Endocrine biomarkers of early fetal loss in cynomolgus macaques (Macaca fascicularis) following exposure to dioxin.
This study examines the endocrine alterations associated with early fetal loss (EFL) induced by an environmental toxin, TCDD (2,3,7, 8-tetrachlorodibenzo-p-dioxin), in the cynomolgus macaque, a well-documented reproductive/developmental model for humans. Females were administered single doses of 1, 2, and 4 microgram/kg TCDD (n = 4 per dose group) on gestational day (GD) 12. Urinary estrogen metabolites (estrone conjugates) were monitored to establish the day of ovulation, and serum hormones (estradiol, progesterone, chorionic gonadotropin, relaxin) were measured to assess ovarian and placental endocrine status before and after treatment. EFL occurred between GDs 22 and 32 in 10 of the 12 animals treated with TCDD. The primary endocrine alterations associated with TCDD treatment were significant decreases in serum estradiol and bioactive chorionic gonadotropin concentrations (p < 0.02). Less pronounced decreases in serum progesterone (p = 0.10) and relaxin (p < 0.08) also followed TCDD treatment. In contrast, immunoreactive chorionic gonadotropin concentrations were not reduced by TCDD exposure at any level, indicating that TCDD targets specific components of the chorionic gonadotropin synthesis machinery within the trophoblast to alter the functional capacity of the hormone. These data demonstrate the value of endocrine biomarkers in identifying a toxic exposure to primate pregnancy many days before direct signs of reproductive toxicity were apparent. The increased EFL that occurred after exposure to TCDD might reflect a toxic response initially mediated via endocrine imbalance, leading to placental insufficiency, compromised embryonic circulation, and subsequent EFL. (+info
Early embryonic death of mice deficient in gamma-adaptin.
Intracellular protein transport and sorting by vesicles in the secretory and endocytic pathways requires the formation of a protein coat on the membrane. The heterotetrameric adaptor protein complex 1 (AP-1) promotes the formation of clathrin-coated vesicles at the trans-Golgi network. AP-1 interacts with various sorting signals in the cytoplasmic tails of cargo molecules, thus indicating a function in protein sorting. We generated mutants of the gamma-adaptin subunit of AP-1 in mice to investigate its role in post-Golgi vesicle transport and sorting processes. gamma-Adaptin-deficient embryos develop until day 3.5 post coitus and die during the prenidation period, revealing that AP-1 is essential for viability. In heterozygous mice the amount of AP-1 complexes is reduced to half of controls. Free beta1- or micro1 chains were not detectable, indicating that they are unstable unless they are part of AP-1 complexes. Heterozygous mice weigh less then their wild-type littermates and show impaired T cell development. (+info
Rac1 is required for the formation of three germ layers during gastrulation.
The Rac1, a member of the Rho family proteins, regulates actin organization of cytoskeleton and cell adhesion. We used genetic analysis to elucidate the role of Rac1 in mouse embryonic development. The rac1 deficient embryos showed numerous cell deaths in the space between the embryonic ectoderm and endoderm at the primitive streak stage. Investigation of the primary epiblast culture isolated from rac1 deficient embryos indicated that Rac1 is involved in lamellipodia formation, cell adhesion and cell migration in vivo. These results suggest that Rac1-mediated cell adhesion is essential for the formation of three germ layers during gastrulation. (+info
Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality.
Mice lacking the RelA (p65) subunit of NF-kappaB die between days 14 and 15 of embryogenesis because of massive liver destruction. Fibroblasts and macrophages isolated from relA-/- embryos were found to be highly sensitive to tumor necrosis factor (TNF) cytotoxicity, raising the possibility that endogenous TNF is the cause of liver cell apoptosis. To test this idea, we generated mice lacking both TNF and RelA. Embryogenesis proceeds normally in such mice, and TNF/RelA double-deficient mice are viable and have normal livers. Thus, the RelA-mediated antiapoptotic signal that protects normal cells from TNF injury in vitro can be shown to be operative in vivo. (+info
Pregnancy in patients after valve replacement.
This report is based on information obtained from a questionnaire sent to major cardiac centres in the United Kingdom. This produced details of 39 pregnancies in 34 patients after valve replacement. The 39 pregnancies gave rise to 30 healthy babies. The small size of the series probably reflects both the increasing rarity of young women with rheumatic heart disease in this country and the cautious attitude of their cardiologists. This makes it likely that these women represented the best end of the spectrum of cardiac function after valve replacement. Twenty-four pregnancies in 20 women who were not given anticoagulants producted 23 healthy babies and 1 spontaneous abortion. This group comprised 6 patients with free aortic homografts, 1 patient with a fascia lata mitral valve, 1 with a Beall tricuspid prosthesis, 1 with a combined mitral homograft and Starr Edwards aortic prosthesis, and 1 with mitral and aortic frame-mounted fascia lata valves. There were no maternal deaths or thromboembolic complications in this group which included 5 patients who were in atrial fibrillation. Fifteen pregnancies in 14 women who received anticoagulants gave rise to 7 healthy babies. The fetal losses were one stillbirth, one intrauterine death at 34 weeks, and 3 spontaneous abortions; one surviving child has hydrocephalus as a result of blood clot and there were 2 maternal deaths. This group included 13 patients with Starr Edwards valves, 11 mitral and 2 aortic. A patient with a Hammersmith mitral valve was the only one to have been treated with heparin and her valve thrombosed. One patient with a mounted mitral homograft had a cerebral embolus. Nine of these patients were in atrial fibrillation. In 3 additional patients the valve replacement was carried out during pregnancy. Two of the patients survived operation. In one of these who was treated with warfarin the pregnancy well, but there is an increased fetal wastage in patients pregnancy gave rise to a congenitally malformed baby who died in the neonatal period. The baby born to the mother who did not receive anticoagulants has a hare-lip and talipes. Women with artificial valves can tolerate the haemodynamic load of pregnancy well, but there is an increased fetal wastage in patients taking oral anticoagulants. This is probably largely attributable to fetal haemorrhage but there is also a risk of malformation caused by a teratogenic effect of warfarin. Experience gained in non-pregnant patients suggests that withholding anticoagulatns in pregnant patients with prosthetic valves would usually be undersirable but warfarin should be avoided. The advantages of biological valves were apparent in this series. (+info
Uterine artery embolization--a successful treatment to control bleeding cervical pregnancy with a simultaneous intrauterine gestation.
A case of a woman suffering from a bleeding heterotopic cervical pregnancy is described. The concurrent cervical pregnancy and intrauterine gestation were diagnosed by ultrasound and bleeding was initially controlled with selective fluoroscopic uterine artery embolization. A selective fetal reduction was done with ultrasound-guided intracardiac potassium chloride. Uterine artery embolization has been used successfully to control haemorrhage in cervical pregnancies when the main goal was to allow preservation of the uterus, thus maintaining potential fertility. This is the first report of arterial embolization used to control bleeding for maintaining a concurrent intrauterine heterotopic pregnancy in an in-vitro fertilization patient. Unfortunately, subsequent conservative measures led to undesired outcome. This procedure initially controlled the bleeding without disrupting the intrauterine fetal cardiac activity. (+info
Maternal diabetes mellitus and congenital malformation. Survey of 205 cases.
Twenty-five out of 205 (i.e. 12%) babies born to diabetic mothers in the Birmingham Maternity Hospital in the period 1969-1974 were malformed as against 6% in a control group. The incidence was highest in the group where mothers were on insulin at the time of conception (17 out of 117, i.e. 15%). No correlation was observed between major malformation in this group and age of onset or duration of the diabetes, progressive vascular complications, maternal age, or parity. Cardiovascular malformations were over-represented. (+info
Consanguinity and recurrence risk of stillbirth and infant death.
OBJECTIVES: The aim of this study was to estimate the recurrence risk for stillbirth and infant death and compare results for offspring of first-cousin parents with results for offspring of unrelated parents. METHODS: The study population consisted of all single births with a previous sibling born in Norway between 1967 and 1994. Altogether, 629,888 births were to unrelated parents, and 3466 births were to parents who were first cousins. The risk of stillbirth and infant death was estimated for subsequent siblings contingent on parental consanguinity and survival of the previous sibling. RESULTS: For unrelated parents, the risk of early death (stillbirth plus infant death) for the subsequent sibling was 17 of 1000 if the previous child survived and 67 of 1000 if the previous child died before 1 year of age. For parents who were first cousins, the risk of early death for the subsequent sibling was 29 of 1000 if the previous child survived and 116 of 1000 if the previous child died. CONCLUSIONS: The risk of recurrence of stillbirth and infant death is higher for offspring of first-cousin parents compared with offspring of unrelated parents. (+info