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Departments of Pediatrics (J.R., N.B.) and Molecular and Integrative Physiology (J.R., X.Z., W.-G.M., S.K.D.), University of Kansas Medical Center, Ralph L. Smith Research Center, Kansas City, Kansas 66160-7338; and Pharmacia Research and Development (T.J.M.), Skokie, Illinois 60077
Address all correspondence and requests for reprints to: S. K. Dey, Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160-7338. E-mail: sdey{at}kumc.edu
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Introduction |
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There are many aspects of reproduction that depend on PG ligand-receptor interactions. Observations of elevated PG levels, responsiveness to PG administration, or inhibition by NSAIDs suggested that PGs are important for ovulation, fertilization, implantation, decidualization, and parturition (3, 19, 20, 21). Cloning and characterization of the COX-1 and COX-2 genes distinguished the specific sites of uterine PG synthesis (22) and led to the production of mice with deletions of the COX-1 or COX-2 gene. COX-1-/- mice are fertile but have delayed onset of parturition (23, 24). In contrast, COX-2-/- mice have multiple reproductive impairments characterized by poor ovulation, reduced fertilization rates, and failure of implantation and decidualization that are responsive to PG replacement (3, 4, 25). Compound heterozygote mice lacking three of the four COX alleles have reproductive phenotypes similar to simple homozygotes, but the fertility of COX-1/COX-2 double knockout mice is unknown due to neonatal lethality (26, 27). Pharmacologic inhibition of COX enzymes by NSAIDs is also associated with infertility (28, 29, 30, 31, 32). However, it is unclear whether acute suppression of PG synthesis results in the same reproductive deficiencies as mice that lack COX-1 or COX-2 throughout development (3, 23). Indeed, there is evidence that PG receptors require exposure to PG ligands during development for correct programming of downstream signaling pathways (33).
We examined the impact of commonly used NSAIDs, or selective COX-1 or COX-2 inhibitors on the reproductive potential of wild-type and COX-deficient mice. Our results show that a COX-1 selective inhibitor had little effect on implantation, whereas a COX-2 selective inhibitor interfered with ovulation, fertilization and implantation in the mouse. NSAIDs were more detrimental to implantation than the COX-selective inhibitors. Furthermore, the effects of null mutation of the COX-2 gene on female reproductive functions are much more severe than those observed after pharmacological COX-2 inhibition. We also observed a dramatic inhibition of implantation and decidualization in COX-1-/- mice after pharmacological inhibition of COX-2, suggesting that inhibition of both isoforms is not compensated by another source of PGs.
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Materials and Methods |
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To induce superovulation, wild-type mice were given an ip injection of 5 IU of PMSG followed by a second injection of 5 IU of human CG (hCG) 48 h later. Mice were placed overnight with fertile males and checked for vaginal plugs the next morning (day 1 = vaginal plug). Mice were killed on day 2 and their oviducts were flushed with saline to recover ovulated eggs and scored for their fertilization.
To induce pregnancy or pseudopregnancy, wild-type and COX-1-/- mice were mated with fertile or vasectomized males of the same strain, respectively. To induce delayed implantation, mice were ovariectomized on the morning (0900 h) of day 4 of pregnancy and maintained with daily injections of progesterone (P4, 2 mg/mouse) from days 5–7. To initiate implantation, P4-primed delayed implanting pregnant mice were injected with estradiol-17ß (E2, 25 ng/mouse). Steroids were dissolved in sesame oil and injected sc (0.1 ml/mouse). Implantation sites were visualized by iv injection (0.1 ml/mouse) of 1.0% Chicago Blue dye solution in saline. If implantation sites (blue bands) were not detected, uterine horns were flushed with saline to recover unimplanted blastocysts. Mice without implantation sites or blastocysts were excluded from the experiment.
To induce decidual cell reaction, sesame oil (25 µl) was infused in one uterine horn on day 4 of pseudopregnancy in wild-type or COX-1-/- mice, whereas the noninfused contralateral horn served as a control. Uterine weights of the oil-infused and noninfused horns were recorded on day 8 and the fold increases in uterine weights were used as an index of decidualization (3).
COX-2 selective inhibitor (celecoxib), COX-1 selective inhibitor (SC-560), or nonselective COX-1/COX-2 inhibitors (ibuprofen and naproxen) were suspended in 0.5% (wt/vol) methylcellulose and 0.1% (vol/vol) polysorbate 80 dissolved in water by constant stirring. Drugs were administered by oral gavage at different doses before induction of ovulation or during the periimplantation period as indicated. The selectivity of inhibition of COX isoforms by the test agents used in this study was assessed in mice using an air pouch model similar to that described (34) except that serum thromboxane was measured as a marker of COX-1 inhibition (data not shown). Doses of celecoxib greater than 100 mg/kg are expected to produce some COX-1 inhibition, whereas lower doses would selectively inhibit COX-2. The 1 mg/kg dose of SC-560 produces selective inhibition of COX-1, whereas a dose of 10 mg/kg of this compound is expected to produce some inhibition of COX-2 as well. The NSAIDs used in this study (i.e. naproxen and ibuprofen) are nonselective inhibitors of both COX isoforms. Moreover, the doses of naproxen and ibuprofen used in this study have been shown to produce effect (i.e. implantation loss) on early pregnancy in mice (Registry of Toxic Effects of Chemicals). The control mice received the vehicle only. Mice were killed at different times and wet weights of the implantation and interimplantation sites were recorded. These tissues were kept frozen at -70 C for measuring prostaglandins by immunoassay or for in situ hybridization of implantation-specific genes.
In situ hybridization
The protocol followed the procedure as previously described
(35). Frozen sections (10 µm) were mounted onto
poly-L-lysine coated slides and fixed in 4%
paraformaldehyde in PBS for 10 min at 4 C. After prehybridization,
section were hybridized at 45 C for 4 h in 50% fomamide buffer
containing 35S-labeled sense or antisense cRNA
probes specific for mouse LIF, HB-EGF,
COX-1, COX-2, Flk-1, or PPAR
. After
hybridization and washings, sections were incubated with RNase A (20
µg/ml) at 37 C for 20 min, and RNase A-resistant hybrids were
detected by autoradiography using Kodak (Rochester, NY)
NTB-2 liquid emulsion. Sections were poststained with hematoxylin and
eosin. Sections hybridized with sense probes served as negative
controls.
Prostaglandin assays
Tissue samples were maintained frozen at -80 C until
processing. The samples were transferred directly to tubes on ice
containing 3 ml of 70% ethanol, and homogenized. Homogenates were
placed in a centrifuge at 4 C, and spun at 18,000 x g
for 20 min. Entire supernatants were transferred to fresh tubes,
evaporated to dryness under a stream of N2.
Samples were re-suspended in 0.5 ml ELISA buffer. The samples were
assayed for both PGE2 and
6-keto-PGF1
in duplicate at several
concentrations by competition ELISA. PGE2 was
assayed using plates coated with donkey antimouse IgG (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA), the
monoclonal ‘2B5' anti-PGE2 antibody (produced by
Pharmacia Research and Development, Skokie, IL) and
PGE2 tracer (Cayman Chemical, Ann Arbor, MI).
Samples were assayed for 6-ketoPGF1 using
plates coated with donkey antirabbit antibody (Jackson ImmunoResearch Laboratories, Inc.) and 6-keto
PGF1 tracer and antibody (Cayman
Chemical).
Statistical analysis
Differences among sample means were assessed by Student’s
t test. Groups were analyzed by ANOVA with posthoc analysis
by Dunnett’s test for multiple comparisons (SPSS, Inc.,
Chicago, IL, version 9.0).
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). Thus, the severity of these defects
was less in magnitude in celecoxib-treated females than those observed
in COX-2-/-
mice (3).
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). Compared with the
vehicle-treatment, mice that received SC-560 (1 mg or 10 mg/kg/dose,
BID), a selective COX-1 inhibitor, had no difference in the number of
implantation sites or uterine weight on days 5 or 6. There was an
apparent reduction in the number of implantation sites on day 8 of
pregnancy, although implantation was successful in both groups of mice.
These results are similar to our previous observations in mice treated
with aspirin, which also preferentially inhibits COX-1
(3). In that study, normal implantation rates were
observed in wild-type or COX-1 deficient females exposed to aspirin. No
apparent adverse physical effects were observed in SC-560-treated
females.
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), suggesting that
reproductive impairments were primarily related to COX inhibition
rather than systemic illness.
Females treated with celecoxib showed a reduction in the number and/or
weight of implantation sites. Dose ranging studies on days 1–5 and
3–7 of pregnancy formed the basis for analyses at other time points
and dosing schedules (Table 1). The first visible sign of implantation
occurs at midnight on day 4 (35). Compared with the
vehicle treatment, females treated with high doses of celecoxib (600
mg/kg/dose) on days 1–4 of pregnancy had reduced number of
implantation sites (blue bands) with increasing number of unimplanted
blastocysts at midnight on day 4. However, lower doses of celecoxib
showed little effects on the morning of day 5 with respect to blue
bands, and there was reduction only in the weight but not number of
implantation sites by day 6. Females receiving high doses of celecoxib
showed less signs of toxicity than ibuprofen- or naproxen-treated
females. There were no maternal deaths, although a single mouse was
euthanized due to its morbid condition.
The levels of PGE2 and
6-keto-PGF1 (ng/mg tissue) were measured in
the implantation sites on day 8 of pregnancy after a large dose of
celecoxib on days 3–7 (600 mg/kg/dose, BID). Surprisingly, PG levels
were only modestly reduced compared with vehicle-treated mice
(PGE2: 15.2 ± 5.2 vs. 18.8
± 0.5; 6-keto-PGF1: 13.5 ± 3.5
vs. 18.8 ± 0.6, P < 0.05). These
results may imply that the reduction in weight or number of
implantation sites in response to treatment with celecoxib may be
caused by factors other than reduced PG levels in the uterus.
Alternatively, the implantation process may be adversely affected by
modest reductions in PG levels, but not completely blocked, as occurs
in COX-2-/-
females.
Together, these experiments suggest that inhibition of COX-1 activity has little or no effect on implantation unless coupled with suppression of the COX-2 enzyme. Selective COX-2 inhibition is less toxic to the mother than the treatment with the nonselective NSAIDs, and results in either delayed onset of the implantation process, or impairment of embryonic growth and/or reduction of uterine decidualization.
To determine whether pharmacologic inhibition of COX enzymes has
effects on uterine expression of multiple implantation-related genes,
such as COX-2, LIF, HB-EGF, PPAR, and Flk-1,
in situ hybridization analysis was performed.
COX-2 is expressed in an implantation-specific manner
(22) and gene-targeting experiments have established that
COX-2 is essential for implantation (3, 4). COX-2 derived
prostacyclin mediates its effects on implantation via PPAR that is
also expressed at the implantation sites (4).
LIF is expressed in a biphasic manner and is essential for
implantation (37, 38). HB-EGF is an EGF-like growth factor
with an expression pattern highly relevant to the implantation process
(35). Its expression is induced solely in the uterine
luminal epithelium at the site of blastocyst apposition 6–7 h before
the attachment reaction. In vitro experiments have shown
that soluble HB-EGF can stimulate proliferation, zona-hatching and
trophoblast outgrowth and tyrosine phosphorylation of ErbB1 in mouse
blastocysts (35). Furthermore, cells expressing the
transmembrane form of HB-EGF can adhere to active, but not dormant,
blastocysts (39). Using growth factor-toxin conjugates and
egfr null blastocysts, we have recently shown that HB-EGF
can interact with blastocyst ErbB4 and heparan sulfate proteoglycan
(HSPG) for the initiation of implantation (40). Flk-1 is
an established marker for angiogenesis that increases with implantation
(41).
In those mice treated with a COX-1 or COX-2 selective inhibitor and in
which implantation occurred, the expression patterns of these genes
were similar to those of the vehicle-treated mice (see Figs. 3 and 4). It is interesting to note that the COX-2 mRNA
expression pattern was normal in COX-2 inhibitor treated mice in which
implantation occurred. These results suggest that inhibition of COX-1
or COX-2 activity does not directly influence other uterine gene
expression and that inhibition of activities of COX enzymes does not
interfere with COX-2 mRNA expression.
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). Implantation of mice treated with
celecoxib plus aspirin was severely affected (Fig. 2A). We previously
reported that aspirin alone has little effects on implantation
(3). These results suggest that pharmacological inhibition
of both COX enzymes is more detrimental to the implantation process
than the inhibition of individual enzymes.
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). All of the vehicle-treated mice showed a significant decidual
response. The oil-infused uterine horns of vehicle-treated mice were
more than 10-fold larger than the noninfused horns within individual
mice. Wild-type mice receiving a high dose (600 mg/kg/dose) of
celecoxib did not respond to induction of the decidual reaction as
frequently as the vehicle-treated mice. Whereas 2/6 mice failed to show
a decidual response, 4/6 mice showed about 8-fold induction of
decidualization, which was not statistically different from the
response obtained in vehicle-treated mice. However, celecoxib-treated
COX-1-/- mice
showed complete absence of the decidual response. Together, these
results suggest that COX-2 suppression may cause failure of the
decidual reaction, but that completion of the decidual reaction once it
is initiated is not limited by the absence of COX-2-derived PGs.
Reproductive outcomes in the absence of PGs
COX-1 deficient mice have normal implantation and are fertile with
parturition defects (3, 23). However, we have recently
shown that COX-2 can compensate for COX-1 deficiency during
implantation (42). Thus, we sought to determine whether
pharmacological inhibition of COX-2 in
COX-1-/- mice
adversely affects reproduction. Mice lacking both COX
isoforms die soon after birth (26, 27). Therefore,
celecoxib was given to
COX-1-/- mice
to evaluate fertility in the virtual absence of PGs. Implantation
outcomes in vehicle-treated COX-1-/- mice were
similar to vehicle-treated wild-type mice (see Table 1). However, a
dramatic, dose-dependent inhibition of implantation was noted in
celecoxib-treated
COX-1-/- mice.
Furthermore, the number and weight of implantation sites were also
lower in similarly treated mice that showed any signs of implantation
(Table 2). A large number of
morphologically dormant-looking blastocysts were recovered from the
uteri of COX-1-/- mice treated with high doses
of celecoxib (600 mg/kg/dose). Similarly, the ability to induce a
decidual response was normal in vehicle-treated
COX-1-/- mice, but was lost in
celecoxib-treated COX-1-/- mice (Fig. 2B).
Overall, these results show that several aspects of the implantation
process are completely blocked in the absence of COX-1 and COX-2
activity and mimic those observed during NSAID treatments. The
implantation failure of estrogen-treated delayed implanting mice after
exposure to both celecoxib and aspirin further supports these
observations (see Fig. 2A).
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Discussion |
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COX-1 is expressed in uterine epithelial cells on the morning of day 4
before implantation, whereas COX-2 is expressed in the luminal
epithelium and underlying stroma surrounding the blastocyst at the time
of the attachment reaction at midnight on day 4 (22). One
of the major observations of this investigation is that pharmacological
inhibition of COX-2, but not COX-1, postpones the onset of
implantation, although implantation eventually occurs. Furthermore,
pharmacological inhibition of COX-2 showed modest inhibitory effects on
ovulation and fertilization. Because ovulation and implantation are
precisely time-dependent processes, the observed differences between
pharmacologic and genetic COX inhibition could be due to the
nonsynchronized timing of drug administration, resulting in incomplete
COX inhibition at a critical period during these events. A delay in the
early process of implantation is reflected in delayed growth of the
implantation sites and decidua. However, the results are not as severe
as those obtained in
COX-2-/- mice.
Again, this difference may be due to the complete absence of COX-2
activity in COX-2 null mice vs. pharmacological
inhibition of COX-2 activity. In the latter case, complete inhibition
is more difficult to achieve due to factors that limit the presentation
of the inhibitor to the enzyme, including drug distribution and
pharmacokinetics, and enzyme turnover in the target tissue. Indeed, the
levels of PGE2 and
6-keto-PGF1 in celecoxib-treated day 8
implantation sites were only modestly reduced compared with
vehicle-treated mice. Thus, the use of a COX-2 inhibitor at
specific times during pregnancy should have less severe effects than
the total absence of activity throughout the life span as occurs in
COX-2 null mice. An alternative consideration is that the
loss of COX-2 activity may be compensated by COX-1. This is perhaps not
the case because reproductive failures in
COX-2-/- mice
are apparently not compensated by COX-1, although the loss of COX-1
activity in
COX-1-/- mice
can be compensated by COX-2 during early pregnancy (3, 42). Nevertheless, the more severe inhibitory effects of NSAIDs
(ibuprofen or naproxen) on implantation suggest that simultaneous
inhibition of COX-1 and COX-2 has more pronounced effects on pregnancy
and general health of the mice than inhibition of either isoform alone.
This is consistent with the inhibition of implantation in apparently
fertile
COX-1-/- mice
by pharmacological inhibition of COX-2 activity (Table 2). Furthermore,
the results obtained using delayed implantation mice suggest that the
target for pharmacological inhibition of COX-2 or COX-1 on implantation
is the uterus and/or embryo, but not the pituitary-ovarian axis.
Another possible cause of less severe effects on ovulation and
implantation by pharmacological inhibition of COX-2 compared with null
mutation could be increased transcription and/or translation of the
COX-2 gene, to compensate for the loss of COX-2 activity.
This is evident from the expression of COX-2 mRNA at the
implantation sites on days 5 and 6 of pregnancy 24 h after the
last dose of celecoxib (Fig. 3).
There is evidence that aspirin can up-regulate the expression of COX-2
in the rat stomach (44) and both COX-1 and COX-2 in human
placental trophoblast cells in culture (45).
Alternatively, salicylates may alter gene expression independent of
COX-2 inhibition. In particular, it has been shown that fatty acids,
PGs and NSAIDs that are substrates, products, and inhibitors,
respectively, of COX enzymatic activity, can also increase COX-2
expression in mammary and colon epithelial cells. This increased
expression is due to the presence of a PPRE in the
COX-2 promoter that is sensitive to these compounds
(46). Thus, pharmacologic inhibitors of COX enzymes might
also have unexpected effects on PG homeostasis in the reproductive
tract.
The initiation of implantation is delayed in celecoxib-treated wild-type mice. Nevertheless, the implantation that eventually occurs appears to be normal with respect to the expression of specific implantation-related genes in the uterus, although the growth of the implantation sites is somewhat retarded. Although it is doubtful that PG levels are maintained by COX-1 compensation in celecoxib-treated mice, the existence of a third COX isoform has been postulated (43). In this regard, the dramatic inhibition of implantation and decidualization in COX-1-/- mice after celecoxib treatment suggests that the loss of activity of both the isoforms cannot be compensated by an alternative source of PGs during early pregnancy. To address this possibility, we previously generated mice lacking both COX-1 and COX-2 isoforms, but COX-1-/-/COX-2-/- pups die soon after delivery and are unavailable for reproductive studies (26). However, we have preliminary results to show that PG levels are virtually undetectable in COX-1-/-/COX-2-/- double mutant embryonic fibroblast cells.
In conclusion, this study demonstrates the distinct and overlapping roles of both COX-1 and COX-2 in embryo implantation. Whether these interactions are operative in other reproductive functions will require further investigation. The development of new COX inhibitors may provide the basis to alter discrete signaling pathways during pregnancy, but the results may not reflect the functions of the COX isoform determined by gene deletion studies. An additive effect of simultaneous inhibition of COX-2 and EGF signaling pathways in treating tumorigenesis has recently been reported (47). That study and our present investigation highlight the importance of pharmacological manipulations of genetically altered mice in determining the significance of distinct or synergistic effects of signaling pathways in a complex system. Further deciphering the mechanisms of prostaglandin signaling in conception and fertility will be an important step toward a better understanding of reproduction.
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Acknowledgments |
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Footnotes |
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2 Recipient of an NICHD MERIT award.
Received January 11, 2001.
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Genes Dev 3:1561–1574
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