scholarly journals Testosterone Decreases the Number of Implanting Embryos, Expression of Pinopode and L-selectin Ligand (MECA-79) in the Endometrium of Early Pregnant Rats

2020 ◽  
Vol 17 (7) ◽  
pp. 2293
Author(s):  
Mohd Helmy Mokhtar ◽  
Nelli Giribabu ◽  
Naguib Salleh
Keyword(s):  
Adverse Effect ◽  
Early Pregnancy ◽  
Structural Changes ◽  
Embryo Implantation ◽  
Normal Endometrium ◽  
Pregnant Rats ◽  
Selectin Ligand ◽  
Implantation Sites

Testosterone could have adverse effect on fertility. In this study, we hypothesized that this hormone could reduce the number of embryo implantations via affecting the normal endometrium ultrastructure and expression of endometrial proteins involved in implantation. Therefore, the aims were to identify these adverse testosterone effects. Methods: Intact pregnant rats were given 250 or 500 µg/kg/day testosterone for three days, beginning from day 1 of pregnancy. Rats were euthanized either at day 4 to analyze the ultra-structural changes in the endometrium and expression and distribution of MECA-79 protein, or at day 6 to determine the number of implantation sites. Results: Administration of 500 µg/kg/day testosterone suppresses endometrial pinopodes development and down-regulates expression and distribution of MECA-79 protein in the uterus. In addition, the number of implantation sites were markedly decreased. Conclusions: Changes in endometrial ultrastructure and expression of implantation protein in the endometrium in early pregnancy period could be the reason for failure of embryo implantation under testosterone influence.

Platelet-activating factor-antagonists reduce implantation in mice at low doses only

1995 ◽  
Vol 7 (1) ◽  
pp. 51 ◽  
Author(s):  
C O'Neill
Keyword(s):  
Early Pregnancy ◽  
Embryo Implantation ◽  
Platelet Activating Factor ◽  
Implantation Rate ◽  
Corpora Lutea ◽  
Detailed Knowledge ◽  
Low Doses ◽  
Paf Antagonists ◽  
Implantation Sites ◽  
Web 2086

The effects of a number of platelet-activating factor (PAF)-antagonists on embryo implantation were investigated. Mice were treated from Day 1 to Day 4 of pregnancy with three defined PAF-antagonists: SRI 63 441, BN 52021, and WEB 2086. Necroscopies were performed on Day 8 and the number of implantation sites, the implantation rate (number of implanted embryos compared with the number of corpora lutea) and the proportion of animals pregnant were determined. Each agent caused a reduction in the number of implantation sites at relatively low doses. The dose that had a maximum contragestational effect was 40 micrograms, 10 micrograms and 10 micrograms (per 30 g bodyweight per day) for SRI 63 441, WEB 2086 and BN 52021 respectively. This contragestational effect was completely lost at twice (SRI 63 441), five times (WEB 2086) and ten times (BN 52021) the most effective dose. Treatment with WEB 2086 on the day of implantation (Day 4) by intraperitoneal injection or instillation into the uterus only did not significantly reduce the implantation rate and neither did treatment after implantation (Days 5-8). The results show that the pharmacology of PAF-antagonists in early pregnancy is not simple. An understanding of the actions of these agents in early pregnancy will require a detailed knowledge of their pharmacokinetics, pharmacodynamics and targets of action in early pregnancy.

scholarly journals Arginine enhances embryo implantation in rats through PI3K/PKB/mTOR/NO signaling pathway during early pregnancy

Reproduction ◽  
2013 ◽  
Vol 145 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Xiangfang Zeng ◽  
Xiangbing Mao ◽  
Zhimin Huang ◽  
Fenglai Wang ◽  
Guoyao Wu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Early Pregnancy ◽  
Control Diet ◽  
Embryo Implantation ◽  
Control Group ◽  
Synthesis Inhibitor ◽  
Nitric Oxide Synthase Inhibitor ◽  
No Signaling ◽  
Implantation Sites ◽  
Arginine Supplementation

Our previous study has demonstrated that dietary arginine supplementation during early pregnancy enhanced embryo implantation in rats. However, the mechanism was not clear. The objective of this study was to determine the mechanism that arginine enhanced embryo implantation during early pregnancy. Rats were fed the basal diets supplemented with 1.3% (wt:wt)l-arginine–HCl or 2.2% (wt:wt)l-alanine (isonitrogenous control) once pregnancy. On d4 of pregnancy, rats were given intrauterine injection ofl-NG-nitro arginine methyl ester (l-NAME, nitric oxide synthase inhibitor), α-difluoromethylornithine (DFMO, polyamine synthesis inhibitor), wortmannin (PI3K inhibitor), or rapamycin (mTOR inhibitor). On d7 of pregnancy, rats were killed. Intrauterine injection ofl-NAME decreased the implantation sites, while dietary arginine supplementation increased the implantation sites. Intrauterine injection of DFMO decreased the pregnancy rate, which was reversed by dietary arginine supplementation. Intrauterine injection of rapamycin or wortmannin inhibited embryo implantation. However, dietary arginine supplementation did not reverse this inhibition. Western blot analysis revealed that the expression of uterine p-PKB and p-S6K1 was greater in rats fed the arginine-supplemented diet in the presence ofl-NAME treatment compared with rats fed the control diet. In the presence of DFMO treatment, the expression of uterine iNOS and eNOS was significantly enhanced in the arginine group compared with the control group. Similarly, intrauterine injection of wortmannin or rapamycin decreased the expression of uterine iNOS and eNOS, which was enhanced by dietary arginine supplementation. These data indicated that dietary arginine supplementation during early pregnancy could enhance embryo implantation through stimulation of PI3K/PKB/mTOR/NO signaling pathway.

scholarly journals Endometrial pyruvate kinase M2 is essential for decidualization during early pregnancy

2020 ◽  
Vol 245 (3) ◽  
pp. 357-368 ◽  
Author(s):  
Yan Su ◽  
Sujuan Guo ◽  
Chunyan Liu ◽  
Na Li ◽  
Shuang Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pyruvate Kinase ◽  
Early Pregnancy ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Pyruvate Kinase M2 ◽  
Ishikawa Cells ◽  
Implantation Sites

Embryo implantation is essential for normal pregnancy. Decidualization is known to facilitate embryo implantation and maintain pregnancy. Uterine stromal cells undergo transformation into decidual cells after embryo attachment to the endometrium. Pyruvate kinase M2 (PKM2) is a rate limiting enzyme in the glycolysis process which catalyzes phosphoenolpyruvic acid into pyruvate. However, little is known regarding the role of PKM2 during endometrial decidualization. In this study, PKM2 was found to be mainly located in the uterine glandular epithelium and luminal epithelium on day 1 and day 4 of pregnancy and strongly expressed in the decidual zone after embryo implantation. PKM2 was dramatically increased with the onset of decidualization. Upon further exploration, PKM2 was found to be more highly expressed at the implantation sites than at the inter-implantation sites on days 5 to 7 of pregnancy. PKM2 expression was also significantly increased after artificial decidualization both in vivo and in vitro. After PKM2 expression was knocked down by siRNA, the number of embryo implantation sites in mice on day 7 of pregnancy was significantly reduced, and the decidualization markers BMP2 and Hoxa10 were also obviously downregulated in vivo and in vitro. Downregulated PKM2 could also compromise cell proliferation in primary endometrial stromal cells and in Ishikawa cells. The migration rate of Ishikawa cells was also obviously suppressed by si-PKM2 according to the wound healing assay. In conclusion, PKM2 might play an important role in decidualization during early pregnancy, and cell proliferation might be one pathway for PKM2 regulated decidualization.

scholarly journals 227.An inhibitor of leukemia inhibitory factor signalling blocks embryo implantation in the mouse

2004 ◽  
Vol 16 (9) ◽  
pp. 227
Author(s):  
E. Dimitriadis ◽  
C. Stoikos ◽  
M. Baca ◽  
W. Fairlie ◽  
A. D. Uboldi ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Leukemia Inhibitory Factor ◽  
Embryo Implantation ◽  
Uterine Horn ◽  
Inhibitory Factor ◽  
Luminal Epithelium ◽  
Pregnant Uterus ◽  
Implantation Sites ◽  
Post Implantation

Embryo implantation is a critical step in the establishment of pregnancy. Endometrial leukemia inhibitory factor (LIF) is essential for embryo implantation in the mouse (1). Uterine LIF is expressed in the luminal epithelium on Day 3 of pregnancy (D3) (D0�=�day of plug detection) and signals via activation of signal transducer and activator of transcription (Stat) 3 (2). We examined the effect of a novel LIF signalling inhibitor on the phosphorylation (p) of Stat3 during early pregnancy and on embryo implantation in the mouse. We injected LIF inhibitor into one uterine horn and PBS into the other uterine horn of the mouse at D3 and examined the effect on pStat3 immunostaining in the luminal epithelium between 30 and 360�min later. We found no immunoreactive pStat3 in luminal epithelium following treatment with LIF inhibitor at 60 and 90�min but variable staining at other time points. The PBS-treated uterine horn showed intense immunostaining at all times. LIF inhibitor (1mg/kg body weight per day) or PBS was administered to mice (a) subcutaneously, (b) intraperitoneally, at 8-hourly intervals for 3�days from D2, or (c) continuously into the peritoneal cavity via Alzet pumps from D2. No effect was seen on implantation at D6. When LIF antagonist (3.5mg/kg/day) or PBS were administered by Alzet pumps from D2 together with ip injections, 4-hourly from D3 for 36�h, there were no implantation sites in the uteri of treated mice (n�=�5) while the control mice (n�=�4) had 3.6���0.5�sites (P�<�0.001). Histologically, the uteri of the treated mice resembled non-pregnant uterus, while the control uterus resembled post-implantation uterus. The results demonstrate that treatment of mice during early pregnancy with a novel LIF inhibitor blocks LIF action in vivo and embryo implantation. This knowledge is important for development of novel contraceptives. (1) Stewart, C. L., Kaspar, P., Brunet, L. J., Bhatt, H., Gadi, I., Kontgen, F., Abbondanzo, S. J. (1992) Nature 359, 76–79. (2) Cheng, J. G., Chen, J. R., Hernandez, L., Alvord, W. G., Stewart, C. L. (2001) Proc. Natl Acad. Sci. USA 98, 8680–8685.

In vivo myometrial activity during early pregnancy and pseudopregnancy in the rat

1991 ◽  
Vol 3 (3) ◽  
pp. 233 ◽  
Author(s):  
LH Crane ◽  
L Martin
Keyword(s):  
Early Pregnancy ◽  
Longitudinal Muscle ◽  
Activity Patterns ◽  
Embryo Implantation ◽  
Oestrous Cycle ◽  
Major Influence ◽  
Systemic Effects ◽  
Pregnant Rats ◽  
Regulatory Factors

Video-laparoscopic studies in early pregnant and pseudopregnant rats showed large changes in frequency, direction of propagation and nature of myometrial contractions. Day 2 patterns of activity were essentially the same as in unmated animals at the equivalent stage of the cycle. From Days 3 to 5 there was a large increase in longitudinal and circular contractions propagating towards the oviduct, circular contractions making the greatest contribution. This circular activity may be important in retaining and spacing embryos. Circular contractions propagating towards the cervix showed smaller increases and there was a transient diminution in the frequency of longitudinal contractions in this direction on Day 5. In pregnant rats, the frequency of discrete contractions declined on Days 6-7. However, circular tone appeared to be increased and uteri showed dramatic twisting and curling, apparently due to resistance to the shortening imposed by longitudinal contractions. None of the major changes in activity appeared to be caused by embryos, because they were seen in pseudopregnant rats and, after embryo implantation, in both horns of unilaterally pregnant rats. The earliest divergence from the activity patterns of unmated rats occurred when progesterone levels first increased significantly above those of the undisturbed oestrous cycle, suggesting that progesterone has a major influence on myometrial activity. The complexity of the changes in activity raises questions about other regulatory factors, particularly in regard to coordination between the circular and longitudinal muscle layers. Anomalous results from pregnant, unilaterally pregnant, and pseudopregnant animals on Day 7 suggested that embryos exert systemic effects on myometrial activity.

scholarly journals Expression of DNA methyltransferases in the mouse uterus during early pregnancy and susceptibility to dietary folate deficiency

Reproduction ◽  
2012 ◽  
Vol 144 (1) ◽  
pp. 91-100 ◽  
Author(s):  
Y B Ding ◽  
J L He ◽  
X Q Liu ◽  
X M Chen ◽  
C L Long ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Embryo Implantation ◽  
Dna Methyltransferases ◽  
Deficient Diet ◽  
Mouse Uterus ◽  
Dietary Folate ◽  
Endometrial Cells ◽  
Pregnant Mice ◽  
Implantation Sites ◽  
Significant Expression

We have characterized the uterine expression of DNA methyltransferases (DNMTs) during early pregnancy in mice and determined whether a folate-deficient diet (FDD) can affect DNMTs in this context. Within endometrial cells, expressions of DNMT (cytosine-5) 1 (Dnmt1),Dnmt3a, andDnmt3bwere significantly elevated during the prereceptive phase of pregnancy but generally returned to baseline levels during receptive and postimplantation periods. As such, the transcription of DNMT genes is temporally regulated during early pregnancy. When comparisons were made between implantation sites (IS) and inter-IS on day 5 of pregnancy, lower levels ofDnmt3awere detected at IS. Comparisons between IS and inter-IS did not reveal significant expression differences for other DNMT genes. When tissue sections were examined, DNMT3A was specifically lower in the stroma of IS. Reduced DNMT1 and DNMT3B levels were also observed in the luminal and glandular epithelia of IS, whereas no obvious differences in the stroma were detected. In pseudo-pregnant mice subjected to a FDD, levels ofDnmt1andDnmt3a(but notDnmt3b) were significantly upregulated in endometrial tissues, as compared with controls. When tissues from these folate-deficient mice were examined, DNMT1 levels were elevated in both the luminal and glandular epithelia, whereas DNMT3A was upregulated in the luminal epithelium and the stroma. A slight increase in DNMT3B levels was detected in the glandular epithelium. These results indicate that DNMTs may regulate the transcription of endometrial genes associated with embryo implantation and that levels of DNMTs are affected by dietary folate in mice.

scholarly journals Expression and function of Pdcd4 in mouse endometrium during early pregnancy

Reproduction ◽  
2018 ◽  
Vol 155 (4) ◽  
pp. 393-402 ◽  
Author(s):  
Yue Zhang ◽  
Mingyun Ni ◽  
Na Liu ◽  
Yongjiang Zhou ◽  
Xuemei Chen ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Quantitative Polymerase Chain Reaction ◽  
Embryo Implantation ◽  
Complex Process ◽  
Programmed Cell Death 4 ◽  
Implantation Sites ◽  
And Function

Embryo implantation is a complex process involving synchronised crosstalk between a receptive endometrium and functional blastocysts. Apoptosis plays an important role in this process as well as in the maintenance of pregnancy. In this study, we analysed the expression pattern of programmed cell death 4 (Pdcd4), a gene associated with apoptosis in the mouse endometrium, during early pregnancy and pseudopregnancy by real-time quantitative polymerase chain reaction, in situ hybridisation, Western blotting and immunohistochemistry. The results showed that Pdcd4 was increased along with days of pregnancy and significantly reduced at implantation sites (IS) from day 5 of pregnancy (D5). The level of Pdcd4 at IS was substantially lower than that at interimplantation sites (IIS) on D6 and D7. In addition, Pdcd4 expression in the endometrium was reduced in response to artificially induced decidualisation in vivo and in vitro. Downregulation of Pdcd4 gene expression in cultured primary stromal cells promoted decidualisation, while upregulation inhibited the decidualisation process by increasing apoptosis. These results demonstrate that Pdcd4 is involved in stromal cell decidualisation by mediating apoptosis and therefore plays a role in embryo implantation in mice.

Decreased mixed lineage leukemia 1 is involved in endometriosis-related infertility

2021 ◽  
Vol 66 (1) ◽  
pp. 45-57
Author(s):  
Xue Wen ◽  
Yao Xiong ◽  
Huimin Liu ◽  
Ting Geng ◽  
Ling Jin ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Stromal Cells ◽  
Expression Patterns ◽  
Embryo Implantation ◽  
Hypoxia Inducible Factor ◽  
Gene Promoter ◽  
Mixed Lineage Leukemia ◽  
Normal Endometrium ◽  
Endometrial Stromal Cells

The aberrant histone methylation patterns contribute to the pathogenesis of endometriosis (EM). Mixed lineage leukemia 1 (MLL1), a histone methyltransferase, is crucial for gene expression by catalyzing the trimethylation of histone 3 lysine 4 (H3K4me3) in gene promoter. This study aimed to explore whether MLL1 is involved in EM-related infertility. The expressions of MLL1 and H3K4me3 were analyzed in the eutopic endometria from EM women with infertility (n = 22) and the normal endometria from EM-free women (n = 22). Mouse EM model was established. The MLL1 and H3K4me3 expression patterns in mice endometria of early pregnancy were also investigated. Immortalized human endometrial stromal cells (iESCs) were cultured and underwent in vitro decidualization. The chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) was performed to find the target gene of MLL1 during decidual process. Results showed that both MLL1 and H3K4me3 decreased in the eutopic endometrium from EM patients compared to that in the normal endometrium. During early pregnancy and the decidual process, MLL1 and H3K4me3 were significantly upregulated in stromal cells. ChIP-seq and ChIP-qPCR found that the cytochrome c oxidase subunit 4I 2 (COX4I2) was directly targeted by MLL1. The dominance of COX4I2-containing enzyme induced the expression of hypoxia-inducible factor-2α (HIF-2α), whose expression in the peri-implantation endometrium is essential for embryo implantation. Further results showed that MLL1 was directly regulated by progesterone (P4) – P4 receptors (PRs). Our study proved that MLL1 was involved in EM-related infertility, which may provide a novel approach to treat the nonreceptive endometrium in EM patients.

scholarly journals Cell–Cell Communication at the Embryo Implantation Site of Mouse Uterus Revealed by Single-Cell Analysis

2021 ◽  
Vol 22 (10) ◽  
pp. 5177
Author(s):  
Yi Yang ◽  
Jia-Peng He ◽  
Ji-Long Liu
Keyword(s):  
Single Cell ◽  
Molecular Mechanism ◽  
Single Cell Analysis ◽  
Embryo Implantation ◽  
Cell Communication ◽  
Human Reproduction ◽  
Mouse Uterus ◽  
Implantation Sites ◽  
Low Efficiency ◽  
Signaling Interactions

As a crucial step for human reproduction, embryo implantation is a low-efficiency process. Despite rapid advances in recent years, the molecular mechanism underlying embryo implantation remains poorly understood. Here, we used the mouse as an animal model and generated a single-cell transcriptomic atlas of embryo implantation sites. By analyzing inter-implantation sites of the uterus as control, we were able to identify global gene expression changes associated with embryo implantation in each cell type. Additionally, we predicted signaling interactions between uterine luminal epithelial cells and mural trophectoderm of blastocysts, which represent the key mechanism of embryo implantation. We also predicted signaling interactions between uterine epithelial-stromal crosstalk at implantation sites, which are crucial for post-implantation development. Our data provide a valuable resource for deciphering the molecular mechanism underlying embryo implantation.

ELECTRICAL STIMULATION HAS NO ADVERSE EFFECT ON PREGNANT RATS AND FETUSES

1999 ◽  
Vol 162 (5) ◽  
pp. 1785-1787 ◽  
Author(s):  
YONGJIN WANG ◽  
MAGDY M. HASSOUNA
Keyword(s):  
Adverse Effect ◽  
Electrical Stimulation ◽  
Pregnant Rats
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