving empty implants (Figure 1). From the changes in epithelial cell heights because of androgen withdrawal, it is apparent that there is an almost 40% decrease in the initial segment and a 40% increase in the cauda region. It appears that the caput and corpus are transition regions from the initial segment to the cauda; epithelial cell height was slightly decreased in the caput and slightly increased in the corpus regions, respectively (Figure 2). In the cauda region after orchidectomy, the diminished luminal content and tubular diameter presumably result in decreased intraluminal pressure, with a consequent increase in the epithelial height; one would expect the cell volume to remain unchanged. However, the large decrease in tubular diameter and cell height in the initial segment can be attributed to diminishing cell volume. A significant increase in epithelial cell height was found after testosterone replacement in regressed epididymides in all regions. We propose that, in the regressed epididymis, testosterone increases both the re-expansion of existing cells and the number of new cells.
In 2.5-month-old rats, 2.2% of principal cells and 1.4% of basal cells of the whole epididymis were labeled after a single injection of 3H-thymidine; this number decreased with age (Clermont and Flannery, 1970). Immunohistochemical evaluation of BrdU labeling of epithelial cells in different epididymal regions has established that the number of nuclei labeled was significantly higher in the caput than in the corpus and cauda (Ramirez et al, 1999). However, the number of cells that are proliferative in the epididymal epithelium after regression and even after testosterone replacement has not been investigated previously. The present results are consistent with the previous reports for the percentage of cell proliferation in intact rats. The weights of the seminal vesicles, coagulating glands, and prostates increase 5–8-fold with 1 mg of testosterone over 2 weeks, after 1-month orchidectomy, whereas epididymal weights increase by only 2-fold (Tuohimaa et al, 1973). Orchidectomy decreases the mitotic activity of the accessory sex organs such as the seminal vesicles and prostate to nondetectable levels; testosterone treatment after 68 hours increases their labeling indexes to 34-fold and 20-fold, respectively (Tuohimaa and Neimi, 1968). Similarly, we found that in the regressed epididymis, the number of BrdU-labeled nuclei decreased to nondetectable levels at all time points. Using the PCNA antibody, we found that the number of nuclei labeled for PCNA is decreased to an undetectable level at 28 days, suggesting that there are cells involved in repair even at 7 days postregression, but not after 28 days. After testosterone replacement, epithelial cells respond to androgen; BrdU incorporation and PCNA expression were differentially increased in a segment-specific and time-dependent manner. Interestingly, the time course of labeling with PCNA appears to be similar to that with BrdU; this level is always higher in PCNA expression than that in BrdU incorporation. A probable explanation is that PCNA is also involved in DNA repair (Toschi and Bravo, 1988; Shivji et al, 1992; Wood and Shivji, 1997), suggesting that it may be expressed by cells that are not cycling; overall, its expression increases during the G1 phase, peaks at the S phase, and declines during G2/M of the cell cycle (Foley et al, 1993). Moreover, the long half-life of PCNA leads to its continuous expression in some cells that are not actively dividing (Morris and Mathews, 1989; Scott et al, 1991). At 3 days postimplantation, testosterone treatment caused extensive mitotic activity, followed by rapid decrease in the corpus, slow increase in the caput and cauda, and constant level in the initial segment (Figures 5 and 6), suggesting that rates and extent of cell proliferation in response to hormone are determined by regional considerations. The latter result agrees with those who reported that in addition to the regulation mediated by androgen, luminal factors also play a role in regulating epididymal function; these are crucial factors for the initial segment (Robaire et al, 1981; Viger and Robaire, 1991; Hinton et al, 1998). The highest mitotic activity shown in the corpus at 3 days indicates the specificity of this region in response to testosterone. That is presumably because of the differences in blood-epididymis barrier in this region.
Specific markers were used to assess the changes in the proportion of each cell type. As previously reported, no changes were found in the proportion of clear cells after orchidectomy (Moore and Bedford, 1979b) or even after testosterone replacement. The nonsignificant change found in the proportion of halo cells at 3 days post–testosterone implantation in the corpus epididymidis could be explained by a transient increase in the number of halo cells in response to testosterone. Halo cells consist of the main types of immune cells, and their distribution in the epididymis increases during aging (Serre and Robaire, 1999). In general, higher concentration of immune cells appeared to be correlated with major alterations of the epithelial structure, such as lysosome accumulation (Serre and Robaire, 1998), suggesting that the recruitment of lymphocytes is an important factor for modification of epithelial integrity.
Mammalian epididymides are often considered as a static tissue without significant cell renewal. However, our observations indicate that there is low cell proliferation in all cell types of the control rat epididymis. Although orchidectomy reduces cell proliferation to undetectable levels, testosterone replacement triggers cell proliferation in a segment-specific and time-dependent manner. Tubule sizes and epithelial cell heights were enlarged after testosterone administration in the regressed epididymides, as judged by histological evaluation. These changes may indicate an increase in the number of new cells and re-expansion of existing cells; these findings illustrate the role of androgen in restoring cellular architecture in the regressed epididymis.
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Footnotes |
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