Laboratory for Pregnancy and Newborn Research, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853
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ABSTRACT |
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Two
estrogen receptor (ER) isoforms, ER and ER
, have been described.
However, no information is available in any species regarding the
comparison of ER
and ER
levels in pregnant intrauterine tissues.
We investigated 1) distribution of ER
and ER
mRNA in myometrium, amnion, choriodecidua, and placenta; 2) their
abundance in intrauterine tissues at term not in labor (NIL) and in
spontaneous term labor (STL); and 3) immunolocalization of
ER
and ER
in pregnant rhesus monkey myometrium. Myometrium,
amnion, choriodecidua, and placenta were obtained at cesarean section
from monkeys in STL at 156-166 days gestational age
(GA) (n = 4) and from control monkeys NIL at
140-152 days GA (n = 4). RT-PCR was conducted to determine
ER
and ER
and glyceraldehyde-3-phosphate dehydrogenase mRNA
abundance in four intrauterine tissues of the pregnant rhesus monkey.
The cloned ER
PCR fragment was subjected to sequence analysis. ER
and ER
were localized in the myometrium by immunohistochemistry. We
demonstrated that 1) rhesus monkey ER
shares >97%
identity with human ER
in the region sequenced; 2) both ERs
were expressed in myometrium, amnion, and choriodecidua but not in
placenta in the current study; 3) ER
and ER
were
differentially distributed in myometrium and amnion; 4) ER
and ER
were immunolocalized in myometrial smooth cells and smooth
muscle and endothelial cells of the myometrial blood vessels. The
biological significance of these quantitative differences in ER
subtypes merits further study.
estrogen receptors and
; myometrium; fetal
membrane
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INTRODUCTION |
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ESTROGEN INFLUENCES the growth, differentiation, and
function of many target tissues, especially those in the female
reproductive tract. Estrogens play an important role in preparing the
myometrium for labor. Estrogens activate myometrial contraction
associated proteins (41, 43), thereby increasing the ability of the
uterus to contract, promoting the synchronization of the contractile units (5, 9, 22). Target tissue response to estrogen is determined by tissue-specific expression of the estrogen receptor (ER).
We have demonstrated that increased ER concentration in the pregnant
sheep myometrium and endometrium is associated with the onset of
spontaneous term labor (STL) (42) as well as glucocorticoid-induced premature labor (38).
ER cDNA was cloned in 1986 from several species (10), and until
recently there has been general acceptance that only a single ER gene
existed. At the end of 1995, a second ER
was cloned from a rat
prostate cDNA library (16), and, subsequently, the homologous human
(21) and mouse (36) genes were cloned. The existence of two ERs
presents the possibility that variation in the presence and relative
extent of ER
or ER
receptor-specific mechanisms is involved in
tissue-specific and physiological state-specific actions of estrogen.
In the rat, ER and ER
mRNA differ in their tissue distribution
and/or the relative concentration (17). However, no studies have
compared levels of ER
and ER
in nonhuman primate or human tissues. Furthermore, no information is available in any species regarding ER
abundance in pregnant intrauterine tissues, which are
important targets for estrogen. In particular, the presence of ER in
human or nonhuman primate placenta and fetal membranes has been
a subject of dispute (2, 6, 15, 31, 33). Using
semiquantitative RT-PCR, we investigated 1) differential distribution of both ER
and ER
mRNA in myometrium, amnion,
choriodecidua, and placenta; 2) change of ER
and ER
mRNA
abundance in intrauterine tissues at term not in labor (NIL) and in
STL; and 3) immunolocalization of ER
and ER
in pregnant
rhesus monkey myometrium.
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METHODS |
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Animals and tissue collection.
Eight pregnant rhesus monkeys from the California Regional Primate
Research Center, Davis, CA, bred only once and of known gestational age
(GA) were studied. Experimental procedures were approved by the Cornell
University Institutional Animal Care and Use Committee. The Cornell
facilities are approved by the American Association for the
Accreditation of Laboratory Animal Care. The pregnant rhesus
monkeys were instrumented at 119-136 days GA with electromyogram electrodes sewn in the myometrium (34). Myometrial activity was monitored continuously and evaluated as being either in
the low-amplitude, infrequent-contracture mode or in the frequent short-duration labor type contraction mode (13). Myometrium, amnion,
choriodecidua, and placenta were obtained at cesarean section from
monkeys in STL at 156-166 days GA (n = 4) determined by
the occurrence of a switch in myometrial activity from contractures to
contractions and from control monkeys NIL at 140-152
days GA (n = 4). Various maternal organs (heart, bladder,
kidney, liver, lung, pancreas, spleen, thymus, and thyroid) were also
collected from one pregnant rhesus monkey. Collected tissues were
frozen in liquid nitrogen for RNA extraction. All tissues were stored at 80°C. One portion of myometrium was frozen in liquid
nitrogen-cooled isopentane for ER
immunolocalization. A second
portion was fixed in 4% paraformaldehyde for ER
immunolocalization.
RNA preparation.
Total RNA was prepared from individual tissues as previously described
(42). Briefly, total RNA was isolated from frozen tissues in 4.2 M
guanidinium thiocyanate solution. RNA was pelleted through a 5.7 M
cesium chloride cushion. The RNA purity and recovery from each tissue
was determined by ultraviolet spectrophotometry (260 and 280 nm). There were no differences in the yield of RNA per
milligram of tissue between control and treatment groups or between
monkeys in labor and monkeys not in labor. Purified RNA was resuspended
in 1 mM EDTA. The poly(A)-enriched RNA was also extracted from multiple
rhesus monkey maternal tissues using a Fast-track kit purchased from
Invitrogen (San Diego, CA). Total RNA and poly(A)-enriched RNA were
stored at 80°C.
RT-PCR. Reverse transcription (RT) was performed in a final volume of 100 µl containing 5 µg total RNA or 1 µg poly(A)-enriched RNA per sample, 5 mM MgCl2, 10 mM Tris · Cl (pH 8.3), 50 mM KCl, 1 mM of each dNTP (dATP, dCTP, dGTP, and dTTP), 5 units of RNAse inhibitor, 12.5 units of Moloney murine leukemia virus RT, and 2.5 µM of random hexamers. The RT mixture was incubated at 42°C for 60 min.
PCR primers were as follows: ERSemiquantitative RT-PCR measurement of ER and
ER
mRNA.
In our previous study, expression of ER
mRNA was very low in
pregnant rhesus monkey intrauterine tissues (39). ER
mRNA is not
detectable by Northern blot analysis in the rhesus monkey myometrium
using 5 µg poly(A) RNA (data not shown). In the present study, we
chose semiquantitative RT-PCR. Because myometrium contained the highest
concentration of ER
mRNA in the various intrauterine tissues
studied, we first determined whether the detection of the ER
PCR
product was linear in the myometrium. We chose three cycle numbers (25, 30, and 35 cycles) and determined the abundance of PCR product in six
samples of myometrium collected from animals NIL and STL. Twenty-five
cycles were insufficient to produce a readily detectable signal and 30 cycles gave barely visible signals when 5 µg of RT reaction
mixture were used (Fig.
1). In contrast, at 35 cycles
there were distinct signals for ER
in different samples. A similar
approach was used to determine the linear cycle range for ER
and
GAPDH. As a result of this preliminary validation, we chose 35 cycles
for ER
and ER
and 30 cycles for GAPDH.
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Subcloning and sequencing of ER cDNA.
PCR products containing a single band were cloned directly in the pCR
2.1 vector using the TA cloning kit (Invitrogen, San Diego, CA) under
the conditions recommended by the manufacturer. The plasmid DNA was
purified using the Biorobot system (QIAGEN), and the sequencing was
done by Taq cycle sequencing using DyeDeoxy terminators in an
Applied Biosystems automated sequencer (ABI 377 DNA sequencer) at the
core sequencing facility of Cornell University. The cloned fragments of
ER
were sequenced from at least two different clones and from both
the coding and noncoding strands. The DNASTAR program (DNASTAR,
Madison, WI) was used for alignments.
Immunolocalization of ER and ER
in
the myometrium.
Because there were no fetal membranes available for immunocytochemical
analysis of ERs and placental ERs were too low to be detected by
immunostaining, immunolocalization of ERs was only performed in the
myometrium. Immunolocalization of ER
was performed on floating
sections of the myometrium fixed with 4% paraformaldehyde and
validated as described previously (38). The use of anti-human ER
monoclonal antibody (kindly provided by Dr. Edwards, Colorado University) in the present study was verified as described previously (38).
Statistical analysis.
After normalization of the content of ER and ER
mRNA to GAPDH in
individual samples, ER
and ER
mRNA concentration in each set of
PCR was expressed as a ratio of ER
and ER
to GAPDH mRNA. Differences between different groups (NIL vs. STL) or between different
tissues were subjected to two-way ANOVA followed by multiple comparison
using a Tukey-Kramer procedure. Data throughout are presented as means ± SE.
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RESULTS |
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Expression of ER mRNA in intrauterine tissues of the
pregnant rhesus monkey.
ER
mRNA was expressed in the myometrium, choriodecidua, and amnion
by quantitative RT-PCR analysis; however, there was no detectable ER
mRNA in the placenta when 5 µg RT reaction mixture was used at 35 cycles. Nested PCR further confirmed the specificity of primary ER
PCR product (data not shown). Myometrium contained the highest
concentration of ER
mRNA compared with amnion and choriodecidua
(Fig. 2, P < 0.01). There was no
significant change of the abundance of ER
mRNA in myometrium,
amnion, and choriodecidua during spontaneous labor when compared with
control monkeys which were not in labor (Fig. 2).
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Expression of ER mRNA in intrauterine tissues of the
pregnant rhesus monkey.
Quantitative RT-PCR analysis of ER
mRNA in intrauterine tissues of
the pregnant rhesus monkey revealed that myometrium contained the
highest concentration of ER
mRNA compared with the three other
intrauterine tissues examined (Fig. 3,
P < 0.05). Nested PCR further confirmed the specificity of
primary ER
PCR product (data not shown). ER
mRNA abundance in
amnion is significantly higher than choriodecidua. There were no
significant differences in the ER
mRNA level during STL compared
with control animals NIL (Fig. 3). As with ER
, there was no
detectable signal for ER
mRNA in placental samples. The nucleotide
sequence of the 839-bp ER
PCR fragments obtained from pregnant
rhesus monkey myometrium displayed a 97% homology with the comparable
region in human ER
cDNA reported by Mosselman et al.
(21) (Fig. 4).
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Comparison of ER and ER
mRNA
abundances in four intrauterine tissues.
There was twofold higher concentration of ER
mRNA in the pregnant
rhesus monkey myometrium than ER
mRNA (Fig.
5). In contrast, ER
mRNA in amnion is
significantly higher than ER
mRNA, and there was no significant
difference between ER
and ER
mRNA levels in choriodecidua (Fig.
5). There was no detectable signal for either ER
or ER
in
placenta.
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Comparison of ER and ER
mRNA
distributions in multiple maternal tissues.
The relative distributions of ER
and ER
mRNA in all the maternal
tissues examined were very similar, i.e., both ER mRNAs are expressed
in atrium, bladder, kidney, liver, lung, pancreas, and thyroid
ventricle. The spleen and thymus showed no expression of either ER
or ER
mRNA. ER
mRNA abundance was, in general, higher than ER
mRNA in all tissues examined. The atrium and bladder contained less
abundant ER
mRNA, whereas the bladder, ventricle, and myometrium
displayed lower amounts of ER
mRNA compared with other tissues
studied (Fig. 6). All the comparisons for
ER
or ER
mRNA across tissues (myometrium, amnion,
and choriodecidua) were analyzed in one PCR. In addition, all the
comparisons between ER
and ER
within one tissue were analyzed in
a single gel.
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Immunolocalization of ER and ER
in
the pregnant rhesus monkey myometrium.
Positive immunostaining for ER
and ER
was associated with the
myometrial cells in both longitudinal and cross sections (Fig. 7). Both endothelial and smooth muscle
cells of blood vessels in the myometrium (Fig. 7) were immunopositive
for ER
and ER
. All specific staining for ER
and ER
was
restricted to cell nuclei.
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DISCUSSION |
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A pronounced and significant late gestation rise in maternal estrogen concentrations has been demonstrated in pregnant women (3), rhesus monkey (25), and baboons (37). Estrogen also increases immediately before delivery with a varying time course in many other species such as the rat (18) and sheep (4). Maternal administration of androgen results in premature delivery of live young in rhesus pregnancy (20). However, inhibition of aromatization of androgen to estrogen with 4-hydroxyandrostenedione prevents the induction of premature delivery by androgen (23). These studies demonstrate a central role of estrogen including the switch from myometrial contractures to contractions, cervical dilation, and rupture of the fetal membranes. To understand the overall role of estrogen and its receptor in late gestation, it is crucial to obtain information that is precisely documented in relation to the stage of gestation in late pregnancy and parturition. There currently are no human or nonhuman primate studies on intrauterine tissues that have evaluated changes in ER in relation to precise monitoring of the different types of myometrial activity associated with late gestation before and during labor.
Our study is the first to examine the distribution of ER and ER
in four different intrauterine tissues in the same animal. Our data
clearly demonstrate that both ER
and ER
are expressed in
myometrium, choriodecidua, and amnion, but not placenta. The presence
of ER in the primate or human placenta has been a subject of dispute
(14). ER protein has been demonstrated by immunocytochemical localization in cultured human placental syncytiotrophoblasts (2). ER
mRNA has also been demonstrated at very low levels in the human and
nonhuman primate placenta by RNA protection assay and RT-PCR (6, 31).
Finally ER has been demonstrated by classic radioligand binding
techniques in human placenta extracts (15). However, the absence of ER
in the rhesus monkey placenta in the present study is consistent with
one recent report (33) that detected progesterone receptor but failed
to detect ER in human placenta across different gestational ages using
immunocytochemistry, RT-PCR, and receptor binding techniques. Our data
also indicate that the absence of ER is a common feature shared by the
nonhuman primate and human placenta, which is in contrast with the
presence of ER
mRNA in the ovine placenta (42). It is unlikely that our failure to detect the ER in rhesus monkey placenta can be attributed to a low ER density, because PCR is sensitive enough to
detect one copy of a gene. Alternatively, estrogen's action on the
placenta may be mediated by a different unrecognized type of ER, such
as a nonclassical membrane-bound receptor or may be exerted through a
biophysical change in the cell membrane.
Our observation that ERs remained unchanged in myometrium during
spontaneous term labor is consistent with a previous report based on
evaluation of estrogen binding (24). Of interest, the current finding
contrasts with our previous study of ER in ovine uterine tissues, in
which a dramatic increase of ER
mRNA is associated with STL (42) as
well as glucocorticoid-induced premature labor (38). We and others have
clearly demonstrated estradiol-upregulated ER
expression and
progesterone-downregulated ER
expression in nonpregnant uterine
tissues in sheep (43), mouse (1), rhesus monkey (26, 27) and human
breast cancer cell lines (7). In addition, the observation that uterine
ERs are increased by RU-486, which antagonizes progesterone in late
gestation in the pregnant rhesus monkey, is another example of
progesterone's suppressive effect on uterine ER
(11). These results
suggest that the control of uterine ER
is dependent on the complex
interplay of estrogen and progesterone. It is possible that the
differences in the balance of maternal plasma estradiol and
progesterone levels are responsible for the differential expression of
ER in different species during pregnancy. In sheep, the sharply
increased maternal plasma estradiol concentration (4) and decreased
maternal plasma progesterone (35) that occur immediately before
parturition may together be responsible for increased expression of
uterine ER during labor. In nonhuman primates and pregnant women,
however, the gradual increase of estrogen throughout late
gestation and sustained progesterone in maternal plasma during labor
constitute a very different hormone environment and may explain the
species' differences in ER during labor.
Using RT-PCR, we were able to detect ER and ER
mRNA in amnion and
choriodecidua. ER was undetectable in the fetal membranes using
immunocytochemistry (11) or binding techniques (29). In support of our
findings, it should be noticed that ER
mRNA was observed in human
fetal membrane analyzed by RNA protection assay (6). Our observations
represent the first evidence that amnion of nonhuman primate is a
target of estrogen. In both the pregnant nonhuman primate (40) and
pregnant women (28), the amnion is the major source of prostaglandin
(PG) production that is essential to promote parturition. The presence
of ER in the amnion further supports a role for estrogen in the
stimulation of PG production by amnion. We have previously demonstrated
that both estrogen and progesterone are involved in the regulation of
PGH synthase 2 in nonpregnant ovine uterine tissues (41). It is
possible that the balance between estradiol and progesterone also plays
a role in modulating amnion PG production in preparation for and
completion of parturition in nonhuman primates and pregnant women.
Our current study represents the first report to evaluate abundance and
distribution of the new ER subtype, ER, in pregnant intrauterine
tissues in any species. The distribution of ER
and ER
in
intrauterine tissues, as well as the multiple maternal nonintrauterine
tissues of rhesus monkey examined are similar, but they differ in their
concentration of ERs. It has been shown that ER
and ER
signal in
opposite ways when complexed with the natural hormone estradiol from an
AP1 site (30). The ER
and 17
-estradiol complex activated
transcription, whereas the ER
and 17
-estradiol complex inhibited
transcription. These observations suggest that ER
and
ER
may play different roles in gene regulation. The appearance of
both ER
and ER
in the intrauterine tissues during pregnancy adds
another level of complexity to the function of estrogen in promoting parturition.
The nucleotide sequence homology between rhesus monkey of our RT-PCR
product containing 839 bp of rhesus monkey ER was 97% identical to
the comparable region of the human ER
, showing that our amplified
cDNA was complementary to the human ER
cDNA at nucleotides
569-1408.
We observed that both ER and ER
were present in myometrial and
vascular smooth muscle cells as well as endothelial cells of the blood
vessels in the myometrium, indicating that estrogen may influence
myometrial remodeling and uterine blood flow during pregnancy not only
through classical ER
but also through the newly described ER
. A
number of previous studies consistently reported the
presence of ER
in myometrial cells and blood vessels (12, 19, 32);
however, the present study is the first to localize ER
in the
pregnant myometrium in any species.
In conclusion, 1) rhesus monkey ER shares >97% identity
with human ER
in the region sequenced; 2) ER
and ER
were expressed in myometrium, amnion, and choriodecidua, but not in
placenta, of the pregnant rhesus monkey (myometrium contained the
highest concentrations for both ER subtypes); and 3)
differential abundance of ER
and ER
was exhibited in the
myometrium and amnion. The biological significance of these
quantitative differences in ER subtypes merits further study.
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ACKNOWLEDGEMENTS |
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This research was supported by National Institute of Child Health and Human Development Grant HD-21350.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: P. W. Nathanielsz, Laboratory for Pregnancy and Newborn Research, Dept. of Physiology, College of Veterinary Medicine, Cornell Univ., Ithaca, NY 14853-6401 (E-mail: pwn1{at}cornell.edu).
Received 30 June 1999; accepted in final form 18 August 1999.
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