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Departments of Molecular and Integrative Physiology (Sa.K.D., J.T., D.C.J., Su.K.D.) and Obstetrics and Gynecology (D.C.J.), University of Kansas Medical Center, Ralph L. Smith Research Center, Kansas City, Kansas 66160-7338
Address all correspondence and requests for reprints to: Dr. S. K. Das, Department of Molecular and Integrative Physiology, University of Kansas Medical Center, MRRC 37/3017, 39th and Rainbow Boulevard, Kansas City, Kansas 66160-7338. E-mail: sdas{at}kumc.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and
ERß). However, there is evidence that these xenobiotics can regulate
gene expression in the reproductive targets by mechanisms that do not
involve these ERs. To examine this further, we compared the effects of
estrogenic (o,p'-DDT
[1-(o-chlorophenyl)-1-(p-chlorophenyl)2,2,2-trichloroethane]
and Kepone, chlordecone) and nonestrogenic (p,p'-DDD
[1,1-dichloro-2,2-bis(p-chlorophenyl)ethane], a
metabolite of p,p'-DDT) xenobiotics with those of
17ß-estradiol (E2) and 4-hydroxyestradiol-17ß
(4-OH-E2), a catechol metabolite of E2, on
uterine expression of lactoferrin (LF) and progesterone receptor (PR).
These genes are estrogen responsive in the mouse uterus. Normally, LF
is expressed in the uterine epithelium, whereas PR is expressed in both
the epithelium and stroma in response to estrogenic stimulation.
Ovariectomized mice were injected with xenobiotics (7.5 mg/kg),
E2 (10 µg/kg), 4-OH-E2 (10 µg/kg), or the
vehicle (oil, 0.1 ml/mouse), and uterine tissues were processed for
Northern blot and in situ hybridization. The pure
antiestrogen ICI-182780 (ICI; 1 or 20 mg/kg) was used to interfere with
estrogenic responses that were associated with the ERs. The results of
Northern and in situ hybridization demonstrated
increased uterine levels of PR and LF messenger RNAs (mRNAs) by all of
these xenobiotics, but quantitatively the responses were much lower
than those induced by E2 or 4-OH-E2. The
results further showed that the E2-inducible epithelial LF
mRNA accumulation was markedly abrogated by pretreatment with ICI (20
mg/kg). In contrast, this treatment retained the epithelial expression
of PR mRNA, but down-regulated the stromal expression. In contrast, ICI
had negligible effects on LF and PR mRNA responses to
4-OH-E2, indicating that this catechol estrogen exerted its
effects primarily via a mechanism(s) other than the ERs. The heightened
accumulation of LF mRNA in the epithelium in response to Kepone and
o,p'-DDT was also severely compromised by pretreatment
with ICI, but this antiestrogen had little effect on responses to
p,p'-DDD. Similar to E2, Kepone increased
the expression of PR mRNA in both uterine epithelium and stroma.
However, pretreatment with ICI decreased stromal cell expression,
whereas epithelial cell expression remained unaltered or increased.
These responses were not noted in mice treated with
o,p'-DDT or p,p'-DDD. Collectively, the
results demonstrate that catechol estrogens or xenobiotics can alter
uterine expression of estrogen-responsive genes by mechanisms that are
not totally mediated by the classical nuclear ERs, and these
alterations are cell type specific. We conclude that an interaction of
a compound with the nuclear ER and/or ERß is not an absolute
requirement for producing specific estrogen-like effects in the
reproductive target tissues. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(ER) (1, 2, 3, 4). Whether these xenobiotics interact with
recently identified ERß is not yet clearly established, although
recent studies show that a few of these compounds possess an even
higher affinity for this receptor (5). It is possible that
environmental estrogens (xenoestrogens) could exert their effects by
binding to homodimers of ERß or heterodimers of ER and ERß. This
is consistent with the finding that antiestrogens, 4-hydroxytamoxifen
and ICI-182780 [ICI;
7-(9–4,4,5,5,5-pentafluoropenylsulfinyl)nonyl-estra-1,3,4(10-triene-3,17ß-diol)],
bind ERß as well as heterodimers of ER and ERß (6).
Interactions of xenoestrogens with ER have been repeatedly offered as
the basis for their reproductive toxicity (7, 8). However, the
requirement for large concentrations (micromolar) of xenoestrogens to
induce any estrogenic phenotypes and their low affinity for ER have
challenged the idea that prevailing xenoestrogens in the environment
are significant health hazards (9). This argument assumes that the
major effects of xenoestrogens depend upon their interaction with the
classical ER.
The present investigation examined whether xenoestrogens produce
target-specific effects via gene expression that may or may not involve
classical ERs. We selected two natural estrogens, 17ß-estradiol
(E2) and its catechol metabolite 4-hydroxyestradiol-17ß
(4-OH-E2), as well as three polychlorinated hydrocarbons.
Two of the latter are insecticides, chlordecone (Kepone) and
p,p'-DDD (Rhothane;
[1,1-dichloro-2,2-bis-(p-chlorophenyl)ethane]), and the
third is o,p'-DDT
[1-(o-chlorophenyl)-1-(p-chlorophenyl)2,2,2-trichloroethane],
the estrogenic isomer of the insecticide p,p'-DDT (7, 10, 11). Kepone and o,p'-DDT have relatively weak affinity for
ER and exhibit estrogenic effects in vivo (7, 10, 11, 12, 13).
Although p,p'-DDD does not bind to rodent ER or produce
estrogenic effects in vivo, it has weak affinity for
recombinant human ER (14). To examine differential effects of these
xenoestrogens and natural estrogens in uterine functions, the
expression of two estrogen-responsive genes, lactoferrin (LF) and
progesterone receptor (PR), in the adult ovariectomized mouse uterus
was studied. Although they are established as estrogen-responsive
genes, their expression can be influenced by transcription factors
other than ER (15, 16, 17). The contribution of classical ERs in these
responses was examined using the pure antiestrogen ICI (18). All of the
compounds increased the expression of LF and PR, but only the effects
of E2 on LF messenger RNA (mRNA) were markedly attenuated
by pretreatment with ICI. Alteration in cell-specific expression of PR
mRNA after exposure to this antiestrogen suggests that E2,
4-OH-E2, and the xenobiotics have distinct and overlapping
effects in the uterus. Thus, an additional factor(s) other than the
trans-activation effects of the classical ERs must be
considered when evaluating the effects of environmental toxins on the
reproductive tract.
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Materials and Methods |
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Animals and injection schedules
Adult CD-1 mice (Charles River Laboratories, Raleigh, NC) were
maintained in the animal care facilities of the University of Kansas
Medical Center in accordance with NIH standards for care and use of
experimental animals. Virgin female mice (7–9 weeks of age) were
ovariectomized and rested for 10 days before receiving any treatments.
They received a single sc injection (0.1 ml/mouse) of oil (control),
Kepone (3.25, 7.5, 15, or 30 mg/kg), o,p'-DDT (3.25, 7.5,
15, or 30 mg/kg), p,p'-DDD (3.25, 7.5, 15, or 30 mg/kg),
E2 (10 µg/kg), and 4-OH-E2 (10 µg/kg), or
ICI (1 or 20 mg/kg) or were given ICI 30 min before the injection of
the xenobiotics or natural estrogens. Mice were killed at 1, 2, 4, 6,
12, and 24 h. Mice injected with oil were killed 6 or 24 h
after the injection and served as controls.
Northern blot hybridization
Total RNA was extracted from tissues by a modified method as
previously described (19, 20). Total RNA (6.0 µg) was denatured,
separated by formaldehyde/agarose gel electrophoresis, transferred to
nylon membranes, and UV cross-linked. Blots were prehybridized and
hybridized as described previously (20, 21). Briefly, hybridization was
carried out for 20 h at 68 C in 3 x SET (1 x SET
= 150 mM NaCl, 5 mM EDTA, and 10 mM
Tris-HCl, pH 8.0), 0.1% SDS, 20 mM phosphate buffer (pH
7.2), 250 µg/ml transfer RNA, 10% dextran sulfate, and 1 x
106 counts/min of 32P-labeled antisense
complementary RNA (cRNA) probe/ml hybridization buffer. Hybridization
was performed in sequence with probes for mouse PR, LF, and ribosomal
protein L7 (rpL7). Stripping of hybridized probe before subsequent
rehybridization was achieved by boiling blots for 5 min in 0.5 x
SET and 0.1% SDS (21). Transcripts were detected by autoradiography.
Quantitation of radioactivity to hybridized bands was obtained using a
radioimage analysis system (Ambis Systems, San Diego, CA).
In situ hybridization
In situ hybridization was performed as described
previously (20, 22). Briefly, each uterine horn was excised, cut into
halves, and flash frozen in freon. Frozen sections (10 µm) were
mounted onto poly-L-lysine-coated slides and stored at -70
C until used. After removal from -70 C, the slides with the uterine
sections were placed on a slide warmer (37 C) for 2 min and then fixed
in 4% paraformaldehyde in PBS for 15 min at 4 C. After
prehybridization, uterine sections were hybridized to
35S-labeled antisense PR and LF cRNA probes for 4 h at
45 C. As negative controls, uterine sections were hybridized with the
35S-labeled sense PR and LF cRNA probes. After
hybridization and washing, the slides were incubated with ribonuclease
A (RNase A; 20 µg/ml) at 37 C for 20 min. RNase A-resistant hybrids
were detected by autoradiography using Kodak NTB-2 liquid emulsion
(Eastman Kodak, Rochester, NY). The slides were poststained with
hematoxylin and eosin.
Hybridization probes
The subcloning and vectors for mouse LF and rpL7 have been
described (22, 23). A 499-bp complementary DNA fragment for mouse PR in
the DNA- and ligand-binding domains, was derived by RT-PCR using mouse
day 4 pregnant uterine RNA sample. The fragment was then subcloned in
pCR-Script (SK)+ vector, and the sequencing was performed
using the dideoxy method to confirm the nucleotide sequence for the
mouse PR. For Northern blot hybridization, antisense
32P-labeled cRNA probes were generated using SP6
polymerase. For in situ hybridization, sense or antisense
35S-labeled cRNA probes were generated. Probes had specific
activities of about 2 x 109 dpm/µg.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, A and B). As shown previously (24),
the induction of uterine LF mRNA in response to E2 was
bimodal, with an early increase (4-fold) at 4 h followed by
further increases at 12 and 24 h (15-fold; Fig. 1A). The induction
by 4-OH-E2 on uterine LF mRNA levels was also biphasic
(Fig. 1B); however, the first induction was noted at 2 h (7-fold)
followed by further increases at 12 and 24 h (12-fold). With
respect to PR mRNA, both E2 and 4-OH-E2 showed
a similar patter of induction; the peak (7–8 fold) induction was seen
at 6 h.
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). Unlike the natural
estrogens, this dose of either Kepone or o,p'-DDT does not
produce a uterotropic response even if given daily for 3 days, and
p,p'-DDD, has not been shown to be uterotropic at the doses
examined (7). As shown in Fig. 2, uterine LF mRNA levels increased
rapidly after exposure to all of these xenobiotics. With Kepone and
p,p'-DDD, the maximal response (6-fold) was noted at 6
h, followed by a decline at 12 and 24 h. The induction of LF mRNA
levels caused by o,p'-DDT was less than that produced by
Kepone or p,p'-DDD and was biphasic.
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PR mRNA levels increased rapidly within 2–4 h after the injection of Kepone or o,p'-DDT, although the maximal response (2-fold) occurred somewhat earlier with the latter compound. In the case of the nonestrogenic p,p'-DDD, the response was similar in magnitude to that obtained with Kepone or o,p'-DDT, but the peak level was reached at 12 h. In general, the degree of responses induced by these xenobiotics was much less than that observed with natural estrogens.
Effects of the antiestrogen ICI on the expression of uterine
LF and PR mRNAs induced by natural estrogens or
xenobiotics
To determine whether the effects of natural estrogens or
xenobiotics on the induction of LF and PR mRNAs in the mouse uterus was
mediated by ERs, ovariectomized mice were injected with either 1 or 20
mg/kg ICI 30 min before the injections of the natural estrogens (10
µg/kg) or xenobiotics (7.5 mg/kg). The uterine RNA samples were
analyzed by Northern blot hybridization (Fig. 3). Although the induction levels (12- to
15-fold) of LF mRNA in response to E2 or
4-OH-E2 were same, the effects of pretreatment with ICI on
the responses to these natural estrogens were quite different (Fig. 3A). The treatment with 1 mg/kg ICI, a dose 100-fold higher than that
of the estrogens, had little effect on the responses to E2
or 4-OH-E2. However, increasing the dose of ICI to 20 mg/kg
almost completely inhibited the response to E2, but had
only a small inhibitory effect on the response to 4-OH-E2,
suggesting that much of the response to this catechol estrogen was not
mediated by the estrogen receptors, either ER or ERß. Neither dose
of antiestrogen alone had any effect compared with levels in control
animals treated with oil (Fig. 3A). These results are consistent with
our recent findings in mice lacking ER (ERKO) (27). The effects of
antiestrogen pretreatment on the responses induced by xenobiotics are
shown in Fig. 3B. A dose of 20 mg/kg ICI given 30 min before
o,p'-DDT or Kepone prevented much of the increase in LF mRNA
induced by these xenobiotics (Fig. 3B). In contrast, the antiestrogen
had no effect on the response to p,p'-DDD, indicating that
this response was not mediated by uterine ER.
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). Increasing
the dose of ICI (20 mg/kg) had a pronounced inhibitory effect on the
responses to E2, but a minimal effect on the responses to
4-OH-E2, again supporting the view that much of the
response to this catechol estrogen was not mediated by the ERs. The
uterine responses to xenobiotics on uterine PR mRNA accumulation were
much less than those seen with the estrogens (Fig. 4B). ICI at a dose
of 20 mg/kg had little, if any, inhibitory effect on the response to
o,p'-DDT or p,p'-DDD. In contrast, the response
to Kepone on PR mRNA levels increased after pretreatment with the
antiestrogen (Fig. 4B). Again, these results are consistent with the
view that certain steroid-responsive uterine genes activated by
xenobiotics are not solely mediated by the ERs.
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, A and B). However, either
E2 or 4-OH-E2 increased the levels of LF mRNA
in the luminal and glandular epithelial cells (Fig. 5, C and E). The
response induced by E2 was totally abrogated by
pretreatment with ICI at 20 mg/kg (Fig. 5D). In contrast, the response
induced by 4-OH-E2 in epithelial cells was not altered by
pretreatment with this dose of ICI (Fig. 5F). These results are
consistent with those of the Northern blot hybridization experiments
(Fig. 3A
).
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, G–J); ICI appeared to be more effective
against the action of o,p'-DDT than against Kepone. In
contrast, this antiestrogen had little effect on the luminal epithelial
expression of LF mRNA by p,p'-DDD (Fig. 5, K and L). No
positive signals were observed when uterine sections were hybridized
with the sense probe (data not shown).
Effects of natural estrogens and xenobiotics on cell-specific
expression of PR mRNA in the mouse uterus
The cell-type specific effects of the natural estrogens or
xenobiotics on uterine PR mRNA accumulation were examined by in
situ hybridization. In mice treated with oil, autoradiographic
signals for PR mRNA were detected mainly in the uterine luminal
epithelium (Fig. 6, A
and B), and an injection of ICI (20 mg/kg) maintained the low levels of
PR mRNA in the same cell types (data not shown). The expression of PR
mRNA significantly increased in both epithelial and stromal cells after
an injection of E2 (Fig. 6, C and D). The pretreatment with
ICI greatly reduced the E2-induced up-regulation of PR mRNA
levels in stromal cells, but this treatment distinctly maintained the
up-regulated PR mRNA levels in the luminal epithelial cells (Fig. 6, E
and F). This change in the pattern of cellular expression of PR mRNA
was duplicated, albeit with a lower intensity of signals, in the uteri
of mice treated with Kepone and/or ICI (Fig. 6, G–J). Thus, the
pretreatment with ICI significantly attenuated the Kepone-induced
accumulation of PR mRNA in stromal cells, but the luminal epithelial
accumulation remained unaffected. With respect to 4-OH-E2,
PR mRNA accumulation was markedly up-regulated in the epithelial and
subepithelial stromal cells. In contrast to E2 or Kepone,
the pretreatment with ICI failed to show any reduction of PR mRNA
accumulation by 4-OH-E2 in either cell type, although this
treatment modestly increased the signals of PR mRNA throughout the
stroma (Fig. 6, M and N). o,p'-DDT and p,p'-DDD
showed a localization pattern similar to that of 4-OH-E2,
but with a reduced signal intensity; ICI had very little effect on this
expression (Fig. 6, O–V).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Kepone, o,p'-DDT, or p,p'-DDT has similar low
affinity (IC50, 
100 µM) for the androgen
receptor, and thus, interaction with this receptor is not considered a
factor for any possible reproductive toxicity of these compounds (28).
In contrast, although the affinities of Kepone and o,p'-DDT
for the ER (IC50, 4 µM) are considerably
lower than that of E2 (IC50, 0.002
µM), it is much higher than that of p,p'-DDD
(IC50, >1000 µM) (28). When given in large
doses, o,p'-DDT or Kepone mimics the action of
E2 in several in vivo responses (7, 8, 10, 13).
This requirement for large doses of xenoestrogens to produce estrogenic
effects suggests that mechanisms other than those based on DNA-ER
interactions are involved in reproductive toxicity. Models for
examining such a view include examination of gene expression in animals
that lack functional ERs produced by gene targeting (ER knock-out,
ERKO) (25, 27) or antagonism of ER action by a potent antiestrogen (27, 30, 31).
LF and PR are well known estrogen-responsive genes in the mouse uterus (15, 16, 17, 24). However, there is evidence that these genes can be up-regulated by many other factors. For example, although the LF gene is inducible in the uterus and mammary gland by epidermal growth factor (32) and PRL (15, 33), respectively, the PR gene is known to be induced by dopamine, cAMP, and growth factors (17, 34, 35). In the present investigation, the increased accumulation of their mRNAs in the mouse uterus after exposure to E2 or 4-OH-E2 was anticipated. In contrast, increased expression after exposure to o,p'-DDT or Kepone at a relatively low dose (7.5 mg/kg) was unexpected, as little or no uterotropic effects are produced by either of these compounds at this dose. Further, the effects of p,p'-DDD, which is not estrogenic at any dose and does not bind to the rodent uterine ER, was even more surprising. Thus, these xenobiotics influence estrogen-responsive uterine genes at doses that are considered inconsequential when examining for typical phenotypic estrogenic effects.
The LF gene expression by E2 was remarkably abrogated by
pretreatment with ICI (20 mg/kg), a pure antiestrogen, establishing the
involvement of the ER. In contrast, ICI showed only modest effects on
4-OH-E2-induced expression of this gene. This is consistent
with our previous observation in ERKO mice (27). Thus, the effects of
4-OH-E2 on uterine expression of the LF gene does not
appear to be solely dependent on its interaction with the ER. This
catechol estrogen has an affinity for ER and ERß that is about
10% that of E2 (5). The attenuation of uterine LF mRNA
accumulation by ICI in response to o,p'-DDT or Kepone
indicates that this response to a considerable extent was mediated via
ER. In contrast, ICI’s inability to influence uterine LF mRNA
accumulation in response to p,p'-DDD suggests that this
xenobiotic affects the expression of this gene by a factor other than
the nuclear ER.
The regulation of uterine accumulation of PR mRNA by the test compounds
and their interactions with the nuclear ER appear more complex. The
changes in PR mRNA were similar in mice exposed to either
E2 or 4-OH-E2, and ICI showed minimal reduction
in the levels of PR mRNA. There is a report (25) that ICI-164384, a
structurally similar but less potent antiestrogen than ICI (18), at a
dose of 1 mg/kg inhibited the effects of E2 (20 µg/kg) on
PR mRNA expression in the mouse uterus. In the present study, we
observed that ICI at 1 mg/kg was essentially without any effect on the
PR mRNA response to E2 at 10 µg/kg. One explanation for
these observed differences could be the timing of analysis. We examined
the effects of pretreatment of ICI in response to E2 at
6 h, the time of maximal uterine accumulation of PR mRNA, rather
than at 24 h (25). One of the most intriguing findings of the
present investigation is that the pretreatment with ICI altered the
cell type-specific accumulation of PR mRNA in response to
E2 or Kepone. The retention of PR mRNA accumulation in
epithelial cells and its attenuation in stromal cells under these
experimental conditions suggest that PR mRNA expression in the uterus
in response to different estrogenic compounds is dependent upon the
cell types involved. Current explanations for estrogen action involve
ligand binding to homo- or heterodimers of ER or ERß and their
activation of genes containing a consensus estrogen response element in
their promoter region (Ref. 36 and references therein). However, ER can
mediate gene transcription via other enhancer elements, such as
activating protein-1 (AP-1) (37). Recent in vitro studies
show that antiestrogens, including ICI-164384, and E2 can
bind ER and alter gene expression via an AP-1 site (37). The
antiestrogens can also alter gene expression via the AP-1 site when
bound to ERß, but E2 was inhibitory at this site when
acting via ERß. The effects of E2 or Kepone on expression
of PR mRNA in stromal cells are probably mediated via the nuclear ERs,
as this response was essentially abolished by pretreatment with ICI. If
the effect of E2 or Kepone on epithelial cells was
directed via an ER action, it should have also been
eliminated by the antiestrogen. Furthermore, even an indirect
up-regulation of PR mRNA in epithelial cells produced by paracrine
effects originating from stromal cells (38) would be expected to be
removed by ICI. Therefore, the results suggest that increased PR mRNA
expression in epithelial cells by either E2 or Kepone was
mediated not by ER but by some other activator(s). The accumulation of
uterine PR mRNA also exhibited differential regulation in response to
4-OH-E2. Similar to E2 or Kepone, this catechol
estrogen enhanced accumulation of PR mRNA in both epithelial and
subepithelial stromal cells, but unlike E2 or Kepone,
pretreatment with ICI did not down-regulate the accumulation in stromal
cells in response 4-OH-E2; rather an enhanced response in
stromal cells was noted, suggesting that the ER-mediated inhibitory
effects of ICI had been removed. Clearly, the effects of
4-OH-E2 on PR gene expression, similar to those on the LF
gene expression, are not dependent upon ER.
In summary, these studies further establish that environmental
reproductive toxins and other estrogens can alter the functions of
estrogen-responsive genes in reproductive tissues by mechanisms that
are independent of classical ERs. Thus, the affinity of a compound for
ERs (ER or ERß) should not determine its possible in
vivo effects on reproductive functions. The alteration of the LF
and PR genes by environmentally relevant doses of xenobiotics may have
significant impact on uterine responses at the molecular level.
Admittedly, the responses seen in the present study are acute effects,
and their relevance to the consequences of chronic exposure, which
would be expected for exposure to environmental toxins, remain to be
determined.
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Footnotes |
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Received December 4, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß. Endocrinology 138:863–870 and ß form heterodimers on DNA. J Biol
Chem 272:19858–19862 deficient
mice reveal a novel estrogen signaling pathway. Proc Natl Acad Sci USA 94:12786–12791 and ß form heterodimers on DNA. J Biol
Chem 272:19858–19862
and ERß at AP1 sites. Science 277:1508–1510This article has been cited by other articles:
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S. O. Mueller, J. A. Clark, P. H. Myers, and K. S. Korach Mammary Gland Development in Adult Mice Requires Epithelial and Stromal Estrogen Receptor {alpha} Endocrinology, June 1, 2002; 143(6): 2357 - 2365. [Abstract] [Full Text] [PDF]
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W. P. Bocchinfuso, J. K. Lindzey, S. C. Hewitt, J. A. Clark, P. H. Myers, R. Cooper, and K. S. Korach Induction of Mammary Gland Development in Estrogen Receptor-{alpha} Knockout Mice Endocrinology, August 1, 2000; 141(8): 2982 - 2994. [Abstract] [Full Text] [PDF]
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C. Passavant, X. Zhao, S.K. Das, S.K. Dey, and R.A. Mead Changes in Uterine Expression of Leukemia Inhibitory Factor Receptor Gene During Pregnancy and Its Up-Regulation by Prolactin in the Western Spotted Skunk Biol Reprod, July 1, 2000; 63(1): 301 - 307. [Abstract] [Full Text]
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L. C. Hodges, J. S. Bergerson, D. S. Hunter, and C. L. Walker Estrogenic Effects of Organochlorine Pesticides on Uterine Leiomyoma Cells in Vitro Toxicol. Sci., April 1, 2000; 54(2): 355 - 364. [Abstract] [Full Text] [PDF]
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J. Tan, B. C. Paria, S. K. Dey, and S. K. Das Differential Uterine Expression of Estrogen and Progesterone Receptors Correlates with Uterine Preparation for Implantation and Decidualization in the Mouse Endocrinology, November 1, 1999; 140(11): 5310 - 5321. [Abstract] [Full Text]
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D. Ghosh, J. A. Taylor, J. A. Green, and D. B. Lubahn Methoxychlor Stimulates Estrogen-Responsive Messenger Ribonucleic Acids in Mouse Uterus through a Non-Estrogen Receptor (Non-ER){alpha} and Non-ER{beta} Mechanism Endocrinology, August 1, 1999; 140(8): 3526 - 3533. [Abstract] [Full Text]
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D. S. Hunter, L. C. Hodges, P. M. Vonier, R. Fuchs-Young, M. M. Gottardis, and C. L. Walker Estrogen Receptor Activation via Activation Function 2 Predicts Agonism of Xenoestrogens in Normal and Neoplastic Cells of the Uterine Myometrium Cancer Res., July 1, 1999; 59(13): 3090 - 3099. [Abstract] [Full Text] [PDF]
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H. Lim, L. Ma, W.-g. Ma, R. L. Maas, and S. K. Dey Hoxa-10 Regulates Uterine Stromal Cell Responsiveness to Progesterone during Implantation and Decidualization in the Mouse Mol. Endocrinol., June 1, 1999; 13(6): 1005 - 1017. [Abstract] [Full Text]
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B. C. Paria, J. Tan, D. B. Lubahn, S. K. Dey, and S. K. Das Uterine Decidual Response Occurs in Estrogen Receptor-{alpha}-Deficient Mice Endocrinology, June 1, 1999; 140(6): 2704 - 2710. [Abstract] [Full Text]
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S. W. Curtis, J. Clark, P. Myers, and K. S. Korach Disruption of estrogen signaling does not prevent progesterone action in the estrogen receptor alpha knockout mouse uterus PNAS, March 30, 1999; 96(7): 3646 - 3651. [Abstract] [Full Text] [PDF]
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 S. K. Das, J. Tan, S. Raja, J. Halder, B. C. Paria, and S. K. Dey Estrogen Targets Genes Involved in Protein Processing, Calcium Homeostasis, and Wnt Signaling in the Mouse Uterus Independent of Estrogen Receptor-alpha and -beta J. Biol. Chem., September 8, 2000; 275(37): 28834 - 28842. [Abstract] [Full Text] [PDF]
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