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Journal of Histochemistry & Cytochemistry
Effects of Estradiol on Prostate Epithelial Cells in the Castrated Rat
The online version of this article can be found at:
can be found at: Journal of Histochemistry & Cytochemistry Additional services and information for Volume 50(11): 1517–1523, 2002 The Journal of Histochemistry & Cytochemistry Effects of Estradiol on Prostate Epithelial Cells in the Castrated Rat
Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL), and Laval University, Québec, Canada
There is evidence that estrogens can modulate the activity of prostate epithe-
lial cells. To determine whether estradiol can have a direct influence on rat prostate, thisstudy examined the effects of estradiol-17 (E2) administered alone or in combination withdihydrotestosterone (DHT) to castrated rats for 3 weeks on prostate binding protein (PBP)C1 mRNA expression and androgen receptor (AR) localization. PBP C1 mRNA levels weremeasured by semi-quantitative in situ hybridization using a 35S-labeled cDNA probe. In in-tact animals, strong hybridization signal could be observed in prostate sections after 12 hrof exposure to Kodak X-Omat films. In castrated rats, no PBP C1 mRNA could be detectedeven with longer exposure times, an effect that was prevented by administration of DHT. E2 administered alone induced a detectable hybridization signal, and the concomitant ad-ministration of E2 and DHT induced an increase in PBP C1 mRNA that significantly exceededthat obtained in animals that received only DHT. In prostate epithelial cells of intact ani-mals, AR immunostaining was restricted to the nucleus. In castrated animals the alveoliwere decreased in size and the epithelial cells were atrophied. AR staining was weak andwas detected in both cytoplasm and nucleus. DHT administration completely obviated theeffect of castration on epithelial cell histology and on AR immunostaining distribution andintensity. Interestingly, E
K E Y W O R D S
2 administration alone induced moderate hypertrophy of epithe-
lial cells compared to the histological appearance of cells in untreated castrated rats. More-
2-treated animals the nuclear staining was much stronger than that detected in
untreated castrated rats, whereas the cytoplasmic staining was not modified by the treat-
ment. In animals that received both DHT and E
2, the staining was similar to that seen in
DHT-treated rats. These results suggest that E
2 can influence the activity of rat prostate ep-
ithelial cells by mechanisms that remain to be fully clarified. (J Histochem Cytochem 50:1517–1523, 2002) The prostate is a highly androgen-dependent tissue
ventral prostate (Heyns and De Moor 1977). This
(Roy and Chatterjee 1995). In the human and rat
protein consists of two subunits, each containing
prostate, androgen receptors (ARs) have been local-
polypeptide C1 and either polypeptide C2 or C3, all
ized to epithelial secretory cells, stromal cells, and en-
of which are under androgenic control (Parker et al.
dothelial cells in capillaries and large blood vessels
1980; Page and Parker 1982). To measure androgen-
(Iwamura et al. 1994; El-Alfy et al. 1999; Pelletier
dependent prostate activity, the expression of PBP C1
2000; Pelletier et al. 2000). Prostate steroid-binding
mRNA in epithelial cells is a very suitable parameter
protein (PBP) is the major secretory protein of the rat
During the past few years accumulating evidence
suggests that estrogens can play a physiological role in
Correspondence to: Dr. Georges Pelletier, Oncology and Molec-
male reproduction (Sharpe 1998; Simpson et al.
ular Endocrinology Research Center, Laval University Hospital
2000). It is well documented that prostate tissue from
(CHUL), 2705 Laurier Boulevard, Quebec, PQ G1V 4G2, Canada.
several species contains estrogen receptors (ERs)
E-mail: [email protected]
(Tilley et al. 1980,1985; Swaneck et al. 1982; West et
Received for publication February 27, 2002; accepted June 5,
al. 1988). Recently a second ER, called ER, has been
cloned from a rat prostate library (Kuiper et al. 1996),
experiment was duplicated and essentially the same results
and the original one is now designated as ER␣. ER
expressed at high levels in rodent and primate prostate(Kuiper et al. 1996,1997; Couse et al. 1997; Pelletier
2000; Pelletier and El-Alfy 2000; Pelletier et al. 2000).
The plasmid containing cDNA, corresponding to the C1
Low levels of ER␣ mRNA have also been reported in
peptide of PBP cloned in the Pst-1 site of pS64, was provided
rat prostate (Kuiper et al. 1997; Lou et al. 1998). In
by Dr. M.G. Parker (London, UK). The Pst-1 restriction
rat prostate, ER was localized by in situ hybridiza-
fragment was radiolabeled with [ S]-CTP (NEN Life Sci-
tion and immunocytochemistry in epithelial cells in al-
ence Products; Boston, MA), as previously described (Pelle-tier et al. 1988). As control, sections were treated with
veoli (Prins and Birch 1997; Pelletier 2000; Pelletier et
pancreatic RNase A (20 g/ml; Boehringer Mannheim;
al. 2000), whereas no ER␣ expression could be de-
Mannheim, Germany) for 1 hr at 37C before hybridization.
There is some evidence that estrogen itself can exert
an influence on prostate epithelial cell division and
Frozen sections (10 m) were serially cut at –20C and
differentiation. Estrogen administration to castrated
mounted on gelatin- and poly-l-lysine-coated slides. In situ
or hypophysectomized dogs induced glandular hyper-
hybridization was performed as previously described (Pelle-
plasia (Leav et al. 1978; Tunn et al. 1979). In the No-
tier et al. 1988). After hybridization, the sections were ex-
ble rat, estrogen synergizes with androgens to induce
posed to Kodak X-Omat films (Eastman Kodak; Rochester,
glandular hyperplasia and dysplasia (Leav et al. 1989;
NY) for 12 hr. For each experimental group, densitometric
Lou et al. 1998). On the other hand, ER knockout
measurements of autoradiographs of whole sections (six sec-
mice display local prostate hyperplasia with aging
tions/rat) were obtained using an optical system coupled to a
(Krege et al. 1998), suggesting that ER might exert a
Macintosh computer and image software (version 1.6.0 non-
negative regulation on prostate growth.
FPU; W. Rasband, NIH, Bethesda, MD). The optical density
To study the involvement of estrogens in prostate
(OD) of the signal was measured under illumination. TheOD of each tissue was corrected for the average back-
epithelial cell functions, we evaluated the effects of E2
ground signal. Comparisons of the OD between experimen-
administered alone or in combination with DHT to
tal groups was performed by an analysis of variance (Stat-
castrated adult male rats on the expression of PBP C1
mRNA, as evaluated by in situ hybridization and theimmunohistochemical localization of AR.
AR immunostaining was performed on paraffin sections
Materials and Methods
(two sections/glass slide) as previously described (Pelletier2000; Pelletier et al. 2000). An affinity-purified rabbit poly-
clonal antibody reacting with rat AR (N-20; Santa Cruz Bio-
Thirty adult male Sprague–Dawley rats (Charles River;
technology, Santa Cruz, CA) was used at a concentration of
Wilmington, MA) weighing 225–250 g at the beginning of
1 g/ml. This antibody has been successfully used to localize
the experiments were housed under constant temperature
AR in several tissues, including the prostate (Pelletier and El-
(21 Ϯ 1C) and lighting (light on from 0600 to 2000) regi-
Alfy 2000; Pelletier et al. 2000). Control reaction was ob-
mens. They had free access to standard rat chow and tapwa-
tained by substituting preabsorbed antibody with an excess
ter. All the protocols were approved by the Laval Univer-
of the peptide used as an antigen (20 g/ml). After immuno-
staining the sections were counterstained with hematoxylin. To avoid any variations related to the staining procedure,
two sections from each of the 30 prostates (six prostates/
Four groups of animals (six per group) were castrated via
group) were stained in the same run. In each run, immuno-
the scrotal route. One group of sham-operated rats was used
absorption controls (one for each experimental group) were
as intact control. The castrated animals were treated twice
also included. We thus proceeded to four runs. The results
were evaluated by two independent investigators who were
roids were administered SC in 0.5 ml 1% (w/v) gelatin. Theintact animals received only the vehicle (1% gelatin). Thesteroids were purchased from Steraloids (Wilton, NH). On
the morning after the last day of the treatment, animals were
perfused transcardially with 200 ml 4% (w/v) paraformalde-
As shown in Figure 1A, in vehicle-treated, sham-oper-
hyde in 0.1 M phosphate buffer (pH 7.4). Ventral prostates
were excised and postfixed in the same fixative for 48 hr at
ated animals, hybridization with the S-labeled PBP
4C. For immunocytochemistry, the tissues were embedded
C1 cDNA probe induced a strong signal in prostate
in paraffin. For in situ hybridization, the tissues were placed
sections after 12 hr of exposure. Pretreatment of the
in 15% sucrose in 0.1 M phosphate buffer before being
sections with RNase before hybridization completely
quickly frozen in isopentane chilled in liquid nitrogen. This
prevented any labeling (not shown). In castrated ani-
Effects of E2 on Prostate Epithelial Cells
X-ray autoradiographs illustrating the expression of PBP C1 mRNA in rat prostate sections (exposure time 12 hr). (A) Vehicle-
treated intact (INT) rats. (B) DHT-treated castrated (CX) rats. (C) E2-treated castrated rats. (D) Castrated rats treated with both DHT and E2. No detectable reaction could be obtained in sections from vehicle-treated castrated rats. Bars ϭ 4 m.
mals no detectable signal could be obtained even after
intact animals (Figures 1C and 2). Figures 1D and 2
longer exposure times (up to 7 days; not shown). As
show the effect of the administration of both DHT
shown in Figures 1B and 2, administration of DHT to
and E2 on the mRNA levels, which exceeded by 16%
castrated rats completely obviated the effects of cas-
(pϽ0.001) those observed in DHT-treated animals.
tration, the mRNA levels being 18% above the levelsmeasured in vehicle-treated, sham-operated animals
(pϽ0.001). Administration of E2 induced a hybridiza-
In prostate sections from vehicle-treated, sham-oper-
tion signal that could be detected after 12 hr of expo-
ated animals immunostained for AR localization,
sure, the measured PBP C1 mRNA levels correspond-
strong labeling was detected in nuclei of all secretory
ing to approximately 3% of the values obtained in
epithelial cells. The cytoplasm of the epithelial cells
those observed in animals treated only with DHT (Fig-ure 3E). Discussion The present results clearly demonstrate that 3-week administration of E2 can stimulate the mRNA expres- sion of a prostate androgen-dependent protein, PBP C1, in adult castrated rats. The effect of E2 was weak but significant because no hybridization signal could be observed in untreated castrated rats. Moreover, E2 was also effective in stimulating PBP C1 mRNA levels when the activity of epithelial cells was maintained by DHT administration. These data strongly suggest that E2 can directly stimulate the activity of prostate epi- thelial cells in the absence or presence of circulating
Effects of castration and DHT and E2 administration to
castrated rats on PBP C1 mRNA levels as evaluated by semi-quanti-
The hypertrophy of epithelial cells after administra-
tative in situ hybridization. INT, intact animals; C, control (vehicle-
treated). Results are expressed as a percentage of the control value
2 suggests that estrogens can directly stimu-
(vehicle-treated intact animals). ***p Ͻ 0.001 DHT-treated cas-
late the activity of secretory epithelial cells. These re-
trated rats vs all the other experimental groups; ND, non-detect-
sults are in agreement with several reports indicating
that administration of estrogen to castrated or hypo-physectomized animals could exert a stimulatory in-fluence on prostate epithelial cells. In castrated or hy-pophysectomized dogs, estrogen induced hypertrophyof epithelial cells (Leav et al. 1978; Tunn et al. 1979;
did not exhibit any labeling (Figure 3A). Other immu-
Merk et al. 1980,1986; Kwan et al. 1982). Similarly,
nostained nuclei in the stroma surrounding the alveoli
in castrated rats, estrogens increase epithelial cell
were also consistently observed. In castrated animals,
height in the ventral prostate (Salander and Tisell
as shown in Figure 3B, the alveoli were markedly re-
1976; Thompson et al. 1979; Timms and Chandler
duced in size and appeared dispersed throughout the
1985). Moreover, it has been shown that, in the Noble
stroma, which was not modified. The epithelial cells
rat prostate, androgen-supported estrogen could be re-
had a cuboidal appearance, with markedly reduced
sponsible for epithelial proliferation and dysplasia
cytoplasm and an increased nuclear-to-cytoplasmic ra-
(Leav et al. 1989; Lou et al. 1998). Our data also
tio. In contrast to the observations in sham-operated
clearly show that, in DHT-treated animals, E2 could
rats, immunostaining was present in both cytoplasm
further increase PBP C1 mRNA expression. It thus ap-
and nuclei, with a marked reduction in nuclear label-
pears reasonable to hypothesize that estrogens can po-
ing. The staining of stromal cells did not appear to
tentiate the effects of androgens on prostate epithelial
have been modified by castration. As shown in Figure
cell activity. Recently, Yeh et al. (1998) have reported
3C, treatment with DHT completely reversed the ef-
that E2 can activate androgen target genes in the pros-
fect of castration on the epithelial cells. The histology
tate via an interaction with the AR complex.
and AR localization were very similar to what has
AR immunolocalization showed that, in intact ani-
been observed in vehicle treated, sham-operated ani-
mals, the staining was restricted to nuclei in epithelial
mals, with nuclei being strongly immunoreactive. In
cells. After castration there was a marked reduction in
castrated animals treated with E2, the size of the alve-
nuclear labeling and, contrary to what was observed
oli was not modified, but the epithelial cells appeared
in sham-operated rats, cytoplasmic labeling was con-
hypertrophied compared to those observed in vehicle-
sistently found. These results are in agreement with
treated castrated rats (compare Figures 3D and Figure
previous findings indicating a decrease in nuclear an-
3B). The nucleus:cytoplasmic ratio appeared to be de-
drogen-binding sites in ventral prostate in 2-week cas-
creased by E2 treatment. Moreover, in the E2-treated
trated rats (Prins 1989). The presence of immunoreac-
animals the intensity of the reaction was very different
tive material in the cytoplasm of epithelial cells may
from that observed in vehicle-treated castrated rats.
therefore reflect retention of AR in the cytoplasmic
The nuclei were strongly labeled and light cytoplasmic
compartment. It is well known that binding of a ste-
staining was present (Figure 3D). In the stroma, AR
roid (including androgens) to its receptor molecule re-
labeling was also stronger. In animals that received
sults in activation of the receptor in the cytoplasmic
both DHT and E2, the results were very similar to
compartment (Clark et al. 1992). The activated recep-
Effects of E2 on Prostate Epithelial Cells
Immunocytochemical localization of AR in rat prostate
sections. (A) Vehicle-treated intact rats. Nuclear staining is ob- served in all epithelial cells (E). (B) Vehicle-treated castrated rats. The epithelial cells are atrophied. Both nucleus and cytoplasm are weakly labeled. (C) DHT-treated castrated rats. The treatment has completely obviated the effect of castration (compare to A). (D) E2- treated castrated rats. The cytoplasm of epithelial cells (E) is larger than that observed in untreated castrated rats. The nuclear stain- ing is much stronger compared to that seen in untreated castrated rats (B). (E) Castrated rats treated with both DHT and E2. Staining is similar to that observed in DHT-treated rats (C). Bars ϭ 25 m.
tor–steroid complex, which has a high affinity for var-
mechanism(s) of action of E2, which might involve in-
ious nuclear binding sites, then migrates to the nu-
teraction with ER and/or AR, remains to be fully
cleus. In castrated rats that were treated with DHT,
clarified. Other studies involving use of anti-estrogens
no cytoplasmic staining could be detected, whereas
and anti-androgens would help to clarify the exact
strong nuclear staining similar to that observed in
role of estrogens in prostate regulation.
sham-operated animals was present. The histology ofthe epithelial cells was also very similar to that ob-served in intact animals. This appears to be a morpho-
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Anal. Chem. 2004, 76, 3285-3298 Electrochemical Sensors Eric Bakker Department of Chemistry, Auburn University, Auburn, Alabama 36849 Review Contents sensors, even though they are classified as microscopic tech-niques. Hyphenated systems, such as microdialysis probescoupled to an electrochemical detection system, optionally afteran on-line separation step, act as sensors as well. Th
Minutes of the FIA Council Meeting held on Tuesday 10th May 2005 at The Saracens Head Hotel, Towcester at 10.00 a.m. Mike Phillips – ChairmanMike Gilmore – TreasurerPeter LythgoeJohn ColtonLee FunnellDr. Nick Channon 1. Apologies Minutes of the previous meeting held on 9th March 2005 The minutes of the previous meeting held on 9th March 2005 were taken as read and agreed and we