Maternal recognition of pregnancy signal or endocrine disruptor: The two faces of oestrogen during establishment of pregnancy in the pig (original) (raw)
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REPRODUCTION, 2010
In pigs, endometrial functions are regulated primarily by progesterone and placental factors including estrogen. Progesterone levels are high throughout pregnancy to stimulate and maintain secretion of histotroph from uterine epithelia necessary for growth, implantation, placentation, and development of the conceptus (embryo and its extra-embryonic membranes). This study determined effects of long-term progesterone on development and histoarchitecture of endometrial luminal epithelium (LE), glandular epithelium (GE), and vasculature in pigs. Pigs were ovariectomized during diestrus (day 12), and then received daily injections of either corn oil or progesterone for 28 days. Prolonged progesterone treatment resulted in increased weight and length of the uterine horns, and thickness of the endometrium and myometrium. Hyperplasia and hypertrophy of GE were not evident, but LE cell height increased, suggesting elevated secretory activity. Although GE development was deficient, progestero...
Bioscientifica Proceedings, 2020
This review highlights information on conceptus-uterus interactions in the pig with respect to uterine gene expression in response to estrogens and interferons (IF Ns) secreted from elongating conceptuses. Pig conceptuses release estrogens for pregnancy recognition, but also secrete IENs that do not appear to be antiluteolytic. Estrogens and IFNs induce expression of largely non-overlapping sets of genes, and evidence suggests that pig conceptuses orchestrate essential events of early pregnancy including pregnancy recognition signaling, implantation and secretion of histotroph by precisely controlling temporal and spatial (cell-specific) changes in uterine gene expression through initial secretion of estrogens, followed by cytokines including IFNG and IEND. By Day 12 of pregnancy, estrogens increase the expression of multiple genes in the uterine lu rn inal epithelium including SPP1, STC1, IRF2 and STAT1 that likely have roles for implantation. By Day 15 of pregnancy, IFNs upregulate a large array of IFN responsive genes in the underlying stroma and glandular epithelium including ISG15, IRF1, STAT1, SLAs and B2M that likely have roles in uterine remodeling to support placentation.
Progesterone receptor gene expression in preimplantation pig embryos
European Journal of Endocrinology, 2000
Objective: It is not known whether progesterone, which plays a key role in establishing and maintaining pregnancy, acts directly on embryos or indirectly through the mother's reproductive tract. Since the physiological effects of progesterone are mediated by progesterone receptors (PR), the expression of PR during the preimplantation stages of pig embryos was determined. Design and Methods: Preimplantation pig embryos at different developmental stages were examined using reverse transcription-polymerase chain reaction techniques for the purpose of determining PR gene expression. Immunocytochemistry procedures were used to determine whether PR mRNA is translated into PR protein in preimplantation embryos. Results: PR mRNA was found in pig embryos at the two-cell stage, but levels started to decline at the four-cell stage; none was detected at the five-to eight-cell stage, nor at any time during the morula and blastocyst stages. Results showed that PR protein was immunostained in pig oocytes and embryos at the 4-cell stage, but that no significant immunostaining occurred during the morula and blastocyst stages. Conclusion: These results indicate that the effects of PR on early embryogenesis appear to be indirect, perhaps via PR-regulated growth-promoting factors produced in the maternal reproductive tract.
Premature Estrogen Exposure Alters Endometrial Gene Expression to Disrupt Pregnancy in the Pig
Endocrinology, 2007
Establishment and maintenance of pregnancy in the pig involve intricate communication between the developing conceptuses and maternal endometrium. Conceptus synthesis and release of estrogen during trophoblastic elongation are essential factors involved with establishing conceptus-uterine communication. The present study identified endometrial changes in gene expression associated with implantation failure and complete pregnancy loss after premature exposure of pregnant gilts to exogenous estrogen. Gilts were treated with either 5 mg estradiol cypionate (EC) or corn oil on d-9 and -10 gestation, which was associated with complete conceptus degeneration by d-17 gestation. Microarray analysis of gene expression revealed that a total of eight, 32, and five genes were up-regulated in the EC endometrium, whereas one, 39, and 16 genes were down-regulated, on d 10, 13, and 15, respectively. Four endometrial genes altered by EC, aldose reductase (AKR1B1), secreted phosphoprotein 1 (SPP1), CD24 antigen (CD24), and neuromedin B (NMB), were evaluated using quantitative RT-PCR and in situ hybridization. In situ hybridization localized gene expression for NMB, CD24, AKR1B1, and SPP1 in the luminal epithelium, and confirmed the expression patterns from RT-PCR analysis. The aberrant expression patterns of endometrial AKR1B1, SPP1, CD24, and NMB 3-4 d after premature estrogen exposure to pregnant gilts may be involved with conceptus attachment failure to the uterine surface epithelium and induction of endometrial responses that disrupt the establishment of a viable pregnancy. (Endocrinology 148: 4761-4773, 2007) First
Reproductive Biology and Endocrinology, 2010
Establishment and maintenance of pregnancy in the pig involves intricate communication between the developing conceptuses and the maternal endometrium. This process occurs during trophoblast elongation which is spaciotemporally associated with conceptus synthesis and release of IL1B concomitant with pregnancy-specific endometrial up-regulation of IL-1 receptors, providing the potential for activation of the transcription factor, NFKB. The objective of the current investigation was to determine changes in expression and cellular localization of NFKB and associated factors during the estrous cycle and early pregnancy in the pig. In situ hybridization was used to localize changes in PGR, ESR1, and TNFRSF11A during the peri-implantation period. Quantitative RT-PCR was utilized to demonstrate gene expression changes for NFKB1, RELA, TNFRSF11A, TLR4, NFKBIA and NFKBIB. Transcription factor ELISA demonstrated an overall increase in RELA during the peri-implantation period in both cyclic and pregnant gilts. While the presence of TNFSF11A and TLR4 were both detected, TLR4 expression changes were temporally associated with NFKB expression and activation. Collectively, these data demonstrate that NFKB activation may occur during the period of uterine receptivity in both the cyclic and pregnant endometrium.
Biology of Reproduction, 2019
The proposed signal for maternal recognition of pregnancy in pigs is estrogen (E2), produced by the elongating conceptuses between days 11 to 12 of pregnancy with a more sustained increase during conceptus attachment and placental development on days 15 to 30. To understand the role of E2 in porcine conceptus elongation and pregnancy establishment, a loss-of-function study was conducted by editing aromatase (CYP19A1) using CRISPR/Cas9 technology. Wild-type (CYP19A1+/+) and (CYP19A1−/−) fibroblast cells were used to create embryos through somatic cell nuclear transfer, which were transferred into recipient gilts. Elongated and attaching conceptuses were recovered from gilts containing CYP19A1+/+ or CYP19A1−/− embryos on day 14 and 17 of pregnancy. Total E2 in the uterine flushings of gilts with CYP19A1−/− embryos was lower than recipients containing CYP19A1+/+ embryos with no difference in testosterone, PGF2α, or PGE2 on either day 14 or 17. Despite the loss of conceptus E2 productio...
Biology of Reproduction, 2011
Establishment of pregnancy in the pig depends on downregulation of progesterone receptor (PGR) in the uterine luminal and glandular epithelium during the first week after breeding. The present study evaluated the regulation of endometrial PGR by progesterone and the possible role of endometrial tumor necrosis factor (ligand) superfamily member 11 (TNFSF11) and nuclear factor-kappa B (NFKB) activation in PGR expression. Mature, cycling gilts were inseminated (Day 0) and assigned to either untreated control (n ¼ 9) or one of two treatments that employed RU 486 to block progesterone action either before (treatment 1 [T1]) or after (treatment 2 [T2]) the initiation of PGR down-regulation. The T1 gilts were treated with RU 486 (400 mg/day) on Days 3-5 of pregnancy (n ¼ 9), and T2 gilts were treated with RU 486 on Days 6 and 7 of pregnancy (n ¼ 9). Uteri and ovaries were collected on Day 8 or 12 of gestation. The diameter of the conceptuses in T1 gilts was approximately half that in controls by Day 8, and normal conceptuses were not collected from any T1 gilts on Day 12. Endometrial PGR mRNA was more abundant in T1 and T2 gilts compared with control gilts. The PGR-B protein decreased from Day 8 to Day 12 in the luminal epithelium and, to some extent, in superficial glandular epithelium in control and T2 gilts. In T1 gilts, the PGR-B protein remained elevated (i.e., failed to undergo down-regulation) on Day 12. Blocking PGR action early in the cycle (i.e., on or before Day 5), therefore, prevented normal conceptus development, caused elevated PGR mRNA, and prevented the decrease in PGR protein that typically occurs in pigs. We could not confirm a role for NFKB activation in PGR down-regulation, because pigs with extreme differences in PGR and TNFSF11 expression (T1 and controls) had similar NFKB activation on Day 8. Activated NFKB within the luminal epithelium and glandular epithelium (both superficial and deep) was observed in T2 and control pigs on Day 12 when elongating conceptuses (presumably releasing interleukin 1 beta to activate NFKB) were recovered. Gilts treated with RU 486 had greater ovarian follicular growth and greater plasma estradiol concentrations. We conclude that the mechanisms controlling PGR down-regulation are progesteronedependent and occur between Day 3 and Day 6 of pregnancy. NFKB activation did not appear to have a role in PGR downregulation within the period that we studied. Blocking proges-terone action after Day 6 did not reverse the process of PGR down-regulation, nor did it appear to affect the development of conceptuses collected on Day 12.
Domestic Animal Endocrinology, 2017
Progesterone (P4) stimulates production and secretion of histotroph, a mixture of hormones, growth factors, nutrients, and other substances required for growth and development of the conceptus (embryo/fetus and placental membranes). Progesterone acts through the progesterone receptor (PGR); however, there is a gap in our understanding of P4 during pregnancy because PGR have not been localized in the uteri and placentae of pigs beyond Day 18. Therefore, we determined endometrial expression of PGR mRNA and localized PGR protein in uterine/placental tissues throughout the estrous cycle and through Day 85 of pregnancy in pigs. Further, two components of histotroph, tartrate-resistant acid phosphatase 5 (ACP5; uteroferrin) and secreted phosphoprotein 1 (SPP1; osteopontin) proteins, were localized in relation to PGR during pregnancy. Endometrial expression of PGR mRNA was highest at Day 5 of the estrous cycle, decreased between Days 5 and 11 of both the estrous cycle and pregnancy, and then increased between Days 11 and 17 of the estrous cycle (P < 0.01), but decreased from Days 13 to 40 of pregnancy (P < 0.01). PGR protein localized to uterine stroma and myometrium throughout all days of the estrous cycle and pregnancy. PGR were expressed by uterine luminal epithelium (LE) between Days 5 and 11 of the estrous cycle and pregnancy, then PGR became undetectable in LE through Day 85 of pregnancy. During the estrous cycle PGR were down-regulated in LE between Days 11 and 15, but expression returned to LE on Day 17. All uterine glandular epithelial (GE) cells expressed PGR from Days 5 to 11 of the estrous cycle and pregnancy, but expression decreased in the superficial GE by Day 12. Expression of PGR in GE continued to decrease between Days 25 and 85 of pregnancy; however, a few glands near the myometrium and in close proximity to areolae maintained expression of PGR protein. ACP5 protein was detected in the GE from Days 12 to 85 of gestation and in areolae. SPP1 protein was detected in uterine LE in apposition to inter-areolar, but not areolar areas of the chorioallantois on all days examined, and in uterine GE between Days 35 and 85 of gestation. Interestingly, uterine GE cells adjacent to areolae expressed PGR, but not ACP5 or SPP1, suggesting these are excretory ducts involved in the passage, but not secretion, of histotroph into the areolar lumen, and highlighting that P4 does not stimulate histotroph production in epithelial cells that express PGR.
Biology of Reproduction, 2006
Porcine trophoblast attachment to the uterine surface is associated with increased conceptus and endometrial production of prostaglandins. Conceptus secretion of estrogen on Day 12 of gestation is important for establishment of pregnancy; however, early (Days 9 and 10) exposure to exogenous estrogens results in embryonic mortality. Present studies established the temporal and spatial pattern of endometrial PTGS1 (prostaglandin-endoperoxide synthase 1) and PTGS2 expression during the estrous cycle and early pregnancy and determined the effect of early estrogen treatment on endometrial PTGS expression in pregnant gilts. Endometrial PTGS1 mRNA expression increased 2-to 3-fold after Day 10 of the estrous cycle and pregnancy, whereas PTGS2 mRNA expression increased 76-fold between Days 5 and 15 of the estrous cycle and pregnancy. Increased expression of the PTGS2 transcript was detected in the lumenal epithelium after Day 10 in both cyclic and pregnant gilts. There was a 10-and 20-fold increase in endometrial PTGS2 protein expression between Days 5 and 18 of the estrous cycle and pregnancy respectively. Administration of estrogen on Days 9 and 10 of gestation increased endometrial PTGS2 mRNA and protein on Day 10, but decreased PTGS2 mRNA and protein in lumenal epithelium (LE) on Day 12 of gestation compared to vehicle-treated gilts. The present study demonstrates that an increase in uterine epithelial PTGS2 expression occurs after Day 10 of the estrous cycle and early pregnancy in the pig. The conceptus-independent increase in the uterine LE indicates that a novel pathway exists for endometrial induction PTGS2 expression before conceptus elongation and attachment to the uterine surface. Epithelial expression of PTGS2 may serve as one of the signals for placental attachment and embryo survival in the pig. Early administration of estrogen on Days 9 and 10 of pregnancy alters endometrial PTGS2 mRNA and protein expression, which may, at least in part, represent a mechanism by which endocrine disruption of pregnancy causes total embryonic loss during implantation in the pig.
Progesterone and Placental Hormone Actions on the Uterus: Insights from Domestic Animals1
Biology of Reproduction, 2004
Progesterone is unequivocally required for maternal support of conceptus (embryo/fetus and associated extraembryonic membranes) survival and development. In cyclic sheep, progesterone is paradoxically involved in suppressing and then initiating development of the endometrial luteolytic mechanism. In cyclic and pregnant sheep, progesterone negatively autoregulates progesterone receptor (PR) gene expression in the endometrial luminal (LE) and superficial glandular epithelium (GE). In cyclic sheep, PR loss is closely followed by increases in epithelial estrogen receptor (ER␣) and then oxytocin receptor (OTR), allowing oxytocin to induce uterine release of luteolytic prostaglandin F2␣ pulses. In pregnant sheep, the conceptus produces interferon tau (IFN) that acts on the endometrium to inhibit transcription of the ER␣ gene and thus development of the endometrial luteolytic mechanism. After Day 13 of pregnancy, the endometrial epithelia do not express the PR, whereas the stroma and myometrium remain PR positive. The absence of PR in the endometrial GE is required for onset of differentiated function of the glands during pregnancy. The sequential, overlapping actions of progesterone, IFN, placental lactogen (PL), and growth hormone (GH) comprise a hormonal servomechanism that regulates endometrial gland morphogenesis and terminal differentiated function during gestation. In pigs, estrogen, the pregnancy-recognition signal, increases fibroblast growth factor 7 (FGF-7) expression in the endometrial LE that, in turn, stimulates proliferation and differentiated functions of the trophectoderm, which expresses the receptor for FGF-7. Strategic manipulation of these physiological mechanisms may offer therapeutic schemes to improve uterine capacity, conceptus survival, and reproductive health of domestic animals and humans.