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From the Department of Urology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.
| Correspondence to: Gail S. Prins, PhD, Department of Urology, M/C 955, University of Illinois at Chicago, 820 South Wood, Chicago, IL 60612 (e-mail: gprins{at}uic.edu). |
| Received for publication September 9, 2003; accepted for publication December 5, 2003. |
-fetoprotein, which circulates at high levels in neonatal rat
serum (Sheehan and Young,
1979). Consequently, neonatal estradiol is 75-fold less potent
than an equivalent dose of DES (Sheehan
and Branham, 1987) or, put another way, 25 µg of estradiol per
pup is equivalent to 0.33 µg of DES per pup. Recent work from our
laboratory has examined a dose–response relation for increasing neonatal
estradiol exposures and have observed a monotonic effect on the prostate, with
growth inhibition and reduced androgen receptor observed at doses of 10 µg
per pup (equivalent to 0.13 µg of DES per pup) and no prostatic stimulation
at lower estradiol levels (Putz et al,
2001). Neonatal exposure to high-dose estradiol results in a
permanent reduction in prostatic growth and activational response to androgens
during adulthood, an effect mediated in part through a permanent reduction in
androgen receptor (AR) expression (Prins,
1992; Prins et al,
1993; Prins and Birch,
1995; Woodham et al,
2003). Upon aging, prostatic hyperplasia and dysplasia are
prominent in neonatally estrogenized rats and PIN-3 (prostatic intraepithelial
neoplasia) lesions are observed when these animals are given exogenous
testosterone (Prins, 1997;
Putz and Prins, 2002).
Structural and functional epithelial cytodifferentiation during development is
perturbed or, for some endpoints, permanently blocked by neonatal estrogens as
determined by markers for basal and luminal cytokeratins and secretory
proteins (prostate binding protein [PBP], dorso-lateral prostate [DLP]
protein, urokinase, 26-kD protease) (Prins
and Birch, 1995; Chang et al.,
1999; Prins et al,
2001a). Recent evidence indicates that estrogen-induced changes in
the expression of E-cadherin and the gap junction proteins connexin 32 and
connexin 43 in the adult prostate epithelial cells may result in impaired
cell–cell adhesion and defective cell–cell communication, which
may be one of the key mechanisms through which changes toward a dysplastic
state are mediated (Habermann et al,
2001).
Mechanism of Action: Steroid Receptors
Estrogen action in the rat prostate gland is mediated through stromal
estrogen receptor (ER)
(Prins and Birch, 1997) and
epithelial estrogen receptor ß (ERß)
(Prins et al, 1998). Importantly, studies with ER knockout mice (ERKO and ßERKO) showed
that stromal cell ER is the dominant ER mediating developmental
estrogenization of the prostate (Prins et
al, 2001a). During the first 5–10 days of life, ER is
present in the mesenchymal cells of the proximal regions of the growing ducts.
After estrogenic exposure, there is a transient up-regulation of this protein
within periductal stromal cells along the length of the ducts that allows for
amplification of estrogenic action during this critical period
(Prins and Birch, 1997). This,
in turn, leads to a transient expression of progesterone receptor (PR) in
those same stromal cells that do not normally express this receptor
(Sabharwal et al, 2000). In
addition, prostatic retinoid receptors (RARs and RXRs) and intraprostatic
retinoid levels are immediately and permanently elevated after neonatal
estrogenic exposure, which allows for amplification of retinoid signals during
development and with aging (Prins et al,
2002; Pu et al,
2003a). It is particularly significant that these increases in ER,
PR, and RAR levels occur at the same time that AR is drastically
down-regulated (Prins and Birch,
1995; Woodham et al,
2003). These changes are summarized in the schematic shown in
Figure 1. After a brief
exposure to high levels of estrogen during the neonatal critical period, the
temporal expression patterns as well as quantitative levels of several key
steroid receptors (transcription factors) are drastically altered. Thus, the
prostate is no longer under predominant androgen-AR regulation but is rather
driven by estrogenic and retinoid signals through the ERs, PR, RARs, and RXRs.
We propose that the net effect of these changes is that the programming and
organizational signals, which normally dictate and determine prostate
development during discrete temporal windows, are permanently and
irretrievably altered.
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Developmental Genes
Continuous branching morphogenesis of glandular structures is dictated by
time-specific and region-specific expression of master regulatory genes
(Hogan, 1999). Although common
morphogenetic paradigms exist for all branched structures studied to date, the
critical difference is that spatial and temporal combinations of these genes
give rise to unique structures. The morphogenetic codes for lungs and limbs
have been studies extensively and serve as excellent models
(Hogan, 1999). While the
"prostatic code" is not well defined at the present time, recent
activity in this field has led to an early map
(Bieberich et al, 1996;
Kopachik et al, 1998;
Bhatia-Gaur et al, 1999;
Podlasek et al,
1999b,c;
Sreenath et al, 1999;
Thomson and Cunha, 1999;
Prins et al, 2001b;
Lamm et al, 2002). On the
basis of these reports as well as work from our laboratory, we have
schematized the temporal expression pattern and spatial localization of
several of the critical genes involved in prostate development
(Figure 2). We are currently
interested in determining whether neonatal exposure to estrogens can alter
prostatic development through changes in expression of these key developmental
genes.
|
Homeobox Genes
Several specific homeobox genes have been identified within developing
prostate tissue and are thought to account for prostate determination and
morphogenesis. These include members of the Hox gene family
(Warot et al, 1997), the
NK gene family (Bieberich et al,
1996), and the HNF (FOX) gene family
(Peterson et al, 1997; Kopachik et al, 1998).
Importantly, a growing body of evidence supports a role for steroids in
regulating developmental genes. This first came to light with studies on
retinoic acid, which was shown to markedly affect Hox gene expression
and produce homeotic transformations, that is, acquisition of adjacent
structure morphology (Marshall et al,
1996; Wood et al,
1996). Hox genes are arranged in four clusters (A, B, C,
and D) on separate chromosomes, each cluster containing up to 13 Hox
genes expressed sequentially (3' to 5') along the anterior to
posterior body axis. Although retinoids have the strongest effect on anterior
Hox genes, recent data have shown regulation of posterior
Hox genes by estrogens and progesterone. Fetal or neonatal exposure
to 2 µg of DES resulted in strong down-regulation of uterine
Hoxa-10 (Ma et al,
1998) and progesterone receptor directly up-regulated
Hoxa-10 in the uterus during implantation
(Lim et al, 1999). These
observations are particularly relevant to the estrogenized prostate, which
presents with a proximalized phenotype, that is, the formation of the distal
prostate is suppressed while the proximal phenotype is extended into a larger
portion of the tissue (Prins et al,
2001b). We postulate that the effect of estrogen in creating a
proximalized phenotype in the prostate gland reflects a change in the
positional identity of this structure, perhaps mediated by changes in the
expression of genes related to specification of appendicular
(proximal–distal) position. Furthermore, we postulate that estrogens may
disturb the expression of specific genes that regulate differentiation of the
prostate stromal and epithelial cells.
Hox-13
A generalized model for regional tissue specification is that nested,
partially overlapping expression domains of several genes in a Hox
cluster determine segment identity. Hox-13 genes, the most posterior
of the Hox clusters, are involved in prostate gland development
(Warot et al, 1997).
Hoxa-13 and Hoxd-13 are expressed in high levels in the
mouse urogenital sinus (UGS) mesenchyme during fetal life and prostatic
expression declines postnatally (Oefelein
et al, 1996; Podlasek et al,
1999b). In contrast, Hoxb-13 has been localized to
central duct and distal tip epithelial cells in the adult mouse prostate
(Sreenath et al, 1999;
Economides and Capecchi, 2003).
To examine the presence of these genes in the rat prostate and to determine
the influence of estrogens on their expression level, we quantified
Hox-13 mRNAs in developing and adult rat ventral prostates
(Prins et al, 2001b). As
described for mouse prostate, Hoxa-13 mRNA was present in the day 6
prostate in control rats and levels declined with development by day 30. No
immediate differences were observed in Hoxa-13 mRNA levels after
estrogen exposure; however, the maturational decline was delayed in the
estrogen-exposed prostate. In contrast to what was found in the mouse, rat
prostate levels of Hoxd-13 mRNA remained steady during postnatal
development and significantly increased in the mature prostate (day 90).
However, levels for Hoxd-13 did not increase in estrogenized adult
ventral prostates but rather remained at the low expression levels found in
postnatal prostates (Prins et al,
2001b). Epithelial Hoxb-13 expression in the rat prostate
is low at birth and markedly increases as epithelial cells differentiate
between days 6 and 15. Thereafter, high expression of Hoxb-13 is
maintained in the luminal epithelium throughout adulthood
(Prins et al, 2001b). After
neonatal exposure to estrogen, Hoxb-13 expression was immediately and
permanently suppressed. This is highly significant since a recent study has
shown that Hoxb-13 is required for normal differentiation and
secretory function of the mouse ventral prostate
(Economides and Capecchi,
2003). Thus we propose that loss of Hoxb-13 in the
estrogenized prostate may be involved in mediating some of the positional and
differentiation defects observed in the developmentally estrogenized prostate
gland. Although the role of Hox genes has not been determined in
adult structures, evidence suggests that its expression may be involved in
maintaining differentiated states since levels are lost in many cancers
(Friedman et al, 1994). It has
also been hypothesized that normal adult expression of Hoxa-10
maintains glandular architecture in the uterus
(Miller and Sassoon, 1998) and
a similar role for Hoxd-13 and Hoxb-13 may exist in adult
prostate.
Nkx3.1
A novel member of the NK family of homeobox transcription factors
was identified in 1996 and its expression in the male reproductive tract was
restricted to UGS-derived prostate and bulbourethral gland epithelium
(Bieberich et al, 1996;
Schiavolino et al, 1997). Importantly, this gene is expressed in the fetal mouse UGS epithelium at bud
sites before bud formation, suggesting a role for Nkx3.1 in prostate
determination (Bieberich et al,
1996; Bhatia-Gaur et al,
1999). Continued expression of this gene is believed to be
important for epithelial cell differentiation. To determine the effects of
early estrogen exposure on Nkx3.1 expression, we performed in situ
hybridization (Prins et al,
2001b) and real-time reverse transcriptase–polymerase chain
reaction (RT-PCR) on developing and adult prostates of control and
estrogenized rats. At day 6, Nkx3.1 mRNA was expressed in a gradient
fashion throughout the rat prostate, with low levels in the proximal ducts and
high levels in the distal tips. Immediately after estrogen exposure,
Nkx3.1 mRNA was significantly reduced in all prostate lobes as
compared to control levels (Figure
3). However, this effect was transient and by day 30,
Nkx3.1 expression in the estrogenized prostates was equivalent to
that in oil controls (Prins et al,
2001b). We propose that a transient disruption in Nkx3.1
expression at a critical time when epithelial cells normally differentiate
into basal and luminal layers (Prins and
Birch, 1995) may play a direct role in the differentiation defects
observed in the estrogen-exposed prostates.
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Secreted Signaling Molecules
In addition to developmental determination by homeobox genes, branching
morphogenesis occurs as a complex interplay between epithelial and mesenchymal
cells. Although many secreted epithelial–mesenchymal signals have been
characterized, a small number of signaling molecules have been found to be
critical during embryogenesis (Hogan,
1999). In particular, combinations of Hedgehogs, Wnts, bone
morphogenetic proteins (BMP)s, and fibroblast growth factors (FGF)s to a large
extent control soft tissue development. These positive and negative regulatory
molecules are spatially and temporally regulated and communicate signals
between cells via their cognate receptors. We have recently examined the
ontogeny and localization of sonic hedgehog (Shh), BMP-4, and FGF-10
in the normal developing rat prostate lobes and those exposed neonatally to
estradiol to determine if alterations in their signaling pathways are involved
in the estrogenized phenotype.
Shh
Shh is a secreted glycoprotein produced by epithelial cells at
mesenchymal interfaces in developing tissues. In branched structures,
Shh is thought to be a master gene involved in bud initiation and
outgrowth (Bellusci et al,
1997a). Importantly, Shh is has been shown to regulate
many other developmental genes including Hox genes as well as
Nkx3.1. The murine UGS and prostate epithelial cells produce
Shh as early as fetal day 17 and levels decline with development
(Podlasek et al, 1999a). Secreted Shh protein activates target cells through a membrane
receptor, patched (ptc), localized in mesenchymal cells. After a
cascade of molecular signals, this ultimately results in increased levels of
gli transcription factors
(Walterhouse et al, 1999). We
recently characterized the Shh expression patterns in the developing
rat prostate lobes and examined the effects of early estrogen exposure using
whole-mount in situ hybridization (ISH) and real-time RT-PCR
(Pu et al, 2003b). Similar to
the mouse prostate, Shh was highly expressed in the fetal day 19
prostatic buds where it was localized to epithelial cells in the distal tips
of the outgrowing ducts of the ventral, dorsal, and lateral lobes. Thereafter,
a marked decrease was observed in Shh expression from days 1 to 15 of
life in control prostates, with the greatest decrease between days 1 and 6.
Neonatal estradiol exposure resulted in a significant inhibition of
Shh expression in the dorsal and lateral lobes by neonatal day 1,
which persisted throughout development. Although values were always lower in
the estradiol-exposed ventral prostate as compared to controls, the difference
never approached significance. This differential effect on Shh
expression by estrogens may play a role in the previously noted lobe-specific
estradiol response. The lateral and dorsal rat prostate lobes exhibit a
greater reduction in branching than observed in the ventral lobe in response
to neonatal estrogens (Prins,
1992).
Fibroblast Growth Factor-10
Developmental studies have shown a critical role for FGF-10 in initiation
and directional outgrowth of buds as well as ductal branching in lung and more
recently, prostate (Bellusci et al,
1997b; Thomson and Cunha,
1999). FGF-10 interacts with a unique splice variant of the FGF
transmembrane receptor family, the FGFR2iiib. This receptor variant is
expressed on prostatic epithelial cells
(Finch et al, 1995) and
recognizes FGF-7 (KGF) and FGF-10 produced by the mesenchyme, thus
establishing a specific paracrine communication. Using both whole-mount ISH
and real-time RT-PCR, we recently determined that FGF-10 mRNA is expressed in
the distal mesenchyme of the 3 prostate lobes at day 1 of life and that it
condensed most strongly around the distal tips of the outgrowing ducts as the
prostate undergoes branching morphogenesis over the next several days
(Huang et al, 2003). Neonatal
estradiol exposure immediately reduced FGF-10 expression in the dorsal and
lateral lobes between days 1 and 5, whereas expression in the ventral prostate
was unaffected. Since Shh is known to regulate FGF-10 expression in
other developing tissues (Haraguchi et al,
2001; Perriton et al,
2002), we propose that FGF-10 is a downstream gene of Shh
in the prostate gland and that a reduction in Shh and FGF-10
expression in the dorsal and lateral lobes in response to estradiol together
contribute to a greater reduction in branching in those regions.
BMP-4
Bone morphogenetic proteins (BMP) are members of the transforming growth
factor-ß superfamily and, in general, act as inhibitors of proliferation
during development (Hogan,
1996). BMPs initiate cell signaling by activating type I and type
II transmembrane receptors with intracellular pathways involving Smads. In the
mouse prostate, BMP-4 mRNA is localized to the mesenchyme and levels decline
postnatally (Thomas et al,
1998; Podlasek et al,
1999c). Although targeted disruption of BMP-4 is embryonic lethal,
heterozygotes possessed an increased number of branching tips in the murine
ventral prostate (Podlasek et al,
1999c). We have recently localized and quantified BMP-4 expression
in the prostate lobes of the developing rats after estradiol exposure
(Huang et al, 2003). BMP-4
expression was initially intense and broad throughout the mesenchyme of all
lobes at day 1 and subsequently condensed to cells proximate to the elongating
ducts as morphogenesis progressed. Although BMP-4 mRNA levels rapidly declined
in all control prostate lobes between postnatal days 1 and 6, its expression
remained high in the estrogenized prostate lobes until after day 30. We
postulate that the continued expression of prostatic BMP-4 in estrogen-exposed
rats prolongs its inhibitory actions and contributes to reduced growth in all
3 prostate regions.
Conclusions
In summary, we have shown that early exposure to high levels of estrogens
creates a morphologic imprint in the prostate gland, which can be described as
a proximalized phenotype. We propose that this effect is initiated through
up-regulated levels of stromal ER, which in turn result in altered
steroid receptor expression throughout the developing gland. Rather than being
an androgen-dominated process, prostatic development becomes regulated by
alternate steroids including estrogens and retinoids. This, in turn, leads to
disruptions in the coordinated expression of several critical developmental
genes including the homeobox genes Hox-13 and Nkx3.1 as well
as secreted ligands Shh, FGF-10, and BMP-4 (schematized in
Figure 4). Since a precise
temporal expression pattern of these and other molecules is normally required
for appropriate growth and differentiation of the prostatic epithelium and
stroma, the estrogen-initiated disruption in this pattern would lead to
permanent growth, branching, and differentiation defects of the prostate
gland. The ultimate consequences of this developmental estrogenization are a
prostate predisposed to hyperplasia and dysplasia in adulthood and sensitized
to more severe lesions, including cancer, as the animals age.
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Acknowledgments
We gratefully acknowledge Oliver Putz, PhD, for the graphic representation of our data.
Footnotes
Supported by grant DK 40890 from the National Institute of Diabetes and Digestive and Kidney Disease.
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are localized to periductal
stromal cells along the ductal length. After a brief exposure to high levels
of estrogens during the neonatal critical period, the prostatic steroid
receptor profile is drastically altered (bottom). AR is absent in
epithelial cells and is present at very low levels in stromal cells, thus
dampening the androgen signaling pathway in the developing prostate. ER
