* Reproductive Toxicology Division, NHEERL, ORD, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711;
School of Pharmacy,
Molecular and Environmental Toxicology Center, and
Department of Animal Sciences, University of Wisconsin, Madison, WI 53705
Received August 2, 2003; accepted September 3, 2003
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ABSTRACT |
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Key Words: prostatic bud; TCDD; urogenital sinus; prostate development.
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INTRODUCTION |
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Prostate development requires regulation through a number of hormonal, cellular, and molecular pathways (Marker et al., 2003). Epithelial-mesenchymal interactions are essential components of this regulatory battery (Cunha et al., 1980
; Takeda et al., 1986
; Timms et al., 1995
). The mesenchyme of the UGS induces outgrowth and ductal morphogenesis and regulates proliferation of the epithelial cells (Cunha et al., 1992
; Tanji et al., 2001
). Growth factors regulate cellular proliferation, differentiation, and death, and there are numerous studies implicating growth factors as mediators of epithelial-mesenchymal interactions. EGF, TGF-
, TGF-ß, insulin-like growth factors I and II, hepatocyte growth factor (HGF), and keratinocyte growth factor (KGF) are known to either stimulate or inhibit growth of the prostate (Tanji et al., 2001
).
EGF and TGF- mRNA are detected in human fetal prostatic tissue and these growth factor proteins localize to basal epithelial cells (Dahiya et al., 1996
; Leav et al., 1998
). Raghow et al. (1999)
detected TGF-
protein only in the mesenchyme of the 9.5 to 11.5 week old human fetus. EGF and TGF-
also exhibit localized expression patterns in the adult human prostate (Adam et al., 1999
; Cohen et al., 1994
; De Miguel et al., 1999
). There are several studies that examined expression of EGF and TGF-
mRNA and/or protein in the neonatal rat. Analysis of neonatal and postnatal day (PND) 0 rat ventral prostate grown in organ culture detected cell typespecific expression of keratinocyte growth factor (KGF), KGF receptor, TGF-
, and EGF receptor (Thomson et al., 1997
). TGF-
was found to be predominantly epithelial in this study as well as in a study of the PND 520 rat prostate in which TGF-
was localized to ductal epithelium of the ventral prostate (Banerjee et al., 1998
). In the rat at PND 63, expression of TGF-
was detected immunohistochemically in epithelial cells of the ventral and lateral prostatic ducts but not in the dorsal ducts (Taylor and Ramsdell, 1993
). Prostate lobespecific expression of TGF-
was also reported in the adult rat, where it was detected in the lateral lobe with fewer immunostained cells in the dorsal lobe and no expression in the ventral lobe; however, EGF was detected in all lobes of the adult prostate (Wu et al., 1993
). Thus, as has been noted in a number of other developing organ systems, there appears to be specific spatio-temporal expression of growth factors during development and growth of the prostate.
We examined the influence of null expression of EGF and/or TGF- in the fetal mouse on prostatic bud formation and on the response to TCDD. Knockout mice lacking expression of EGF (-/-), TGF-
(-/-), or both EGF and TGF-
(EGF + TGF-
-/-) were exposed in utero to either vehicle or TCDD and the effects on prostatic bud development were evaluated on GD 17.5. We previously studied the EGF (-/-), TGF-
(-/-), and EGF + TGF-
(-/-) and reported no effect of genotype or background strain on litter size, gender ratio, pup body weight, and survival of fetuses in utero (Bryant et al., 2001
). In that study, exposure to 24 µg TCDD/kg increased the maternal and fetal liver weights in all strains and genotypes, both absolute and relative to body weight. The EGF (-/-), TGF-
(-/-), and EGF + TGF-
(-/-) strains were also examined across a range of doses (0.2 to 150 µg TCDD/kg), and there was no increase in maternal or fetal deaths and no effects on maternal body weight at any of the doses (Abbott et al., 2003
). This dosing regimen was applied to the present study for evaluation of the effects of TCDD on prostatic bud development. Lack of expression of EGF and/or TGF-
influenced the development of the prostatic buds and affected the responsiveness to TCDD.
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MATERIALS AND METHODS |
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At the University of Wisconsin, C57BL/6J mice were from a C57BL/6J breeding colony established with mice purchased from Jackson Laboratory. These mice were housed in clear plastic cages with heat-treated chipped aspen bedding in rooms that were kept at 24 ± 1°C and 35 ± 4% relative humidity and lighted from 0600 to 1800 h. Feed (5015 Mouse Diet, PMI Nutrition International, Brentwood, MO) and tap water were available ad libitum. All procedures were approved by the University of Wisconsin Animal Care and Use Committee.
Male and female mice of the same genetic background were housed together overnight. Females were checked for vaginal plugs and weighed the next morning, which was designated as gestation day (GD) 0; plug-positive females were weighed.
Treatments.
Pregnant females were weighed on GD 12 and dosed by gavage with 0, 0.2, 1, 5, 10, 50, 100, or 150 µg TCDD/kg body weight at a dose volume of 5 ml/kg. The number of pregnant females (litters) for each dose and genotype are presented in Tables 1 and 2
. The assignment of dose groups by genotype was based on results from our previous study (Abbott et al., 2003
) in which genetic background was shown to affect responsiveness to TCDD. Responsiveness to TCDD was evaluated in that study using EROD assays of adult liver microsomes, which showed that the WT, EGF (-/-), and EGF + TGF-
(-/-) strains were less responsive than the C57BL/6J and TGF-
(-/-) strains. Based on the EROD outcomes, it was concluded that the WT, EGF (-/-), and EGF + TGF-
(-/-) strains express a low affinity isoform of the AhR, while the C57BL/6J and TGF-
(-/-) strains express a high affinity AhR allele.
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After each necropsy, the tissues were shipped overnight in a cold-pack, insulated shipping container to the University of Wisconsin (Madison, WI). The C57BL/6J females that were bred, dosed, and necropsied at the University of Wisconsin were subjected to the same treatment and necropsy procedures as described for the mice at the EPA, except that at necropsy the processing of the tissues continued without the overnight delay. On arrival (or after bisecting the fetal lower body for tissues prepared at the University of Wisconsin), the UGS complexes were removed and subjected to limited trypsin digestion to separate epithelium from mesenchyme by procedures similar to those described by Cunha and Donjacour (1987a,b)
. Briefly, UGSs were incubated in calcium- and magnesium-free HBSS containing 1% trypsin (Gibco BRL, Grand Island, NY) at 4°C. After 90 min, UGSs were washed twice with HBSS and then incubated for 5 min in HBSS plus 5% charcoal/dextran-stripped fetal bovine serum to attenuate any remaining trypsin activity. UGS mesenchyme was then separated from epithelium using forceps under a dissecting microscope.
The UGS epithelium of one male fetus from each litter was prepared for examination by scanning electron microscopy. Each sample of UGS epithelium was fixed overnight at 4°C in calcium- and magnesium-free HBSS containing 2.5% glutaraldehyde, dehydrated through a graded series of ethanol to 100%, and dried by the critical point procedure using liquid CO2 as the transitional fluid. Dried UGS specimens were mounted on aluminum stubs with double-stick conductive carbon tape, coated with a thin layer of gold using a sputter-coater (Auto Conductavac IV, See Vac Inc., Pittsburgh, PA), and examined at an accelerating voltage of 5 kV on a Hitachi S-570 scanning electron microscope (Hitachi, Tokyo, Japan). Images were captured with a digital capture system (Gatan, Pleasanton, CA). Anterior, dorsal, lateral, and ventral prostatic epithelial bud numbers were determined using images taken at multiple angles. The data are reported as numbers of anterior-dorsolateral buds (ADLBs) and ventral buds (VBs) observed by scanning electron microscopy of the GD 17.5 UGS, after the mesenchyme was removed.
Statistical analysis.
One male fetus from each litter was prepared for SEM analysis of the UGS. For each genotype and treatment, the number of litters in each group is shown in Tables 1 and 2
. All analyses were done using SAS Proc Means and Proc Glm (SAS Institute, 1999
). Each genotype was analyzed separately and for each variable (ADLB and VB) a one-way analysis of variance was run to detect differences among dose groups in the number of buds. In every case, the overall F statistic was highly significant. Pairwise t-tests were performed to compare each dose group with its control. A simple regression model was run in each case to evaluate significant trends in the number of buds across TCDD dose groups. Pairs of genotypes were compared using two-way ANOVA and regression to detect differences among genotypes and interactions between genotype and dose. If there was no interaction the main effects model was run.
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RESULTS |
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In all genotypes, there were significant dose-related decreases in the number of ADLBs and VBs in response to TCDD (p < 0.001). The absence of EGF and/or TGF- expression significantly affected the responsiveness to TCDD, and the responses of the different genotypes were not identical. This was detected in analysis of genotype by TCDD dose interactions, which were significant for ADLB effects: WT versus EGF (-/-), p < 0.01; WT versus EGF + TGF-
(-/-), p < 0.001; and EGF (-/-) versus EGF + TGF-
(-/-), p < 0.01. For VB effects: WT versus EGF (-/-), p < 0.05; and EGF + TGF-
(-/-) versus EGF (-/-), p < 0.01. Genotype interaction was also significant for VB: WT versus EGF (-/-), p < 0.001; and WT versus EGF + TGF-
(-/-), p < 0.001.
In the WT mice, there was a significant decrease in ADLB numbers after exposure to 10 µg TCDD/kg body weight; however, the VB numbers were only affected significantly at 50 µg TCDD/kg or higher. The effects on ADLBs appeared to plateau at 50 µg TCDD/kg when the mean values were examined; however, as shown in Figure 1, fetuses exposed to 150 µg TCDD/kg exhibited more severe effects than observed in the lower exposures. There was a significant TCDD doserelated trend for effects on VBs. The numbers of these buds were observed to be less as TCDD exposures increased in the representative UGS images of prostatic bud formation (Figs 1B
1F
). The fetuses exposed at 100 and 150 µg TCDD (Figs 1E
and 1F
) exhibited fewer and smaller dorsal buds and appeared not to have VBs. Also, as shown graphically in Figure 2A
, responsiveness of ADLBs to TCDD appeared to plateau at a dose of 10 µg/kg in the WT group, as there was no further decrease in the ADLBs with increasing TCDD dose. This is in contrast to the response of the ventral UGS region in which the VBs continued to decrease across all TCDD doses. The UGS shown in Figures 1D
1F exhibit few or no VBs.
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The effects of increasing TCDD dose on the number and size of prostatic buds in EGF (-/-) and EGF + TGF- (-/-) UGS are shown for representative fetuses in Figs 3
and 4
. In the EGF (-/-) fetus, TCDD exposure reduced the number and size of the buds and the response was more severe as the dose increased from 1 to 150 µg TCDD/kg (Figs 3B
3F
). Although the trend for this effect was present across the doses, significance relative to control was only present at exposures of 50 µg TCDD/kg or higher. Ventral buds were strongly reduced at 10 µg TCDD/kg and frequently no buds were observed in that region (Fig. 3C
). At exposures of 50 µg TCDD/kg or higher, few buds were seen on the EGF (-/-) UGS. In the EGF + TGF-
(-/-) fetus, the decrease in ADLBs and VBs was apparent after a dose of 1 µg TCDD/kg (Fig. 4B
), and few or no buds were seen at a dose of 50 µg/kg or higher (Figs 4D
4F
). In the EGF + TGF-
(-/-), the effects of TCDD on VB and ADLB were significant at doses of 50 µg TCDD/kg or higher. Relative to WT (Fig. 1A
) and EGF (-/-) (Fig. 3A
), the EGF + TGF-
(-/-) control (Fig. 4A
) had fewer and less developed prostatic buds. It would appear that in the mixed genetic background found in WT, EGF (-/-), and EGF + TGF-
(-/-) fetuses, expression of TGF-
, or both EGF and TGF-
, is important for outgrowth and formation of the prostatic buds.
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DISCUSSION |
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One possible interpretation of these observations is that balanced expression of EGF and TGF- regulates bud outgrowth and that at least one of these growth factors needs to be expressed. The role of each growth factor in influencing bud numbers may be different, as TGF-
expressed in the absence of EGF was able to produce appropriate numbers of buds in all regions, while EGF expressed in the absence of TGF-
appeared to overstimulate ADLB outgrowth. It is also possible that TGF-
acts as a negative regulator or suppressor of ADLB development and that could also explain the increased numbers of ADLB when TGF-
is not expressed. From these data, it was not possible to definitively identify the activity that results in more ADLB, stimulation by EGF, or negative regulation by TGF-
. It may also be hypothesized that UGS regionspecific patterns of EGF and TGF-
expression are required to provide the appropriate stimulus for outgrowth and to regulate the numbers of prostatic buds formed.
The expression of these growth factors also affects the sensitivity of the fetal response to TCDD. The influences of each growth factor on the response to TCDD differ and may reflect divergent roles in regulation of bud outgrowth. The effects of TCDD were most severe in the double-null fetuses that had neither EGF nor TGF- expression. The fetuses without TGF-
expression and the C57BL/6J fetuses responded to TCDD similarly, suggesting that TGF-
is not playing a critical or determinant role in the response to TCDD. However, the increased severity of VB response in the EGF + TGF-
(-/-) relative to the EGF (-/-), i.e., the significant genotype and dose interaction, suggests that TGF-
as well as EGF mediate the response. Although fetuses with EGF expression respond to TCDD with dose-related decreases in prostatic bud outgrowth, the response is clearly more severe in the absence of EGF, particularly in the ventral region. The modulation of the response to TCDD by EGF may be through a mechanism involving upregulation of the growth factor. Increased EGF expression might stimulate prostatic bud outgrowth sufficiently to counteract the inhibitory effects of TCDD. This could explain the more severe responses of fetuses lacking EGF expression, since those compensatory mechanisms would be totally absent in EGF (-/-) and EGF + TGF-
(-/-) fetuses.
A balanced expression of the growth factors may be critical to regulate the development of the prostate, and disruption of that balance by TCDD may be a major factor in abnormal morphogenesis. As stated above, some information is available regarding the expression of EGF and TGF- during later stages of prostate development but no information could be found in the literature describing patterns of EGF and TGF-
expression during bud formation. Also, there are no reports of the specific effects of TCDD on that expression. However, TCDD is known to alter the expression of these growth factors in the palate and developing urinary tract (Abbott and Birnbaum, 1990a
,b
; Bryant et al., 1997
). Both EGF and TGF-
protein and mRNA are upregulated in response to TCDD in the embryonic palatal epithelium and EGF expression is increased in ureteric epithelial cells. In the urinary tract, as in the prostatic buds, expression of TGF-
in the absence of EGF provided an enhanced response to TCDD (Bryant et al., 2001
). In the developing urinary tract, TCDD produced hydronephrosis by stimulating proliferation of the ureteric epithelial cells with a resulting occlusion of the ureteric lumen (Abbott et al., 1987
). EGF (-/-) fetuses exhibited an increased incidence of hydronephrosis in response to TCDD (Bryant et al., 2001
). In ureteric epithelial cells, both EGF and TGF-
are expressed during formation of the urinary tract. In response to TCDD, EGF but not TGF-
expression was increased, and it was hypothesized that this imbalance in expression of these growth factors plays a role in the hyperplasia of the epithelial cells (Bryant et al., 1997
).
In contrast to the increased sensitivity of the UGS and urinary tract in the absence of EGF expression, in the developing palate the absence of EGF expression reduced the incidence of cleft palate (Abbott et al., 2003). In the palate, the predominant ligand expressed is EGF and exposure to TCDD has been shown to increase expression of that growth factor (Abbott and Birnbaum, 1990b
). The induction of cleft palate by TCDD is attributed to increased expression of EGF, which correlates with hyperplasia of the medial epithelial cells and consequent failure of the palatal shelves to fuse. Thus, in the absence of EGF [in either the EGF (-/-) or EGF + TGF-
(-/-)], this response was not produced and the fetuses did not exhibit cleft palate at exposures less than 100 µg TCDD/kg. The differential responses reported in the palate, urinary tract, and in this study for the UGS could be due to different spatial and temporal expression patterns of EGF and TGF-
in these tissues. The evidence in the palate and urinary tract supports the hypothesis that the expression patterns during development and the specific alterations in expression produced by TCDD can be instructive concerning the outcome in the target organ.
Detailed information is lacking regarding the expression patterns of EGF and TGF- in the UGS of the prenatal rodent, and no reports were found that describe specific effects of TCDD treatment on these expression patterns. However, these growth factors are expressed in the fetal human prostate and during development of the prostate postnatally in rodent and human. The in vitro experiments using ventral prostatic cells or neonatal prostatic organ cultures suggest a complex interplay of EGF and TGF-
in regulating growth of the prostate and influencing outgrowth of the prostatic buds. In isolated prostatic epithelial and stromal cells derived from 20-day-old rats, Itoh et al. (1998)
reported epithelial expression of TGF-
and EGFR with region-specific expression. This study also reported expression of TGF-
and EGFR mRNA in both epithelial and stromal cells; it examined the interplay of these growth factors and found that exposure to EGF stimulated expression of TGF-
in stromal but not epithelial cells and that proliferation of both cell types was stimulated by EGF. Interestingly an antibody to inhibit TGF-
activity significantly decreased proliferation in response to testosterone in both cell types.
Numerous in vitro models for cultured rat ventral prostate report stimulation of growth with exposure to either EGF or TGF- (Ilio et al., 1995
; Saito and Mizuno, 1997
). Also, Saito and Mizuno (1997)
reported that both EGF and TGF-
stimulate prostatic bud formation in cultured UGS, even in the absence of androgens in the medium. This implies that a complex interplay of growth factor signals is important in mediating stromal-epithelial interactions that are involved in regulating ductal development of the various lobes of the prostate. Obviously, the complexity of these mesenchymal-epithelial cell interactions, which are integral to formation of buds and subsequent branching, are likely to require expression of regulatory molecules and signaling pathways in addition to the EGFR pathway. Sonic hedgehog, a stimulatory factor, is produced in the UGS, and the homeobox genes Hoxa-13 and Hoxd-13 play lobe-selective roles in prostate development (Podlasek et al., 1997
, 1999
). Prostatic epithelial bud formation also requires expression of p63 and fibroblast growth factor-10 (FGF-10; Donjacour et al., 2003
; Lamm et al., 2001
; Signoretti et al., 2000
). Several growth factors, including FGF, KGF, and HGF, are known to regulate prostatic growth through a mesenchymal paracrine mechanism (Story, 1995
; Sugimura et al., 1996
; Thomson, 2001
; Thomson and Cunha, 1999
).
In summary, this study provides evidence for the importance of EGF and TGF- in prostate development. The results suggest that both EGF and TGF-
are needed for the formation of the prostatic buds and that their role(s) may differ by region. The differing outcomes in specific regions of the UGS and in EGF (-/-) and TGF-
(-/-) fetuses suggest that UGS regionspecific expression patterns of these growth factors may influence the response to TCDD and that a disruption of balanced, UGS regionspecific expression could provide a key to understanding the response of the developing prostate to TCDD.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at the U.S. Environmental Protection Agency, 2525 East Highway 54, NHEERL Building (Room 1425), Durham, NC 27713. Fax: (919) 541-4017. E-mail: abbott.barbara{at}epa.gov.
2 Present address: School of Medicine, University of Wisconsin, Madison, WI 53706.
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