Effects of thyroxin on palatogenesis, fetal resorptions, and fetal weights in A-Jax mice.
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Nonspecific immunopotentiators and pregnancy loss: complete Freund adjuvant reverses high fetal resorption rate in CBA x DBA/2 mouse combination.
CBA/J female mice mated with DBA/2J males show a high incidence of fetal resorptions. This paper presents data demonstrating that nonspecific immunopotentiation by complete Freund adjuvant (CFA) reversed pregnancy loss in CBA/J mothers. Immunization of more than 70 CBA/J females mated with DBA/2J males with CFA reduced the incidence of fetal resorption from 27.3 +/- 1.9 to 7.9 +/- 1.5%. The injection of Thymus Humoral Factor known to be a potent T cell stimulator did not reduce the number of fetal resorptions. The route of CFA distribution was found to be important--only foot pad injections were effective in fetal protection, whereas i.p. treatment did not reduce fetal resorptions. Fetal protection could be transferred by splenocytes of CFA-injected CBA/J mothers (9.6 +/- 5.0% fetal resorptions). Sera from treated CBA/J mice could not cause such an effect (17.6 +/- 4.6 vs. 21.3 +/- 6.1 in control animals). Thus, stimulation of the maternal immune system by nonspecific immunopotentiators can improve reproductive performance of this mouse combination which has an increased rate of pregnancy loss. Possible mechanisms of this fetal protection are discussed.
Animals↗
Lipopolysaccharide-induced fetal resorption in mice is associated with the intrauterine production of tumour necrosis factor-alpha.
Certain strains of mice display an increased frequency of fetal resorption, but little is known about the effector mechanisms involved. We have examined the events associated with lipopolysaccharide (LPS)-induced fetal resorption in mice. Administration of 25 micrograms LPS on Day 12 of gestation resulted in the appearance of tumour necrosis factor-alpha (TNF-alpha) in the amniotic fluid and fetal resorption. Levels of LPS-induced TNF-alpha were reduced by 90% after pretreatment with the TNF-alpha-suppressing drug pentoxifylline (PXF). Treatment of pregnant mice during early gestation with 0.1 micrograms LPS resulted in fetoplacental resorption which was maximal when the LPS was given on Day 8. Resorption induced by 0.1 micrograms LPS on Day 8 of gestation was significantly reduced by pretreatment with PXF. Infiltration of asialo-GM1-positive cells was observed in the decidual-ectoplacental cone area of embryonic units from LPS-treated mice. In addition, treatment with anti-AGM1 antiserum prevented the LPS-induced resorption. Our results suggest that TNF-alpha and asialo-GM1-positive cells are involved in LPS-induced fetal resorption.
Amniotic Fluid↗
Sex ratio manipulation in wild house mice: the effect of fetal resorption in relation to the mode of reproduction.
First generation laboratory-born descendants of wild-caught house mice (Mus musculus domesticus Rutty) were bred to produce litters of primipares and of dams that had conceived a second litter either after lactational anestrus or within the postpartum estrus. At the day of birth, pups were sexed and the number of implanted and resorbed embryos was determined to evaluate the influence of mode of reproduction on litter gender composition and its relation to fetal resorption. No significant deviations from an even sex ratio occurred in the sample. The results indicate that primipares produced litters with subnormal dispersion of the gender distribution, but this could not unequivocally be attributed to fetal resorption. No significant bias in the litter gender composition was detectable within litters conceived after lactational anestrus. In contrast, the dispersion of the gender distribution was significantly supernormal in the litters of dams inseminated at postpartum estrus. Within this group, fetal resorption had a significant effect upon the sex ratio, and this relationship was significantly affected by the number of implanted embryos: resorbing dams produced male-biased litters at small and intermediate numbers of implantation sites and female-biased litters when the number of implanted embryos was large. It is argued that this is most likely attributable to sex-selective fetal resorption.
Animals↗
Murine fetal resorption and experimental pre-eclampsia are induced by both excessive Th1 and Th2 activation.
It has been proposed that immune responses in mammalian normal pregnancy are Th2-like, thereby protecting the fetus and placenta from being rejected. Administration of exogenous Th1 cytokines into pregnant mice is reported to induce feto-placental resorption. However, the effects of exogenous Th2 cytokines and Th2 directed responses in pregnant animals have not been well studied. In this study, we examined IL-4 and IL-12, which play decisive roles in the development of Th2 and Th1 responses, respectively, in the induction of fetal resorption and development of experimental pre-eclampsia. Transfer of either IL-4 and/or IL-12 stimulated splenocytes from BALB/C virgin female mice into BALB/C pregnant mice mated with either C57BL/6 or BALB/C male mice resulted in fetal resorption and glomerular nephritis associated with hypertension and proteinuria. In mice treated with IL-12 stimulated splenocytes, fatty liver degeneration associated with bile retention was observed. These results indicate that both excessive Th1 and Th2 activation contribute to the development of fetal resorption and pre-eclampsia, but that Th1 is critical to the development of liver degeneration.
Adoptive Transfer↗
Expression of cytokines in placentas of mice undergoing immunologically mediated spontaneous fetal resorptions.
It is clear that the immune system and the reproductive system interact with and influence each other and that the immune system can have positive and negative regulatory effects on the outcome of pregnancy. The discovery of murine models of immunologically mediated spontaneous fetal resorptions has proved to be very useful for the study of immunological influences on pregnancy. In an attempt to elucidate the mechanisms underlying pregnancy impairment in one such "natural" model of pregnancy loss, we compared the expression of the cytokines tumor necrosis factor alpha, interferon tau, and interleukin-2 in placental tissue from a resorption-prone strain combination with the expression from a normal combination. We found significantly enhanced expression of these three cytokines in placentas from the resorption-prone combination using dot-blot hybridization and Northern hybridizations. Since these cytokines are abortifacients in vivo and have detrimental effects on the placenta, and hence on fetal development and survival, our demonstration of enhanced expression of these deleterious cytokines may give insight into the mechanisms involved in immunologically mediated spontaneous abortions.
Animals↗
Progesterone levels and socially-induced implantation failure and fetal resorption in golden hamsters (Mesocricetus auratus).
Levels of circulating progesterone (P) were significantly reduced in socially subordinate female golden hamsters following brief exposures to another female. Reduced P levels were accompanied by an increased incidence of implantation failure when social interactions occurred on days 2-4 after mating and by increased fetal mortality when interactions occurred later during pregnancy (days 5-7 or 10-12). P levels, the incidence of implantation failure and rate of fetal resorption were highly correlated with the number of attacks and chases sustained by subordinate females. Smaller reductions in plasma P levels and marginally significant decreases in fecundity were also noted among dominant animals and among females paired with unfamiliar males later in pregnancy. The fact that these effects occurred even with relatively brief exposure periods suggests that they could occur in the wild.
Animals↗
Effect of abdominal vagotomy of the pregnant rat on LH and progesterone concentrations and fetal resorption.
Abdominal vagotomy on Day 8 of pregnancy in rats decreased the number of live fetuses at Day 16 and increased the number of resorbing fetuses. The activity of delta5-3beta-hydroxysteroid dehydrogenase (3beta-HSD) in the corpus luteum and interstitial gland, LH and progesterone values in plasma and progesterone values in ovarian tissue were all lower in vagotomized rats than in sham-operated controls. Ovarian PGF levels were not affected. We suggest that these effects were caused by a direct effect of vagotomy on LH secretion which in turn lowers 3beta-HSD activity and progesterone levels in ovarian tissue and plasma, leading to fetal resorption.
Animals↗
Preventive effect of monoclonal antibodies to intercellular adhesion molecule-1 and leukocyte function-associate antigen-1 on murine spontaneous fetal resorption.
PROBLEM: Are cell adhesion molecules involved in the murine model of immunologically-mediated spontaneous abortion? METHOD OF STUDY: Pregnant CBA/J female mice mated with DBA/2 male mice were injected with monoclonal antibodies (MAbs) to intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-associate antigen-1 (LFA-1). On day 13 of gestation. viable and resorbed embryos were counted. Natural killer (NK) cell activity in the spleen, mixed lymphocyte reactions (MLR), mixed lymphocyte-placenta reactions (MLPR), and levels of interferon (IFN)-gamma were assayed. RESULTS: Significant suppression of fetal resorption was observed by the injection of MAb to ICAM-1 and LFA-1. NK cell activity and the MLR anti-(CBA/J x DBA/ 2)F1 were reduced in the antibody-treated CBA/J spleen. Moreover, the level of IFN-gamma was significantly lower in the MLPR supernatants from the antibody-treated group than those of the control group. CONCLUSIONS: One mechanism in the murine model of spontaneous abortion may be through the interaction of cell adhesion molecules, which may modulate NK cell activities and cytokine production.
Animals↗
Fetal resorption in rats treated with an antiestrogen in relation to luteal phase nidatory estrogen secretion.
Centchroman was administered to rats in relation to luteal phase nidatory estrogen secreted between 21.00 on day 4 and 10.00 on day 5 of pregnancy. A single oral dose of 1.25 mg/kg before the secretion of nidatory estrogen, i.e. until 21.00 on day 4, prevented implantation in 100% of the rats without altering plasma estradiol or progesterone concentration. Administration of a dose of up to 62.5 mg/kg at 10.00 on day 5 even failed to inhibit implantation, but caused dose-dependent resorption of implantations. Resorption of all implantations at a dose of 62.5 mg/kg was associated with a decrease in circulating progesterone levels, but was only partially reversed by progesterone or progesterone + estrone supplementation. Apparently normal morulae and blastocysts recovered between days 4 and 10 from rats treated with anti-implantation doses before release of nidatory estrogen, when transferred to the uteri of control rats exhibited lower pregnancy, implantation and development rates with increasing confinement in the genital tract of treated donors. None of the embryos recovered from control or centchroman treated females implanted in the uteri of treated rats. Centchroman administration on day 1, but not on day 5, abolished endometrial receptivity to an artificial stimulus for decidualization. All term fetuses were apparently normal and their weight comparable to that of control fetuses. The study provides evidence of post-implantation fetal resorption, occurring primarily between days 10 and 19 post-coitum, in rats treated with a potent antiestrogen before or immediately after the prenidatory estrogen secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Maternal anti-placental reactivity in natural, immunologically-mediated fetal resorptions.
Observations on maternal recognition of the fetus and the demonstration of the effects of cytokines on reproductive events led to the "immunotrophism" model, which suggests that maternal immune recognition of fetally-derived Ags results in the release of cytokines that promote the growth of the placenta; any disturbance in this balance of cytokines could result in deleterious consequences for the placenta and, in turn, the fetus. We have focused our attention on the murine CBA/J x DBA/2 model of spontaneous abortions and compared them with normal CBA x BALB/c pregnancies. Our results indicate that the extent of stimulation of maternal strain lymphocytes in response to stimulator placental cells in mixed lymphocyte-placenta reactions (MLPR) was much higher in the normal mating combination compared with the abortion-prone mating combination. Cytokine analysis of the supernatants from MLPR indicates that there is significantly higher production of TNF-alpha, IFN-gamma, and IL-2 in supernatants from the abortion-prone combination than in supernatants from the normal combination. Furthermore, MLPR-stimulated cells induce resorptions in normal pregnant mice; maternal strain lymphocytes stimulated by placentas from the abortion-prone combination induce high rates of fetal resorptions, but lymphocytes stimulated with placentas from the normal combination do not. Together, these results suggest that immunologically mediated fetal resorptions probably result from improper or inappropriate maternal responses to placental Ags. Our observations also suggest that such effects are probably mediated by cytokines.
Animals↗
Fetal resorption in rats following intrauterine instillation of alcohol.
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Animals↗
[Fetal resorption during the early stage of twin pregnancy].
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Adult↗
Defects in embryonic hindbrain development and fetal resorption resulting from vitamin A deficiency in the rat are prevented by feeding pharmacological levels of all-trans-retinoic acid.
Vitamin A is required for reproduction and normal embryonic development. We have determined that all-trans-retinoic acid (atRA) can support development of the mammalian embryo to parturition in vitamin A-deficient (VAD) rats. At embryonic day (E) 0.5, VAD dams were fed purified diets containing either 12 micrograms of atRA per g of diet (230 micrograms per rat per day) or 250 micrograms of atRA per g of diet (4.5 mg per rat per day) or were fed the purified diet supplemented with a source of retinol (100 units of retinyl palmitate per day). An additional group was fed both 250 micrograms of atRA per g of diet in combination with retinyl palmitate. Embryonic survival to E12.5 was similar for all groups. However, embryonic development in the group fed 12 micrograms of atRA per g of diet was grossly abnormal. The most notable defects were in the region of the hindbrain, which included a loss of posterior cranial nerves (IX, X, XI, and XII) and postotic pharyngeal arches as well as the presence of ectopic otic vesicles and a swollen anterior cardinal vein. All embryonic abnormalities at E12.5 were prevented by feeding pharmacological amounts of atRA (250 micrograms/g diet) or by supplementation with retinyl palmitate. Embryos from VAD dams receiving 12 micrograms of atRA per g of diet were resorbed by E18.5, whereas those in the group fed 250 micrograms of atRA per g of diet survived to parturition but died shortly thereafter. Equivalent results were obtained by using commercial grade atRA or atRA that had been purified to eliminate any potential contamination by neutral retinoids, such as retinol. Thus, 250 micrograms of atRA per g of diet fed to VAD dams (approximately 4.5 mg per rat per day) can prevent the death of embryos at midgestation and prevents the early embryonic abnormalities that arise when VAD dams are fed insufficient amounts of atRA.
Animals↗
In vivo immunosuppressive effects of recombinant ovine interferon-tau (trophoblastin): r.oTP (r.oIFN-tau) inhibits local GVH reaction in mice (PLN assay), prevents fetal resorptions, and favors embryo survival and implantation in the CBA/J x DBA/2 mice combination.
PROBLEM: Ovine trophoblastin protein, be it natural or recombinant (oTP,r.oTP), a member of the tau interferon family (r.oIFN-tau), has been shown to possess immunosuppressive properties in vitro. It acts as a cytostatic agent across species. Indeed, it was immunosuppressive when tested on human and murine lymphocytes in a variety of in vitro immune assays, as it is also on syngenic (ovine) lymphocytes. METHODS: In the present paper, we first verified that this property to act across species also occurred in vivo assays; r.oTP was able to down regulate a local GVH reaction assay (PLN assay) in mice. We then took advantage of these properties of r.oTP to investigate its in vivo effects during murine pregnancy as there is no ovine equivalent of the murine CBA/J x DBA/2 resorption prone mating combination. RESULTS: When given in the postimplantation period, r.oTP drastically boosted resorptions in the CBA/J x DBA/2 matings, as did murine recombinant gamma interferon. However, the same r.oTP treatment in the peri-implantation period resulted in a reduction in resorptions in this spontaneous abortion system. CONCLUSION: The data suggested that r.oTP might have acted more by favouring implantation and embryo survival than by preventing the resorption process itself. The mechanisms possibly underlying these effects, as well as the putative uses of r.oTP evolving from these data, are discussed.
Age Factors↗
T helper 1 response against Leishmania major in pregnant C57BL/6 mice increases implantation failure and fetal resorptions. Correlation with increased IFN-gamma and TNF and reduced IL-10 production by placental cells.
Maternal immune responses can influence fetal survival and several cytokines have harmful or protective effects on pregnancy. The Th1 cytokines IFN-gamma and IL-2 can cause fetal loss, whereas the Th2 cytokine IL-10 is protective. However, infections such as leishmaniasis show the opposite pattern: resistance is associated with the preferential mounting of a Th1 response, whereas a Th2 response exacerbates the disease. We therefore asked whether the curative Th1 response against Leishmania major in genetically resistant C57BL/6 mice, would compromise concurrent pregnancy. The number of resorptions as assessed by uterine scars was significantly increased in infected C57BL/6 mice and this was associated with a decreased production by placental cells of the Th2 cytokines IL-4 and IL-10 and increased production of IFN-gamma and TNF. Interestingly, the frequency of pregnancy failure before implantation in C57BL/6 mice was also substantially increased. In contrast to C57BL/6 mice, early infection did not reduce implantations in BALB/c mice that mount a Th2 anti-L. major response and succumb to infection. For both resorptions and implantations, there appeared to be a short period early in infection that was detrimental to pregnancy, followed by a period with lesser effects, and a later period that again induced higher resorptions or pre-implantation losses. These results suggest that a beneficial anti-parasite Th1 response can adversely affect pregnancy outcome. Furthermore, Th1 cytokines may be deleterious for not only placental maintenance but also preimplantation events.
Animals↗
Abnormal development of the sinuatrial venous valve and posterior hindbrain may contribute to late fetal resorption of vitamin A-deficient rat embryos.
BACKGROUND: Normal embryonic development and survival in utero is dependent on an adequate supply of vitamin A. Embryos from vitamin A-deficient (VAD) pregnant rats fed an inadequate amount of all-trans retinoic acid (atRA; 12 microg per g of diet or approximately 230 microg per rat per day) exhibit severe developmental abnormalities of the anterior cardinal vein and hindbrain by embryonic day (E) 12.5 and die shortly thereafter. METHODS: In the present study, we sought to determine whether supplementation of VAD-RA supported (12 microg per g of diet) pregnant rats with retinol (ROL) at the late-gastrula (presomite or rat E9.5) or early somite stages (E10.5), or provision of higher levels of atRA throughout this period could prevent abnormalities in the developing cardiovascular and nervous systems. RESULTS: A newly described defect in the sinuatrial venus valve along with enlarged anterior cardinal veins and nervous system abnormalities and the later death of embryos are prevented by supplementing pregnant animals with ROL on the morning of E9.5. If ROL supplementation is delayed by 1 day (E10.5), most embryos are abnormal and die by E18.5. Supplementation of VAD rats with atRA (250 microg per g of diet) between E8.5 and E10.5 also prevents the cardiovascular and nervous system abnormalities and a significant number of these embryos survive to parturition. Thus, high levels of atRA can obviate the need for ROL between E9.5 and E10.5. CONCLUSIONS: These results support an essential role for retinoid signaling between the late gastrula and early somite stages in the rat embryo for normal morphogenesis of the primitive heart tube and the posterior hindbrain. Further, these results suggest that embryonic death occurring at midgestation in the VAD rat may be linked to the abnormal development of one or both of these embryonic structures.
Abnormalities, Multiple↗
Morphometric analysis of the histology of spontaneous fetal resorption in a murine pregnancy.
Immunopathology of the spontaneous resorption phenomenon in the CBA x DBA/J murine model was explored using morphometric analysis. Accompanying the previously reported presence of natural killer (NK) cells in resorptive feto-placental units we find major changes in tissue morphology indicating that early infiltration of the feto-placental unit by maternal leukocytes plays a direct role with NK cells in fetal demise. Total number of cell nuclei per field and total nuclear area per field were significantly elevated in feto-placental units containing abnormally increased NK cell presence before detectable resorption as early as day 7 of gestation. This difference persisted throughout all stages of early gestation up to and including the final resorption event at day 10 to 12. Increases in cell density were also detected in areas of the embryonic unit not associated with NK infiltration. These results demonstrate that the spontaneous resorption phenomenon in this model involves: (i) Early (day 7-8) cellular infiltration of the decidual-ectoplacental cone junction associated with the presence in this area of NK cells. (ii) Late (day 8-9) cellular infiltration of the ectoplacental cone.
Animals↗