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Department of Urology, University of Illinois College of Medicine, Chicago, Illinois 60612
Address all correspondence and requests for reprints to: Gail S. Prins, Ph.D., Department of Urology, M/C 958, University of Illinois, 820 South Wood Street, Chicago, Illinois 60612.
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Abstract |
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Autoregulation of ER expression was next examined in adult prostates that had been exposed to oil or estrogens neonatally. Day 70 rats were castrated and given testosterone with or without estradiol for 7 days before death. Estrogen exposure in adulthood induced low levels of epithelial cell ER in the lateral lobe. Neonatal estrogenization increased the sensitivity of lateral lobe epithelial cells to this autoregulation, as the incidence and intensity of ER immunostaining were markedly increased. No autoinduction of ER was observed in adult ventral or dorsal prostatic lobes.
From the present study we conclude that smooth muscle cells are the targets of estrogen action in the developmentally estrogenized prostate and that estrogen amplifies its own effects through auto-up-regulation of ER. In addition, lateral lobe epithelial cells are sensitive to estrogen up-regulation of ER, which may in part account for the lobe-specific effects observed after neonatal estrogenization of the prostate gland.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To further delineate the mechanism of estrogen imprinting, it is necessary to determine which prostatic cells are the direct targets of estrogen action at the time of exposure. Using autoradiography, Cooke et al. (11) localized estrogen receptor (ER) to the mesenchymal cells of the newborn murine prostate. As mesenchymal cells differentiated, smooth muscle cells lost ER, whereas fibroblasts retained [3H]estrogen labeling through postnatal day 10. The prepubertal dorsolateral guinea pig prostate was also shown to contain ER-positive stromal cells by immunocytochemistry (12); however, those researchers concluded that ER-positive cells were a subpopulation of smooth muscle cells. Although this combined work suggests that mesenchymal/stromal cells may be the direct target of estrogen action in the developing prostate gland, the specific cell type in the rat prostate is presently unclear.
Neonatal exposure to estrogen or diethylstilbestrol (DES) has been shown to stimulate the expression and detectability of uterine ER in female mice (13, 14), whereas neonatal DES induced the expression of ER in murine male reproductive tract tissues (15). In addition, prenatal exposure to DES has been shown to induce both stromal and epithelial ER in murine seminal vesicles (16). As estrogen is known to up-regulate the expression of its cognate receptor in many tissues (17), autoregulation must be considered when evaluating the mechanisms of estrogen in neonatally estrogenized rat prostates. The first goal of the present research was to localize estrogen target cells in the developing rat prostate lobes and to characterize the effects of neonatal estrogenization on the ER expression pattern at both the protein and messenger RNA (mRNA) levels. We next sought to determine whether neonatal estrogen exposure leads to increased prostatic sensitivity to estrogens in adulthood. This may be significant because neonatally estrogenized rat prostates exhibit lobe-specific epithelial dysplasia and squamous metaplasia with aging (6, 18), and estrogen levels increase in the aging male (19). We chose to examine ER expression in the adult prostate after a brief exposure to estrogen to determine whether the glands were more sensitive to autoregulation of ER and thus potentially more sensitive to estrogenic effects as adults.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In Exp I, pups from both treatment groups were killed by decapitation on days 6, 10, 15, 30, and 45. In addition, oil control pups were killed on days 1, 3, and 5. Accessory sex gland complexes were quickly removed and placed in ice-cold PBS. Prostatic complexes or individual lobes were microdissected at 4 C using watchmakers forceps under a dissecting microscope. The tissues used for immunocytochemistry were arranged on a nylon square, covered with OCT compound (Miles Laboratories, Elkhart, IN), frozen in liquefied propane, and subsequently stored in liquid nitrogen.
In Exp II, adult rats were treated with estrogen. As this treatment
would affect the pituitary-testicular axis and result in decreased
circulating testosterone, we castrated our adult animals and
administered replacement testosterone to maintain constant circulating
levels. Rats from both neonatal oil- and estrogen-treated groups were
castrated on day 70, and each received a 2-cm sc SILASTIC brand implant
(id, 1.575 mm; od, 3.175 mm; Dow Corning, Midland, MI) packed with
crystalline testosterone (Sigma) to maintain circulating levels of
about 1.5 ng/ml testosterone (8). Half of the animals in each group
were additionally given 2-cm sc SILASTIC implants packed with
crystalline estradiol (Sigma). Previous work has shown that this tube
length in 70-day-old Sprague-Dawley rats provides 
100 pg/ml
estradiol (20). All rats were killed by decapitation 1 week later, and
their prostates were removed. The individual ductal systems of the
ventral, dorsal, and lateral lobes were microdissected at 4 C and
frozen in liquefied propane, as described above, before final storage
in liquid nitrogen. The lateral lobe contains two ductal morphologies,
termed LP1 and LP2 (21), and these were individually microdissected and
stored. The ducts were sectioned along their longitudinal axis, so that
proximal, central, and distal tip regions were easily
distinguished.
Immunocytochemistry
Prostatic tissue was examined for ER expression by an indirect
immunocytochemical method, as previously described (22, 23). Briefly,
frozen prostatic complexes or individual lobes were mounted on
precooled chucks (-20 C) in a Reichert-Jung cryostat. Whenever
possible, individual lobes were sectioned longitudinally to reveal the
proximal-distal orientation. Sections (6 µm) were thaw-mounted on
gelatin-coated glass slides and freeze-substituted for 2 days in
anhydrous acetone containing calcium chloride at -90 C. The
freeze-substituted sections were warmed to -20 C and transferred to 4
C, where subsequent fixation and rinsing were performed. The sections
were fixed in 2% paraformaldehyde, rinsed, incubated with 2% blocking
serum (goat), and incubated overnight at 4 C with ER-21 (2 µg/ml), a
rabbit polyclonal anti-ER antibody raised against a synthetic peptide
corresponding to the first 21 amino acids of the rat ER (a gift from G.
Greene, University of Chicago, Chicago, IL). The primary antibody was
reacted with an antirabbit IgG biotinylated secondary antibody, and the
biotin was detected with an avidin-biotin peroxidase kit (ABC-Elite,
Vector Laboratories, Burlingame, CA) using diaminobenzidine
tetrachloride as a chromagen. As a final step, the sections were
dehydrated gradually with alcohol, cleared with xylene, and
coverslipped with Permount (Fisher Scientific, Itasca, IL). Some
sections were stained with Gill’s no. 3 hematoxylin (1:4) as a blue
nuclear counterstain. The various regions of the resultant
immunostained ducts were classified as proximal, central, or distal
depending on their distance from the urethra (24). For comparative
studies, tissues from Exp I or Exp II for control and estrogenized rats
were always run in the same immunocytochemical assay to reduce
discrepancies related to interassay variability in staining intensity.
Photographs were taken with an Olympus microscopic system (Olympus
Corp., New Hyde Park, NY) using Kodak Ektachrome Elite 100 film or
Technical Pan black and white film (Eastman Kodak, Rochester, NY).
ER-21 has been previously characterized for immunocytochemistry in rat brain and shown to identify the same ER-positive cells as H222 and ER715 anti-ER antibodies (25). It produces a single band on Western blots of ER-positive tissues at 66 kDa (Greene, G., personnel communication). Sections of negative control tissue (rat spleen) and positive control tissue (rat uterus and human mammary tumor) were incubated with ER-21 for every ER immunocytochemical assay. Rat spleen, which does not express ER, was always devoid of nuclear staining, whereas uterine epithelial and stromal cells and mammary tumor epithelial cells showed a dark nuclear reaction product. Substitution of normal rabbit IgG (Vector Laboratories) for the primary antibody produced a faint background cytoplasmic staining. Competition studies with the antigenic peptide (amino acids 1–21 of rat ER) were performed to demonstrate specificity. Three serial sections were incubated with 1) ER-21 antibody alone (2 µg/ml), 2) ER-21 preincubated for 1 h with a 10-fold molar excess of antigenic peptide (ER21), or 3) ER-21 preincubated with a 10-fold molar excess of an unrelated peptide (AR21 corresponding to amino acids 1–21 of the rat AR).
To identify smooth muscle cells specifically in the developing
estrogenized rat prostates, sections adjacent to those stained for ER
were stained for 
-actin with an antiactin mouse monoclonal antibody
(Enzo, Biochemicals, New York, NY). Slides were processed as described
above, except that freeze-substitution was omitted and rat-absorbed
biotinylated horse antimouse IgG (Vector Laboratories) was used as a
secondary antibody. Normal mouse ascites fluid (Sigma) was substituted
for primary antibody to determine nonspecific binding.
In situ hybridization
A 171-bp antisense ER complementary RNA (cRNA) probe
corresponding to 1542–1713 bp of the rat ER (kindly supplied by Dr. R.
Handa, Loyola University Medical Center, Maywood, IL) was used for
in situ hybridization of rat ER (26). This fragment was
subcloned into a pGEM3Zf- plasmid, and after linearization
with EcoRI, T7 polymerase was used to transcribe
35S-labeled antisense cRNA probe via the Riboprobe kit
(Promega, Madison, WI) with [35S]UTP (Amersham, Arlington
Heights, IL; 40 mCi/ml). 35S-Labeled sense cRNA was
transcribed from a HindIII linearized template using SP6
polymerase. Frozen 6-µm sections from day 1, 3, 6, and 10 prostate
complexes of oil-control rats and from day 6 and 10 prostate complexes
of estrogen-treated rats were thaw-mounted on coated slides (Superfrost
Plus, Fisher Scientific) and fixed in 4% formaldehyde for 5 min at
room temperature. After acetylation for 10 min (0.25% acetic
anhydride, 0.1 M triethanolamine, and 0.9% sodium
chloride, pH 8), the tissue was rinsed in 2 x SSC (standard
saline citrate) and dehydrated in ascending alcohol. Ninety microliters
of heat-denatured hybridization solution (50% formamide, 0.25
M NaCl, 1 x Denhardt’s solution, 10% dextran
sulfate, 25 µg yeast transfer RNA, 500 µg total yeast RNA, 100 µg
sheared salmon DNA, 50 mM dithiothreitol, 0.05% sodium
thiosulfate, and 0.25% SDS) containing 20 x 106
cpm/ml ER cRNA probe were applied to each slide, and the slides were
incubated for 16–20 h at 60 C in a humidified container. Slides were
washed in a series of 2 x SSC rinses, treated with ribonuclease
for 30 min at 37 C, and rinsed in SSC under increasing stringency
conditions with a final wash in 0.1 x SSC at 60 C. After
dehydration in alcohol, the slides were apposed to ß-max Hyperfilm
(Amersham, Arlington Heights, IL) for 7 days. The slides were then
dipped in Kodak NTB-3 emulsion and exposed for 3–6 weeks at 4 C before
developing. Hybridization with sense RNA probe defined background
levels of silver grains. The slides were counterstained with 0.013%
cresyl violet, dehydrated with alcohol, cleared with xylene, and
coverslipped with Permount (Fisher Scientific, Itasca, IL). No
hybridization signal was detected on control slides that were incubated
with radiolabeled sense strand RNA probes or in negative control tissue
(spleen). Control and estrogenized prostates from days 6 and 10 were
always processed on the same slide to allow direct comparison of silver
grain intensity between the treatment groups. Photographs of control
and treated tissues were taken from the same slide using Kodak X-Plus
or Ectachrome film.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows that in
rat prostate (A and B) and uterus (C and D), a 10-fold molar excess of
the antigenic peptide completely blocked nuclear staining for ER by the
ER-21 antibody. Coincubation of ER-21 antibody with unrelated peptide
AR21 had no effect on staining incidence or intensity (data
not shown).
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). The cells immediately surrounding the epithelial
buds had the highest incidence and intensity of ER-positive staining,
whereas interductal mesenchymal cells were sporadically ER positive. ER
was not detected in central or distal mesenchymal cells of the
prostate, nor was it observed within the epithelial cells of the
budding glands (Fig. 2B). No noticeable differences were observed among
the ventral, dorsal, and lateral lobes. As the prostate lobes underwent
branching morphogenesis between days 1–15, ER-positive cells were
confined to the proximal region of the gland, where 10–20% of
mesenchymal cells were positive (Fig. 2, C and D). During early puberty
(between days 15–30), ER immunoreactivity was lost entirely within the
proximal stromal cells of all three lobes. On day 45, ER was not
apparent in any of the prostate lobes by immunocytochemistry.
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, A–D). Actin
staining confirmed that these ER-positive periductal cells were
differentiated smooth muscle (Fig. 4). Interacinar
mesenchymal cells were ER positive in only the proximal regions of the
gland, and no ER staining was observed in epithelial cells. This
staining pattern persisted through day 15 (Fig. 3, E and F). By day 30,
the incidence of ER-positive smooth muscle cells declined to 30% in
the distal tips and 50% in the central ducts, but remained high
(90% incidence) within the proximal region. On day 45, ER-positive
stromal cells were mostly confined to proximal regions of estrogenized
prostates, where 50% of periductal smooth muscle cells were ER
positive (Fig. 3G). ER immunoreactivity was sporadic in the central
ducts and distal tips, comprising less than 10% of smooth muscle cells
(Fig. 3H).
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, A–C). In contrast, ER mRNA
was observed in periductal stromal cells of each prostate lobe of rats
that were estrogenized between days 1–5. Although the specific
hybridization signal in the periductal cells was most intense in the
proximal ductal region on days 6 and 10 (Fig. 5, D and E), clusters of
silver grains were visualized over periductal stromal cells along the
entire length of the ducts out to the distal tips (Fig. 5, G and H).
Hybridization of adjacent sections with sense probe showed only
background signal in all stromal cells (Fig. 5, C, F, and I). No
hybridization signal was observed over epithelial cells with the
antisense probe.
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).
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, B and C). Not only was the
incidence of immunoreactive cells increased in the neonatally
estrogenized lateral lobes, but the ER immunostaining in the lateral
LP2 epithelial cells was markedly stronger than that observed in the
oil-treated controls after estrogen treatment. Together, these data
suggest that neonatal estrogen treatment resulted in increased amounts
of ER in the lateral lobe epithelial cells. This ER immunostaining
appeared to be specific because it was competed out with a 10-fold
molar excess of antigenic peptide (Fig. 6, C and D), whereas excess
unrelated peptide had no effect on ER immunostaining. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rats exposed to high levels of estrogens during the neonatal period exhibited significant autoinduction of ER expression in the differentiating periductal smooth muscle cells, such that strong ER-positive immunostaining was observed along the ductal length from the proximal regions out to the distal tips of the developing gland. This up-regulation of ER expression within the periductal cells persisted through the period of morphogenesis and declined after puberty, although ER-positive cells were still present in adulthood in the proximal ducts. From the present data we conclude that smooth muscle cells are direct targets of estrogen action in developmentally estrogenized prostates and that estrogens amplify the estrogenic signal and action within this gland. Data from in situ hybridization studies indicate that this autoregulation of ER is mediated at the mRNA level, which, in turn, allows increased ER protein expression at inappropriate times within the periductal smooth muscle cells.
ER induction by neonatal exposure to estradiol or DES has been documented within the murine uterus (13, 14) and male genital tracts, including the prostate gland (15). In the later study, ER was not visualized in the control prostates of newborn mice, and after estrogen exposure, no induction of ER mRNA was observed within prostatic cells. The discrepancies between that study and the present findings may be related to species differences, lack of analysis along the ductal length by the previous investigators, and/or exposure to DES in the previous study compared to estradiol injections in the present investigation. However, similar conclusions are drawn in all of these studies; that is, estrogen-induced ER expression is involved in mediating the abnormalities observed in various reproductive tissues after early exposure to estrogens. This conclusion was not reached by Pylkkanen et al. (4), who examined ER in the neonatally estrogenized urethro-prostatic complex of mice and found no difference in ER immunostaining compared to controls. However, in that study, the animals were analyzed at 10 weeks of age and not immediately after estrogen exposure. In the present study, the elevated ER expression in the estrogenized prostates decreased as the rats matured, such that by adulthood, only minor ER immunostaining was observed in proximal ducts. Previous work from our laboratory and others has clearly shown that neonatal estrogenization of the prostate results in marked alterations in epithelial cell differentiation and functional capacity (4, 9, 32). As the smooth muscle cells were the primary cells that expressed the classic ER, the present findings implicate the involvement of smooth muscle-derived paracrine factor(s) in mediating estrogenic imprints on the epithelial cells. It is well established that paracrine factors from the AR-positive mesenchyme are responsible for normal, androgen-mediated development and differentiation of the prostate epithelium (33). Early estrogen exposure may influence the ability of this supporting mesenchyme to produce the appropriate inductive/determination factors. Preliminary studies have shown an increase in immunolocalization of transforming growth factor-ß1 (TGFß1) in the periductal region of estrogenized prostates on days 6–15 compared to control rats (34). As TGFß1 mRNA has been localized to the periductal mesenchymal cells in the developing mouse prostate (35), it is possible that estrogens, acting via ER in smooth muscle cells, increase TGFß1 production and secretion by those cells and that this paracrine factor alters prostatic epithelial cell differentiation. Other potential paracrine factors possibly involved in mediating estrogenic effects include hepatocyte growth factor, keratinocyte growth factor, and the insulin-like growth factor family. As the urogenital sinus and proximal prostate mesenchyme normally contain ER-positive cells at this early stage, it is possible that in addition to alterations in smooth muscle secretions, estrogen may perturb the normal function of the ER-positive mesenchymal cells, resulting in altered production of inductive factors from that specific cell population.
Another possibility that awaits further exploration is that estrogens act on the prostate epithelium via an alternate mechanism. Recently, a new member of the steroid receptor superfamily was cloned from a rat prostate library and termed ERß because its in vitro translation product possessed high binding affinity for estradiol (36). In situ hybridization studies revealed that ERß mRNA localized to prostate epithelium, although this awaits confirmation at the protein level. Current collaborative studies are underway in our laboratory to determine the expression of ERß in the developing rat prostate lobes.
In the adult rat prostate of control animals, ER was not observed by immunocytochemistry. However, after a week of exposure to estrogens with constant levels of testosterone, a fraction of epithelial cells in the lateral lobe LP2 ducts expressed low levels of ER, indicating that adult exposure to estrogen can autoinduce ER within that specific lobe. Neonatal estrogenization increased the sensitivity of the lateral lobe epithelial cells to this ER autoinduction, as most epithelial cells in all LP2 ducts and some LP1 ducts of neonatally estrogenized rats immunostained for ER at a much greater intensity after adult estrogen treatment compared to neonatal oil controls. As adult ER expression was not increased by estrogens in ventral or dorsal lobes of neonatally estrogenized rats, we conclude that early estrogen exposure does not increase the sensitivity of those regions to estrogens as the animals age. Our prior work on adult rat prostates that were exposed to exogenous neonatal estrogens documented a lobe-specific effect, in that the ventral and dorsal lobes bore permanent differentiation and functional defects, whereas the lateral lobe, although smaller in size, contained differentiated secretory epithelium that expressed AR and secretory products (8, 9). In addition, as neonatally estrogenized rats aged, there was a lobe-specific incidence of prostatic dysplasia and adenoma formation in the ventral and dorsal prostates, whereas the lateral lobes were free of these lesions (18). Perhaps the epithelial ER within the lateral prostate provides a protective effect through modulation of the function of this region.
In conclusion, the present study has shown that smooth muscle cells are targets of estrogen action in the developmentally estrogenized prostate and that estrogen markedly amplifies its own effects by inducing ER message and protein expression within those cells. We propose that ER up-regulation amplifies the estrogenic effect and that this amplification is a critical component of the permanent imprint that estrogens impose upon the prostate. In addition, epithelial cells in the adult lateral prostatic lobe are sensitive to estrogen-induced ER expression, and this sensitivity is heightened after neonatal exposure to estrogens. This end-organ difference in ER localization may in part account for the lobe-specific effects observed after neonatal estrogenization of the prostate gland.
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Acknowledgments |
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Footnotes |
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Received September 13, 1996.
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J. G. Ramos, J. Varayoud, C. Sonnenschein, A. M. Soto, M. Munoz de Toro, and E. H. Luque Prenatal Exposure to Low Doses of Bisphenol A Alters the Periductal Stroma and Glandular Cell Function in the Rat Ventral Prostate Biol Reprod, October 1, 2001; 65(4): 1271 - 1277. [Abstract] [Full Text] [PDF]
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 Y. Wang, D. Sudilovsky, B. Zhang, P. C. Haughney, M. A. Rosen, D. S. Wu, T. J. Cunha, R. Dahiya, G. R. Cunha, and S. W. Hayward A Human Prostatic Epithelial Model of Hormonal Carcinogenesis Cancer Res., August 1, 2001; 61(16): 6064 - 6072. [Abstract] [Full Text] [PDF]
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G. S. Prins, L. Birch, J. F. Couse, I. Choi, B. Katzenellenbogen, and K. S. Korach Estrogen Imprinting of the Developing Prostate Gland Is Mediated through Stromal Estrogen Receptor {alpha}: Studies with {alpha}ERKO and {beta}ERKO Mice Cancer Res., August 1, 2001; 61(16): 6089 - 6097. [Abstract] [Full Text] [PDF]
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S. J. McPherson, H. Wang, M. E. Jones, J. Pedersen, T. P. Iismaa, N. Wreford, E. R. Simpson, and G. P. Risbridger Elevated Androgens and Prolactin in Aromatase-Deficient Mice Cause Enlargement, But Not Malignancy, of the Prostate Gland Endocrinology, June 1, 2001; 142(6): 2458 - 2467. [Abstract] [Full Text] [PDF]
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N. Atanassova, C. McKinnell, K. Williams, K. J. Turner, J. S. Fisher, P. T. K. Saunders, M. R. Millar, and R. M. Sharpe Age-, Cell- and Region-Specific Immunoexpression of Estrogen Receptor {{alpha}} (But Not Estrogen Receptor {beta}) during Postnatal Development of the Epididymis and Vas Deferens of the Rat and Disruption of This Pattern by Neonatal Treatment with Diethylstilbestrol Endocrinology, February 1, 2001; 142(2): 874 - 886. [Abstract] [Full Text] [PDF]
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H. Habermann, W. Y. Chang, L. Birch, P. Mehta, and G. S. Prins Developmental Exposure to Estrogens Alters Epithelial Cell Adhesion and Gap Junction Proteins in the Adult Rat Prostate Endocrinology, January 1, 2001; 142(1): 359 - 369. [Abstract] [Full Text] [PDF]
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R. A. Jarred, B. Cancilla, G. S. Prins, K. A. Thayer, G. R. Cunha, and G. P. Risbridger Evidence That Estrogens Directly Alter Androgen-Regulated Prostate Development Endocrinology, September 1, 2000; 141(9): 3471 - 3477. [Abstract] [Full Text] [PDF]
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M. K. Dienhart, R. J. Sommer, R. E. Peterson, A. N. Hirshfield, and E. K. Silbergeld Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Developmental Defects in the Rat Vagina Toxicol. Sci., July 1, 2000; 56(1): 141 - 149. [Abstract] [Full Text] [PDF]
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 J. F. Couse and K. S. Korach Estrogen Receptor Null Mice: What Have We Learned and Where Will They Lead Us? Endocr. Rev., June 1, 1999; 20(3): 358 - 417. [Abstract] [Full Text]
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W. Y. Chang, L. Birch, C. Woodham, L. I. Gold, and G. S. Prins Neonatal Estrogen Exposure Alters the Transforming Growth Factor-{beta} Signaling System in the Developing Rat Prostate and Blocks the Transient p21cip1/waf1 Expression Associated with Epithelial Differentiation Endocrinology, June 1, 1999; 140(6): 2801 - 2813. [Abstract] [Full Text]
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W. Y. Chang, M. J. Wilson, L. Birch, and G. S. Prins Neonatal Estrogen Stimulates Proliferation of Periductal Fibroblasts and Alters the Extracellular Matrix Composition in the Rat Prostate Endocrinology, January 1, 1999; 140(1): 405 - 415. [Abstract] [Full Text]
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G. S. Prins, M. Marmer, C. Woodham, W. Chang, G. Kuiper, J.-A. Gustafsson, and L. Birch Estrogen Receptor-{beta} Messenger Ribonucleic Acid Ontogeny in the Prostate of Normal and Neonatally Estrogenized Rats Endocrinology, March 1, 1998; 139(3): 874 - 883. [Abstract] [Full Text] [PDF]
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