bromochloroacetic-acid and Fetal-Growth-Retardation

Restrictive dermopathy (RD) is a lethal autosomal recessive genodermatosis (MIM No. 275210) in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence (FADS). Polyhydramnios with reduced fetal movements is followed by premature delivery at around 31 weeks gestation. Manifestations include a tightly adherent, thin, translucent skin with prominent vessels, typical facial changes, generalized joint contractures, enlarged fontanelles, dysplasia of clavicles, respiratory insufficiency, and an enlarged placenta with short umbilical cord. Histologic abnormalities of the skin include thin dermis with paucity and hypoplasia of the appendages and abnormally arranged collagen bundles. Elastic fibers are nearly missing. The subcutaneous fat is slightly increased. These skin findings usually appear after 22 or 24 weeks of gestation, which is why prenatal diagnosis with skin biopsy may fail. This disease is easily differentiated from other congenital FADS, such as Pena-Shokeir syndrome, COFS syndrome, Parana hard-skin syndrome, etc. We report on an affected boy of consanguineous parents and 30 previous cases are reviewed.

Topics: Calcification, Physiologic; Chromosome Inversion; Chromosomes, Human, Pair 9; Collagen; Contracture; Fatal Outcome; Female; Fetal Growth Retardation; Genes, Recessive; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Karyotyping; Keratins; Kyphosis; Male; Natal Teeth; Pregnancy; Skin Diseases; Syndrome

What is the impact of chronic hypertension on placental development, fetal growth and maternal outcome in the stroke-prone spontaneously hypertensive rat (SHRSP)?. SHRSP showed an impaired remodeling of the spiral arteries and abnormal pattern of trophoblast invasion during placentation, which were associated with subsequent maternal glomerular injury and increased baseline hypertension as well as placental insufficiency and asymmetric fetal growth restriction (FGR).. A hallmark in the pathogenesis of preeclampsia (PE) is abnormal placentation with defective remodeling of the spiral arteries preceding the onset of the maternal syndrome. Pregnancies affected by chronic hypertension display an increased risk for PE, often associated with poor maternal and fetal outcomes. However, the impact of chronic hypertension on the placentation process as well as the nature of the factors promoting the development of PE in pregnant hypertensive women remain elusive.. Timed pregnancies [n = 5] were established by mating 10-12-week-old SHRSP and Wistar Kyoto (WKY, normotensive controls) females with congenic males. Maternal systolic blood pressures (SBPs) were recorded pre-mating, throughout pregnancy (GD1-19) and post-partum by the tail-cuff method. On selected dates, 24 h urine- and blood samples were collected, and animals were euthanized for isolation of implantation sites and kidneys for morphometrical analyses.. The 24 h proteinuria and the albumin:creatinine ratio were used for evaluation of maternal renal function. Renal injury was assessed on periodic acid Schiff, Masson's trichrome and Sirius red stainings. Placental and fetal weights were recorded on gestation day (GD)18 and GD20, followed by determination of fetal cephalization indexes and developmental stage, according to the Witschi scale. Morphometric analyses of placental development were conducted on hematoxylin-eosin stained tissue sections collected on GD14 and GD18, and complemented with immunohistochemical evaluation of isolectin B4 binding for assessment of placental vascularization. Analyses of vascular wall alpha actin content, perforin-positive natural killer (NK) cells and cytokeratin expression by immunohistochemistry were used for evaluation of spiral artery remodeling and trophoblast invasion.. SHRSP females presented significantly increased SBP records from GD13 to GD17 (SBPGD13 = 183.9 ± 3.9 mmHg, P < 0.005 versus baseline) and increased proteinuria at GD18 (P < 0.01 versus WKY). Histological examination of GD18 kidneys revealed glomerular enlargement and mesangial matrix expansion, which were not evident in pregnant WKY or age-matched virgin SHRSP. At GD20, SHRSP displayed a significant reduction of placental mass (P < 0.01 versus WKY) and signs of placental insufficiency (i.e. hypertrophy and reduced branching morphogenesis of the labyrinth layer), associated with decreased offspring weights and increased cephalization index (both P < 0.001 versus WKY) indicating asymmetric FGR. Notably, SHRSP placentas displayed an incomplete remodeling of spiral arteries starting as early as GD14, with luminal narrowing and reduced densities of perivascular NK cells followed by decreased infiltration of endovascular trophoblasts at GD18.. n/a.. A pitfall of the present study is the differences in the blood pressure profiles between rats and humans (i.e. unlike pregnancies affected by PE, blood pressure in SHRSP and other hypertensive rat models decreases pre-delivery), which limits extrapolation of the results.. Our findings provide new insights on the role of chronic hypertension as a risk factor for PE by interfering with early events during the placentation process. The SHRSP strain represents an attractive model for further studies aimed at addressing the relative contribution of intrinsic (i.e. placental) and extrinsic (i.e. decidual/vascular) factors to defective spiral artery remodeling in pregnancies affected by PE.. This work was supported by research grants from Fundación Florencio Fiorini to G.B., from Charité Stiftung to S.M.B. and University of Buenos Aires (UBACyt) to J.T. The authors have no competing interests to declare.

Topics: Actins; Animals; Biomarkers; Decidua; Female; Fetal Growth Retardation; Fetus; Gene Expression; Keratins; Kidney; Placentation; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Trophoblasts; Uterine Artery; Vascular Remodeling

We previously reported a diminished expression of the heme-degrading enzymes heme oxygenases (HO)-1 and HO-2 in decidua and placenta from mice undergoing Th1-mediated abortion, strongly indicating the protective effect of HO in murine pregnancy maintenance. Here we investigated whether the expression of HO-1 and HO-2 is also reduced at the feto-maternal interface of pathologic human pregnancies.. Immunohistochemistry was used to detect HOs expression in placental and decidual first-trimester tissue from patients with: spontaneous abortion (n = 14), choriocarcinoma (n = 14), hydatidiform mole (H-mole) (n = 12), compared with normally progressing pregnancies (n = 15). Further, we investigated early third-trimester decidual and placental tissue from patients with pre-eclampsia (n = 13) compared with fetal growth retardation (n = 14) as age-matched controls.. In first trimester tissue, we observed a significant reduction of HO-2 expression in invasive trophoblast cells, endothelial cells, and syncytiotrophoblasts in samples from patients with spontaneous abortion compared with normal pregnancy. H-mole samples showed a diminished expression of HO-2 in invasive trophoblast cells and endothelial cells in comparison with NP, whereas choriocarcinoma samples showed no significant differences compared with the control. In third trimester tissue, HO-2 was also reduced in syncytiotrophoblasts and invasive trophoblast cells from pre-eclampsia compared with samples from fetal growth retardation. HO-1 expression was diminished in all pathologies investigated; however, the differences did not reach levels of significance.. Our data indicate that HOs play a crucial role in pregnancy and low expression of HO-2, as observed in pathologic pregnancies, may lead to enhanced levels of free heme at the feto-maternal interface, with subsequent upregulation of adhesion molecules, allowing enhanced inflammatory cells migration to the feto-maternal interface.

Topics: Abortion, Spontaneous; Adult; Choriocarcinoma; Decidua; Down-Regulation; Endothelial Cells; Female; Fetal Growth Retardation; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Hydatidiform Mole; Immunohistochemistry; Keratins; Membrane Proteins; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Trophoblasts

In this study we tested the hypothesis that expression of heme oxygenases HO-1 and HO-2, which are responsible for the production of carbon monoxide, are reduced in the placenta and placental bed of pregnancies complicated by preeclampsia (PE) and fetal growth restriction (FGR) compared with control third-trimester pregnancies. Placental protein expression was determined by Western blotting (n=10 in each group) and immunohistochemistry (controls n=18, PE n=19, FGR n=10). Extravillous trophoblast expression was determined by immunohistochemistry of placental bed biopsy samples (controls n=17, PE n=19, FGR n=10). Western blot analysis of placental homogenates showed no overall differences in HO-2 among groups. However, immunohistochemical analysis showed a reduction in HO-2 expression in endothelial cells in both abnormal groups (PE P<0.01; FGR P<0.0005 vs. control group) but no differences in villous trophoblast staining. HO-1 was undetectable by Western blotting in control and abnormal pregnancies and immunoreactivity was very low, suggesting that there is little HO-1 in the placenta. Within the placental bed, HO-2 but not HO-1 was detected on all populations of extravillous trophoblast, but expression of HO-2 or HO-1 did not change in PE or FGR. The reduced expression of HO-2 on endothelial cells in PE and FGR may be responsible for reduced placental blood flow in these conditions. The data do not show changes in HO in the placental bed in PE or FGR.

Topics: Adult; Biopsy; Blotting, Western; Case-Control Studies; Endothelium; Female; Fetal Growth Retardation; Fetus; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Immunohistochemistry; Keratins; Membrane Proteins; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Protein Isoforms

To investigate the expression and biological roles of cytokeratin 19 (K19) in development and in adult tissues, we inactivated the mouse K19 gene (Krt1-19) by inserting a bacterial beta-galactosidase gene (lacZ) by homologous recombination in embryonic stem cells, and established germ line mutant mice. Both heterozygous and homozygous mutant mice were viable, fertile, and appeared normal. By 7.5-8.0 days post coitum (dpc), heterozygous mutant embryos expressed lacZ in the notochordal plate and hindgut diverticulum, reflecting the fact that the notochord and the gut endoderm are derived from the axial mesoderm-originated cells. In the adult mutant, lacZ was expressed mainly in epithelial tissues. To investigate the possible functional cooperation and synergy between K19 and K8, we then constructed compound homozygous mutants, whose embryos died approximately 10 dpc. The lethality resulted from defects in the placenta where both K19 and K8 are normally expressed. As early as 9. 5 dpc, the compound mutant placenta had an excessive number of giant trophoblasts, but lacked proper labyrinthine trophoblast or spongiotrophoblast development, which apparently caused flooding of the maternal blood into the embryonic placenta. These results indicate that K19 and K8 cooperate in ensuring the normal development of placental tissues.

Topics: Animals; Crosses, Genetic; Embryo, Mammalian; Female; Fetal Death; Fetal Growth Retardation; Fluorescent Antibody Technique; Galactosidases; Gene Deletion; Gene Targeting; Genes, Reporter; Genotype; Germ-Line Mutation; In Situ Hybridization; Keratins; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Phenotype; Placenta; Placental Circulation; Pregnancy; Recombination, Genetic; RNA, Messenger; Stem Cells; Trophoblasts

Intrauterine growth retardation (IUGR) due to vascular insufficiency in humans results in newborn infants with marked loss of subcutaneous fat and a poorly characterized "dysmature" appearance of the epidermis. In this study, we examined selected indices of epidermal development in 20 and 21 day old growth retarded fetal rats. IUGR was produced by unilateral ligation of the uterine artery and vein on gestational day 17. Littermate rats from the opposite uterine horn were utilized as pair matched experimental controls. A total of 49 consecutive fetal pairs were examined. Mean body weight (+/- SEM) for controls was 4.2 +/- 0.1 g versus 2.6 +/- 0.2 g for the treatment group on gestational day 20 (n = 74, P less than 0.01) and 6.0 +/- 0.1 versus 4.0 +/- 0.2 g, respectively, on the day 21 (n = 24, P less than 0.01). Examination by light and electron microscopy showed marked diminution in overall epidermal thickness in the growth retarded animals, particularly of the stratum granulosum and stratum corneum. Epidermal DNA content was decreased in IUGR pups on day 20 (0.99 +/- 0.05 versus 1.26 +/- 0.07 micrograms DNA/mg wet weight, P less than 0.05). Soluble epidermal proteins showed a similar reduction in IUGR animals (30.2 + 0.8 versus 34.7 +/- 1.6 micrograms protein/mg wet weight, P less than 0.05). IUGR also decreased the total amount of epidermal protein extractable in 8 M urea. Differentiation-specific epidermal proteins (keratins, filaggrin) were markedly reduced in the growth retarded animals following normalization to epidermal surface area and analysis by polyacrylamide gel electrophoresis. Overall, these changes in the growth retarded fetal rat lead to formation of a thin, hypoplastic, and poorly keratinized epidermal covering.

Topics: Animals; DNA; Epidermis; Female; Fetal Growth Retardation; Filaggrin Proteins; Gestational Age; Keratins; Microscopy, Electron; Pregnancy; Proteins; Rats; Rats, Inbred Strains

The influence of prenatal growth retardation on epidermal growth and keratinization was studied in small-for-dates human babies, runt piglets and in rat fetuses subject to maternal protein deprivation. In the human babies and rat fetuses growth retardation was associated with reduced epidermal growth but normal patterns of differentiation were present. Thus, epidermal thickness was less and keratinizing zones narrower than seen in normal weight individuals. In the runt (small-for-dates) piglet, epidermal development differed from that seen in normal weight piglets of the same gestational age and from that seen in the human and rat. The epidermis was thicker with a negligible stratum granulosum and with the stratum corneum containing nucleated cells, a condition resembling 'parakeratosis'. This pattern was less often seen in normal weight piglets. Differences between the skins of the three speecies studied at a perinatal stage may be related to clear dissimilarities which exist in the tissues later. Parakeratosis as a transitory phase in the development of pig skin is probably related to a higher rate of epidermal keratinization in this species than occurs in either human babies or rat fetuses.

Topics: Animals; Cell Differentiation; Dietary Proteins; Epidermal Cells; Epidermis; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Keratins; Pregnancy; Rats; Skin; Swine