Effects of thyroxin on palatogenesis, fetal resorptions, and fetal weights in A-Jax mice.
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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.
OBJECTIVES: To determine the prevalence of fetal resorption in 77 pregnant bitches and its association with the age, size and body condition score of the bitch and to determine the frequency of transuterine migration of embryos. METHODS: The number and position of embryos or fetuses and placental zones were registered postmortem. The prevalence of fetal losses was determined by comparing the number of corpora lutea with the number of embryos or fetuses in each bitch. The prevalence of transuterine migration of embryos was determined by correlating the number of fetuses in each horn and the number of corpora lutea in the ipsilateral ovary. RESULTS: Fetal resorption zones were demonstrated in 42.9 per cent of the bitches. However, pregnancy continued in 84.9 per cent of cases. Of the fetal losses, 25.9 per cent were determined by counting the number of corpora lutea and viable embryos or fetuses. Young bitches tended to have a higher probability of fetal resorption than adult bitches (P<0.06). The presence of fetal resorption zones was not associated with size or body condition. Transuterine migration of embryos had occurred in 15.8 per cent of the bitches. CLINICAL SIGNIFICANCE: This study demonstrated that embryo resorption is a normal event in the bitches, with a higher prevalence than previously thought.
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.
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.
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.
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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.
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.
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.
PROBLEM: To investigate whether the allograft inflammatory factor-1 (AIF-1) is expressed and plays a role in the reproductive system. METHOD OF STUDY: AIF-1 expression was examined in uteri of non-pregnant and pregnant mice by Northern blot analysis, RT-PCR and immunohistochemistry. RESULTS: The expression of AIF-1 varied during the estrous cycle with a peak at estrus. After the insemination, the expression of AIF-1 mRNA diminished gradually and again increased in the pre-implantation or implantation period in allogeneic or syngeneic pregnancy, respectively. Enhanced expressions of AIF-1, tumor necrosis factor-alpha (TNF-alpha) and nitric oxide synthase 2 (NOS2) mRNA were observed in the embryos of resorption-prone pregnancy injected with poly(I:C). CONCLUSIONS: This study demonstrated for the first time that AIF-1 was expressed in uterus. The expression level was associated with the population size of macrophage and varied during the estrous cycle and the pregnancy period. The augmented expression of AIF-I with concomitant expressions of TNF-alpha and NOS2 mRNA in poly(I:C)-injected mice suggests a correlation between AIF-1 production and 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.
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)
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.
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