Embryonic loss after bovine embryo transfer.
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Journal Article↗
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Immunological prevention of spontaneous early embryo resorption is mediated by non-specific immunosimulation.
PROBLEM: Spontaneous early embryo resorption following implantation occurs in many species, but little is known regarding the causes or the prevention of early pregnancy failure. Embryo and fetal loss have widely been assumed to be due to maternal allospecific immune rejection. Alloimmunization therapy with paternal tissues has been successfully used in human and murine pregnancies to prevent early embryo demise. The mechanisms of this treatment have been assumed to be the induction of antigen specific, fetal "graft" enhancing antibodies and suppressor cells. The purpose of this study was to investigate the validity of this assumption. METHOD: To investigate these general assumptions, female CBA/J mice were immunized with either specific or nonspecific antigens prior to mating with DBA/2 or Balb/c males. Further, a model system for the study of bacterial lipopolysaccharide (LPS) induced abortion was used to demonstrate the nature of antigen specific immune protection against abortion. RESULTS: Whereas the administration of 1 microgram of LPS to CFW female x CFW male pregnant mice on day 7 of gestation induced complete fetal resorption, prior immunization with 20 micrograms of LPS completely prevented LPS induced abortion as long as the anti-LPS antibody titers remained above a threshold value of about 1/500. Therefore, early embryo loss could be induced by a bacterial infection and could be prevented by appropriate immunity to abortogenic factors. However, due to the short half-life of IgM antibodies, immunity to LPS was short-lived and the protective effect of LPS immunization against LPS induced abortion waned after 5 wk. Through the use of the CBA/J female x DBA/2 male model system to study spontaneous early embryo loss, previous vaccination of CBA/J female mice with Balb/c spleen cells expressing paternal MHC antigens, complete Freund's adjuvant (CFA) or LPS, all decreased the incidence of spontaneous resorption in subsequent pregnancies. Similarly, a previous mating with a Balb/c male prevented spontaneous embryo loss for a period of up to 6 wk. However, none of the immunotherapeutic vaccinations or matings had a permanent effect on CBA/J female x DBA/2 male embryo survival, which one would have expected if specific immune mediators were involved. CONCLUSION: The results of this study indicated that the decrease in the incidence of spontaneous embryo resorption following alloimmunization was more likely to be due to nonspecific immunomodulatory effects on the immune system of the female mice, as opposed to specific antipaternal immunity. This may, in part, explain the placebo effects observed for alloimmunization therapy for human habitual pregnancy loss. The relevance of these results to the development of immunotherapy strategies for the prevention of habitual abortion is discussed.
Animals↗
[Real-time ultrasonic pregnancy diagnosis (B-mode) in sheep. 1. Frequent examinations during the first month of pregnancy].
Transrectal ultrasonography was performed on 63 ewes (four breeds) to determine the earliest day at which pregnancy, the first embryo, the number of embryos, the embryonal heartbeat and placentoms could be detected. The ewes were examined at intervals of two to three days on day 12/13 to 30 post breeding. An Aloka SSD 500 ultrasound unit was used with a 5-Mhz probe. The diagnosis of the pregnant ewes took place on day 17.6 +/- 1.8 p.c. The first embryo was detected on day 20.5 +/- 1.9 p.c., but not all of the embryos were counted accurately until day 26. The heartbeat of the embryos was detected on day 22.9 +/- 2.9 p.c. and placentoms on day 27.6 +/- 2.4 p.c. The influence of the breed on the results will be discussed. The proportion of sheep with a loss of embryos was 24.6% (partial loss of embryos 18.0%, total loss of embryos 6.6%). In conclusion, transrectal ultrasound is a good method to describe the early pregnancy in sheep.
Animals↗
Water loss and survival in embryos of the domestic chicken.
In this report we show that the amount of water lost during incubation is an important determinant of hatchability in embryos of the domestic chicken. However, when the loss of water is restricted to the first half versus the second half of the total incubation period, it is the loss of water during the first half that affects hatching success. We propose that regulating the permeability of the egg shell may be important in preventing excessive drying of the inner shell membrane during early development along with limiting the total amount of water lost from the embryo during incubation.
Animals↗
Frequency and occurrence of late-gestation losses from cattle cloned embryos.
Nuclear transfer from somatic cells still has limited efficiency in terms of live calves born due to high fetal loss after transfer. In this study, we addressed the type of donor cells used for cloning in in vivo development. We used a combination of repeated ultrasonography and maternal pregnancy serum protein (PSP60) assays to monitor the evolution of pregnancy after somatic cloning in order to detect the occurrence of late-gestation losses and their frequency, compared with embryo cloning or in vitro fertilization (IVF). Incidence of loss between Day 90 of gestation and calving was 43.7% for adult somatic clones and 33.3% for fetal somatic clones, compared with 4.3% after embryo cloning and 0% in the control IVF group. Using PSP60 levels in maternal blood as a criterion for placental function, we observed that after somatic cloning, recipients that lost their pregnancy before Day 100 showed significantly higher PSP60 levels by Day 50 than those that maintained pregnancy (7.77 +/- 3.3 ng/ml vs. 2.45 +/- 0.27 ng/ml for normal pregnancies, P < 0.05). At later stages of gestation, between 4 mo and calving, mean PSP60 concentrations were significantly increased in pathologic pregnancy after somatic cloning compared with other groups (P < 0.05 by Day 150, P < 0.001 by Day 180, and P < 0.01 by Day 210). In those situations, and confirmed by ultrasonographic measurements, recipients developed severe hydroallantois together with larger placentome size. Our findings suggest that assessing placental development with PSP60 and ultrasonography will lead to better care of recipient animals in bovine somatic cloning.
Animals↗
Identification of genes associated with tumor suppression in Syrian hamster embryo cells.
Loss of a tumor-suppressor gene function appears to play a critical role in the multistep process of neoplastic transformation of Syrian hamster embryo (SHE) cells in vitro. Clonal variants of two independent, preneoplastic cell lines have been isolated that have either retained (termed supB+) or lost (termed supB-) the ability to suppress the tumorigenicity of a highly malignant benzo[alpha]pyrene-transformed SHE cell line (BP6T) in cell hybrids. We have pursued several approaches in an attempt to identify genes that are responsible for tumor suppression in these cells. The only consistent differences detected in two-dimensional gel analyses of supB+ and supB- cellular proteins were decreases in the levels of two high molecular weight isoforms of tropomyosin in supB- cells. Differential screening of a supB+ cDNA library for genes that are preferentially expressed in supB+ cells yielded cDNA clones for four genes, i.e., collagen type II, collagen type IX, H19, and a previously unidentified gene (clone 5). Nuclear run-on assays suggested that higher transcription rates were responsible for the increased steady-state levels of some of these transcripts in supB+ cells. DNA sequence comparisons showed that two copies of a 9 bp element, previously identified in each of the mouse H19 enhancers, were also present in the 5' flanking region of the rat type II collagen gene. A transcription factor that controls expression of the collagen and H19 genes through binding to this conserved motif would be an attractive candidate for the supB+ gene or at least a mediator of the supB+ phenotype.
Animals↗
Embryo quality and pregnancy potential of fresh compared with frozen embryos--is freezing detrimental to high quality embryos?
To determine the effect of cryopreservation on embryo quality and the pregnancy potential of embryos, donated oocytes from the same donor (n = 24) were randomly allocated, with subsequent transfer to two or more different ovum recipients resulting in at least one fresh and one frozen embryo transfer cycle from the same cohort of oocytes. Endometrial receptivity was controlled in all ovum recipients, and male factor patients were excluded. The number of embryos transferred, mean embryo grade transferred, number of high quality embryos (grade < or = 2.5, grade 1 being best) transferred and embryo implantation and live birth rates are reported. Significantly more embryos (4.4 +/- 1.2 versus 3.3 +/- 1.2, P < 0.00003) of higher quality (1.9 +/- 0.5 versus 2.1 +/- 0.5, P < 0.013) and of a more advanced cell stage (3.0 +/- 0.6 versus 2.6 +/- 0.7, P < 0.019) were transferred fresh than after cryopreservation respectively. Implantation rates/embryo [19/151 (12.6%) and 9/111 (8.1%)] and live birth rates/transfer [11/42 (26.2%) and 6/45 (13.3%)], from fresh and frozen transfers respectively, were not significantly different despite the larger number of high quality embryos transferred fresh. Embryo cryopreservation adversely affects embryo quality, but does not have detrimental effects on the implantation or pregnancy potential of high quality embryos. Because of the loss of embryos during freeze-thawing during frozen embryo cycles, every effort should be made to attempt a fresh transfer.
Adult↗
Production of immunosuppressor factor(s) by preimplantation human embryos.
Embryonic loss prior to implantation appears to be a significantly frequent phenomenon and this is further reinforced by the very low pregnancy rates reported by in vitro fertilization and embryo transfer programs. Implantation failure may possibly be the result of rejection of the antigenic embryo by the hostile maternal immune system. The mechanism by which embryos in successful pregnancies escape these rejection responses may depend upon their ability to produce factor(s) that suppress in vitro mitogen-induced lymphocyte proliferation. Only 43% of cleaved embryos demonstrated this ability. We postulate that successful pregnancies are dependent upon the production by embryos of immunosuppressor factor(s) that has a direct suppressive effect on the maternal immune response.
Blastocyst↗
Genetic dissection of nodal function in patterning the mouse embryo.
Loss-of-function analysis has shown that the transforming growth factor-like signaling molecule nodal is essential for mouse mesoderm development. However, definitive proof of nodal function in other developmental processes in the mouse embryo has been lacking because the null mutation blocks gastrulation. We describe the generation and analysis of a hypomorphic nodal allele. Mouse embryos heterozygous for the hypomorphic allele and a null allele undergo gastrulation but then display abnormalities that fall into three distinct mutant phenotypic classes, which may result from expression levels falling below critical thresholds in one or more domains of nodal expression. Our analysis of each of these classes provides conclusive evidence for nodal-mediated regulation of several developmental processes in the mouse embryo, beyond its role in mesoderm formation. We find that nodal signaling is required for correct positioning of the anteroposterior axis, normal anterior and midline patterning, and the left-right asymmetric development of the heart, vasculature, lungs and stomach.
Alleles↗
Regionalization of the anterior hypothalamus in the chick embryo.
Loss-of-function experiments in mice have shown that the transcription factors Sim1, Otp, Sim2, and Brn2 form a cascade essential for the differentiation of neuroendocrine cells of the anterior hypothalamus that produce vasopressin, oxytocin, somatostatin (SS), thyrotropin-releasing hormone (TRH), and corticotropin-releasing hormone (CRH). Very little is known about how the differentiation of these cell types is regulated in chick. Here, we report the cloning of the chick homolog of Otp. Moreover, we have systematically compared the expression of Sim1, Sim2, Brn2, and Otp with that of the markers of terminal differentiation TRH, SS, CRH, vasotocin, and mesotocin during development of chick embryos. We have found that the cell types studied generally develop in domains expressing these transcriptional regulators but that the pattern of neuronal differentiation and the spatial distribution of some regulators were not the same as in mice. Our results provide a framework useful for the functional analysis of hypothalamus development in chick.
Animals↗
Laparoscopic transfer of ovine and cervine embryos using the transpic technique.
A transpic technique was developed to transfer embryos to 352 sheep and 4 deer recipients using a laparoscope, a modified pair of Allis forceps and a modified Cassou aspic normally used for laparoscopic uterine insemination. The overall proportion of uncomplicated transfers in Experiment 1 in 216 recipient ewes was 90.7% (range between groups 80 to 100%), 3.7% of the transfers were presumed to be loss of embryos during expulsion from the transpic, and 5.6% were apparent transfers into the uterine wall. In Experiment 2,83% of transfers into 136 ewe recipients were uncomplicated, 5% were presumed to be loss of embryos during expulsion, 1% was apparent transfer into the uterine wall, and 11% involved 2 attempts at transfer. Only 34% of 116 recipients receiving low-quality frozen-thawed embryos were pregnant and 24% of the 226 embryos survived to term. In contrast, high pregnancy rates (>80%) and embryo survival rates (>70%) were achieved following uncomplicated and twice attempted transfers of fresh embryos. Pregnancy rates and embryo survival rates were low (<2%) following the presumed loss of embryos during expulsion and apparent transfers into the uterine wall. All 4 deer transfers were uncomplicated and 2 2 good-quality embryos survived to term compared with 0 2 low-medium quality embryos. The transpic technique is a moderately invasive technique which permits fast (15 to 20/h) and reliable transfer of embryos in small ruminants. With appropriate care, nearly all of the embryos can be correctly placed in the uterus, and high pregnancy rates and embryo survival rates can be achieved using this technique.
Journal Article↗
Causes of early embryonic loss in human pregnancy.
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Abortion, Spontaneous↗
Patterns of expression of cut, a protein required for external sensory organ development in wild-type and cut mutant Drosophila embryos.
The loss of cut activity in Drosophila results in the transformation of the neurons and support cells of external sensory (es) organs into those of chordotonal (ch) organs. The cut locus encodes a homeo domain-containing protein, which is expressed in the cells of es, but not in ch, organs. We show by Western analyses the presence of two embryonic protein species whose approximate relative molecular masses of 280 and 320 kD are compatible with that predicted from the primary sequence. We also describe the development of the Cut protein expression pattern and show that Cut is expressed in sensory precursor cells that divide to give rise to es organs. Finally, we analyze the changes in the Cut expression pattern of several mutant alleles of the complex cut locus and show that the mutations affecting es organ development are associated with either altered protein distribution in the PNS or incorrect subcellular Cut protein localization.
Animals↗
Polycystic ovary syndrome, infertility, familial thrombophilia, familial hypofibrinolysis, recurrent loss of in vitro fertilized embryos, and miscarriage.
OBJECTIVE: To study reversible determinants of infertility and recurrent loss of transferred embryos after failure of 7 of 10 embryo transfers, 1 live birth, and 2 miscarriages. DESIGN: Measures of thrombophilia, hypofibrinolysis, reproductive hormones, and androgenic steroids before and after metformin therapy. SETTING: Outpatient clinical research center. PATIENT(S): A 32-year-old amenorrheic, infertile woman with polycystic ovary syndrome (PCOS) who had 7 of 10 embryo transfers fail, 1 premature live birth, and 2 miscarriages at 8 and 17 weeks. INTERVENTION(S): Metformin (2.55 g/d) was given to ameliorate the endocrinopathy of PCOS. MAIN OUTCOME MEASURE(S): Coagulation, insulin, reproductive hormones, and androgenic steroids. RESULT(S): The propositus had thrombophilia (familial protein S deficiency [free protein S 32%; normal >/=65%]). She also had familial hypofibrinolysis with 4G4G polymorphism of the plasminogen activator inhibitor (PAI-1) gene and high PAI-1 activity (PAI-Fx), 42.5 U/mL, normal <21.1. Polycystic ovary syndrome was characterized by amenorrhea, polycystic ovaries, high fasting serum insulin (39 microU/mL, normal <20), androstenedione (763 ng/dL, normal <250), and testosterone (229 ng/dL, normal <83). After she received metformin for 4 months, PAI-Fx normalized (12.4 U/mL), as did insulin (12 microU/mL), androstenedione (185 ng/dL), and testosterone (39 ng/dL); weight fell from 109 to 91.3 kg (16%). CONCLUSION(S): Metformin reversed the endocrinopathy of PCOS. Familial thrombophilia and hypofibrinolysis may lead to thrombosis-mediated uteroplacental vascular insufficiency, failure to achieve pregnancy after embryo transfer, and miscarriage.
Abortion, Habitual↗
The orphan steroid receptor Nur77 family member Nor-1 is essential for early mouse embryogenesis.
Nur77 and its family members, Nor-1 and Nurr1, are orphan steroid receptors implicated in a wide variety of biological processes, including apoptosis and dopamine neuron agenesis. Expression of these family members can be detected at low levels in many tissues but they are expressed at very high levels when cells are stimulated by outside signals, including serum, nerve growth factor, and receptor engagement. Introduction of a dominant negative Nur77 protein that blocks the activities of all family members led to inhibition of apoptosis in T cells. Nur77-deficient mice, however, exhibit no phenotype, and a line of Nor-1 mutant mice was reported to exhibit a mild ear development phenotype but no other gross abnormalities. Here, we report the generation of Nor-1-deficient mice with a block in early embryonic development. Nor-1 is expressed early during embryogenesis, and its loss leads to embryonic lethality around embryonic day 8.5 of gestation. The mutant embryos fail to complete gastrulation and display distinct morphological abnormalities, including a decrease in overall size, developmental delay and an accumulation of mesoderm in the primitive streak during gastrulation. Abnormal expression of a number of early developmental markers and defects in growth or distribution of emerging mesoderm cells were also detected. These data suggest that Nor-1 plays a crucial role in gastrulation.
Animals↗
The singleton, term gestation, and live birth rate per cycle initiated: a 1-year experience in in vitro fertilization cycles with native and donated oocytes.
OBJECTIVE: To investigate the singleton, term gestation, and live birth rate per cycle initiated in our IVF program during a 1-year period. DESIGN: Retrospective study of all first IVF cycles performed in the year 2002, with or without intracytoplasmic sperm injection (ICSI), with day 2/3 embryo transfer and using native or donated oocytes. SETTING: Instituto Valenciano de Infetilidad (IVI), Valencia, Spain. PATIENT(S): Of 3,158 IVF cycles initially considered, 165 were excluded because of embryo freezing, follow-up loss, or embryo reduction. Of the remaining cycles, only 1,836 were first cycles with day 2/3 embryo transfer; of these, native oocytes were employed in 1,095 and donated oocytes in 741. INTERVENTION(S): No patient underwent any additional procedure or intervention. MAIN OUTCOME MEASURE(S): The singleton, term gestation, and live birth rate per cycle initiated was used as a primary outcome measure. Results were analyzed according to the origin of the oocytes (native vs. donated) and the woman's age (<37 and > or =37 years old). RESULT(S): The ectopic pregnancy rate was higher in the native oocyte group. The singleton, term gestation, and live birth rate per cycle initiated was similar in native and donated oocyte groups (15.3% vs. 13.4%). In the native oocyte group, patients <37 years old showed a significantly better outcome. The singleton, term gestation, and live birth rate per cycle initiated was 16.7% and 10.8% in younger and older women, respectively. CONCLUSION(S): The singleton, term gestation, and live birth rate per cycle initiated constitutes an essential parameter for determining the real possibility of a healthy baby for a specific assisted reproduction technology (ART).
Adult↗
LET-711, the Caenorhabditis elegans NOT1 ortholog, is required for spindle positioning and regulation of microtubule length in embryos.
Spindle positioning is essential for the segregation of cell fate determinants during asymmetric division, as well as for proper cellular arrangements during development. In Caenorhabditis elegans embryos, spindle positioning depends on interactions between the astral microtubules and the cell cortex. Here we show that let-711 is required for spindle positioning in the early embryo. Strong loss of let-711 function leads to sterility, whereas partial loss of function results in embryos with defects in the centration and rotation movements that position the first mitotic spindle. let-711 mutant embryos have longer microtubules that are more cold-stable than in wild type, a phenotype opposite to the short microtubule phenotype caused by mutations in the C. elegans XMAP215 homolog ZYG-9. Simultaneous reduction of both ZYG-9 and LET-711 can rescue the centration and rotation defects of both single mutants. let-711 mutant embryos also have larger than wild-type centrosomes at which higher levels of ZYG-9 accumulate compared with wild type. Molecular identification of LET-711 shows it to be an ortholog of NOT1, the core component of the CCR4/NOT complex, which plays roles in the negative regulation of gene expression at transcriptional and post-transcriptional levels in yeast, flies, and mammals. We therefore propose that LET-711 inhibits the expression of ZYG-9 and potentially other centrosome-associated proteins, in order to maintain normal centrosome size and microtubule dynamics during early embryonic divisions.
Animals↗
Role of phosphoinositide 3-kinase regulatory isoforms in development and actin rearrangement.
Class Ia phosphoinositide 3-kinases (PI3Ks) are heterodimers of p110 catalytic and p85 regulatory subunits that mediate a variety of cellular responses to growth and differentiation factors. Although embryonic development is not impaired in mice lacking all isoforms of the p85alpha gene (p85alpha-/- p55alpha-/- p50alpha-/-) or in mice lacking the p85beta gene (p85beta-/-) (D. A. Fruman, F. Mauvais-Jarvis, D. A. Pollard, C. M. Yballe, D. Brazil, R. T. Bronson, C. R. Kahn, and L. C. Cantley, Nat Genet. 26:379-382, 2000; K. Ueki, C. M. Yballe, S. M. Brachmann, D. Vicent, J. M. Watt, C. R. Kahn, and L. C. Cantley, Proc. Natl. Acad. Sci. USA 99:419-424, 2002), we show here that loss of both genes results in lethality at embryonic day 12.5 (E12.5). The phenotypes of these embryos, including subepidermal blebs flanking the neural tube at E8 and bleeding into the blebs during the turning process, are similar to defects observed in platelet-derived growth factor receptor alpha null (PDGFRalpha-/-) mice (P. Soriano, Development 124:2691-2700, 1997), suggesting that PI3K is an essential mediator of PDGFRalpha signaling at this developmental stage. p85alpha-/- p55alpha+/+ p50alpha+/+ p85beta-/- mice had similar but less severe defects, indicating that p85alpha and p85beta have a critical and redundant function in development. Mouse embryo fibroblasts deficient in all p85alpha and p85beta gene products (p85alpha-/- p55alpha-/- p50alpha-/- p85beta-/-) are defective in PDGF-induced membrane ruffling. Overexpression of the Rac-specific GDP-GTP exchange factor Vav2 or reintroduction of p85alpha or p85beta rescues the membrane ruffling defect. Surprisingly, reintroduction of p50alpha also restored PDGF-dependent membrane ruffling. These results indicate that class Ia PI3K is critical for PDGF-dependent actin rearrangement but that the SH3 domain and the Rho/Rac/Cdc42-interacting domain of p85, which lacks p50alpha, are not required for this response.
Actins↗