scispace - formally typeset
Search or ask a question

Showing papers on "Fetus published in 1997"


Journal ArticleDOI
27 Feb 1997-Nature
TL;DR: The birth of lambs from differentiated fetal and adult cells confirms that differentiation of that cell did not involve the irreversible modification of genetic material required for development to term and reinforces previous speculation that by inducing donor cells to become quiescent it will be possible to obtain normal development from a wide variety of differentiated cells.
Abstract: Fertilization of mammalian eggs is followed by successive cell divisions and progressive differentiation, first into the early embryo and subsequently into all of the cell types that make up the adult animal. Transfer of a single nucleus at a specific stage of development, to an enucleated unfertilized egg, provided an opportunity to investigate whether cellular differentiation to that stage involved irreversible genetic modification. The first offspring to develop from a differentiated cell were born after nuclear transfer from an embryo-derived cell line that had been induced to become quiescent. Using the same procedure, we now report the birth of live lambs from three new cell populations established from adult mammary gland, fetus and embryo. The fact that a lamb was derived from an adult cell confirms that differentiation of that cell did not involve the irreversible modification of genetic material required for development to term. The birth of lambs from differentiated fetal and adult cells also reinforces previous speculation that by inducing donor cells to become quiescent it will be possible to obtain normal development from a wide variety of differentiated cells.

4,721 citations


Journal ArticleDOI
TL;DR: Unifying models postulate how proinflammatory cytokines might lead to IVH and neonatal white matter damage during prenatal maternal infection and intervene to prevent later disability in those born near the end of the second trimester.
Abstract: To evaluate the hypothesis that the proinflammatory cytokines IL-1, IL-6, and tumor necrosis factor-alpha might be the link between prenatal intrauterine infection (IUI) and neonatal brain damage, the authors review the relevant epidemiologic and cytokine literature. Maternal IUI appears to increase the risk of preterm delivery, which in turn is associated with an increased risk of intraventricular hemorrhage, neonatal white matter damage, and subsequent cerebral palsy. IL-1, IL-6, and TNF-alpha have been found associated with IUI, preterm birth, neonatal infections. and neonatal brain damage. Unifying models not only postulate the presence of cytokines in the three relevant maternal/fetal compartments (uterus, fetal circulation, and fetal brain) and the ability of the cytokines to cross boundaries (placenta and blood-brain barrier) between these compartments, but also postulate how proinflammatory cytokines might lead to IVH and neonatal white matter damage during prenatal maternal infection. Interrupting the proinflammatory cytokine cascade might prevent later disability in those born near the end of the second trimester.

876 citations


Journal ArticleDOI
TL;DR: Examination of placental glucocorticoid metabolism in dually perfused freshly isolated intact human placentas found placental 11β‐hydroxysteroid dehydrogenase is unstable in vitro, and enzyme activity thus detected may not be relevant to the proposed barrier role.
Abstract: Objective Placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which converts active cortisol to inactive cortisone, has been proposed to be the mechanism guarding the fetus from the growth retarding effects of maternal glucocorticoids; however, other placental enzymes have also been implicated. Placental 11 beta-HSD is unstable in vitro, and enzyme activity thus detected may not be relevant to the proposed barrier role. We have therefore examined placental glucocorticoid metabolism in dually perfused freshly isolated intact human placentas. Design Placentas were obtained from randomly selected normal term deliveries. The maternal circuit was perfused with physiological concentration of cortisol, the fetal effluent collected and steroid metabolites separated and quantified using silica columns (Sep-pak Plus) and HPLC. Results Most of the maternally administered cortisol was metabolized to cortisone, and no conversion of cortisone to cortisol was detected. Cortisone was the only product of cortisol metabolism. Inhibition of 11 beta-HSD with glycyrrhetinic acid allowed cortisol to gain direct access to the fetal circulation. Conclusion We conclude that human placental 11 beta-HSD plays a crucial role in controlling glucocorticoid access to the fetus. Other enzymes are not significant contributors at physiologically relevant cortisol concentrations.

547 citations


Journal ArticleDOI
TL;DR: Data supports the assumption that CYP3A4 expression is transcriptionally activated during the first week after birth and is accompanied by a simultaneous decrease of CYP2A7 expression, in such a way that the overall CYP 3A protein content and the level of pentoxyresorufin dealkylase catalyzed by the two proteins remain nearly constant.
Abstract: CYP3A isoforms are responsible for the biotransformation of a wide variety of exogenous chemicals and endogenous steroids in human tissues. Two members of the CYP3A subfamily display developmentally regulated expression in the liver; CYP3A7 is expressed in the fetal liver, whereas CYP3A4 is the major cyrochrome P-450 isoform present in the adult liver. To gain insight into the descriptive ontogenesis of CYP3A isoforms during the neonatal period, we have developed several approaches to explore a neonatal liver bank. Although CYP3A4 and CYP3A7 are structurally closely related, they differ in their capacity to carry out monooxygenase reactions. We have cloned CYP3A4 and CYP3A7 and established stable transfectants in Ad293 cells to investigate their substrate specificities. The 16alpha hydroxylation of dehydroepiandrosterone is catalyzed by both proteins, but CYP3A7 has a higher affinity and maximal velocity than CYP3A4. Conversely, the conversion of testosterone into its 6beta derivative is essentially supported by CYP3A4. We used these two probes to determine the ontogenic evolution at the protein level; CYP3A7 was very active in the fetal liver and its activity was maximal during the first week following birth before to progressively decline and reached a very low level in adult livers. Conversely, the activity of CYP3A4 was extremely weak in the fetus and began to raise after birth to reach 30-40% of the adult activity after one month. CYP3A4 RNA accumulation displays a similar pattern of evolution; when probed with an oligonucleotide, its concentration increased rapidly after birth to reach a plateau as soon as the first week of age. These data supports the assumption that CYP3A4 expression is transcriptionally activated during the first week after birth and is accompanied by a simultaneous decrease of CYP3A7 expression, in such a way that the overall CYP3A protein content and the level of pentoxyresorufin dealkylase catalyzed by the two proteins remain nearly constant.

514 citations


01 Jan 1997
TL;DR: In this article, the distribution of mR-NAs encoding leptin and the leptin receptor (which has at least six splice variants) in the 14.5-day postcoitus mouse fetus and in the placenta using reverse transcription-PCR and in situ hybridization.
Abstract: Leptin is a 167-aa protein that is secreted from adipose tissue and is important in the regulation of energy balance. It also functions in hematopoiesis and repro- duction. To assess whether leptin is involved in fetal growth and development we have examined the distribution of mR- NAs encoding leptin and the leptin receptor (which has at least six splice variants) in the 14.5-day postcoitus mouse fetus and in the placenta using reverse transcription-PCR and in situ hybridization. High levels of gene expression for leptin, the leptin receptor, and the long splice variant of the leptin receptor with an intracellular signaling domain were observed in the placenta, fetal cartilageybone, and hair follicles. Re- ceptor expression also was detected in the lung, as well as the leptomeninges and choroid plexus of the fetal brain. Western blotting and immunocytochemistry, using specific antibodies, demonstrated the presence of leptin and leptin receptor protein in these tissues. These results suggest that leptin may play a role in the growth and development of the fetus, both through placental and fetal expression of the leptin and leptin receptor genes. In the fetus, leptin may be multifunctional and have both paracrine and endocrine effects.

475 citations


Journal ArticleDOI
TL;DR: The results suggest that leptin may play a role in the growth and development of the fetus, both through placental and fetal expression of the leptin and leptin receptor genes, which may be multifunctional and have both paracrine and endocrine effects.
Abstract: Leptin is a 167-aa protein that is secreted from adipose tissue and is important in the regulation of energy balance. It also functions in hematopoiesis and reproduction. To assess whether leptin is involved in fetal growth and development we have examined the distribution of mRNAs encoding leptin and the leptin receptor (which has at least six splice variants) in the 14.5-day postcoitus mouse fetus and in the placenta using reverse transcription–PCR and in situ hybridization. High levels of gene expression for leptin, the leptin receptor, and the long splice variant of the leptin receptor with an intracellular signaling domain were observed in the placenta, fetal cartilage/bone, and hair follicles. Receptor expression also was detected in the lung, as well as the leptomeninges and choroid plexus of the fetal brain. Western blotting and immunocytochemistry, using specific antibodies, demonstrated the presence of leptin and leptin receptor protein in these tissues. These results suggest that leptin may play a role in the growth and development of the fetus, both through placental and fetal expression of the leptin and leptin receptor genes. In the fetus, leptin may be multifunctional and have both paracrine and endocrine effects.

465 citations


Journal ArticleDOI
TL;DR: The sixfold elevation of fetal cells observed in maternal blood when the fetus had trisomy 21 indicates that noninvasive cytogenetic diagnosis of trisomally normal fetuses should be feasible and feto-maternal transfusion of nucleated cells appears to be influenced by fetal karyotype.
Abstract: Fetal cells in maternal blood are a noninvasive source of fetal genetic material for prenatal diagnosis. We determined the number of fetal-cell DNA equivalents present in maternal whole-blood samples to deduce whether this number is affected by fetal karyotype. Peripheral blood samples were obtained from 199 women carrying chromosomally normal fetuses and from 31 women with male aneuploid fetuses. Male fetal-cell DNA-equivalent quantitation was determined by PCR amplification of a Y chromosome-specific sequence and was compared with PCR product amplified from known concentrations of male DNA run simultaneously. The mean number of male fetal-cell DNA equivalents detected in 16-ml blood samples from 90 women bearing a 46,XY fetus was 19 (range 0-91). The mean number of male fetal-cell DNA equivalents detected in 109 women bearing a 46,XX fetus was 2 (range 0-24). The mean number of male fetal-cell DNA equivalents detected when the fetus was male compared with when the fetus was female was highly significant (P = .0001). More fetal cells were detected in maternal blood when the fetus was aneuploid. The mean number of male fetal-cell DNA equivalents detected when the fetal karyotype was 47,XY,+21 was 110 (range 0.1-650), which was significantly higher than the number of male fetal-cell DNA equivalents detected in 46,XY fetuses (P = .0001). Feto-maternal transfusion of nucleated cells appears to be influenced by fetal karyotype. The sixfold elevation of fetal cells observed in maternal blood when the fetus had trisomy 21 indicates that noninvasive cytogenetic diagnosis of trisomy 21 should be feasible.

398 citations


Journal ArticleDOI
TL;DR: Leptin levels are high in the fetus and in the mother at term, and it is hypothesized that high leptin levels could represent an important feed-back modulator of substrate supply and subsequently for adipose tissue status during late gestation.
Abstract: The mechanisms by which maternal and fetal weight are regulated during pregnancy are poorly understood. The ob protein, termed leptin, is produced by adipocytes. It is involved in the regulation of body weight by suppressing appetite and stimulating energy expenditure both in humans and rodents. In this study we examined whether leptin concentrations in the mother and the newborn correlate with birth weight, placental weight, and maternal weight at term. Leptin concentrations were measured in amniotic fluid, venous and arterial cord blood, and maternal serum at birth (n = 27) using a specific RIA employing human recombinant leptin for tracer and standard preparation. Gestational age was 38-42 weeks, maternal age was 21-42 yr, mean maternal weight at birth was 80.0 +/- 10.8 kg, and mean body mass index before pregnancy was 23.4 +/- 2.8 kg/m2. The newborns' mean weight was 3450 +/- 580 g, and mean placental weight was 616 +/- 120 g. Serum leptin levels from nonpregnant women ranged between 1.7-18.4 ng/mL, median 5.5 ng/ml (n = 30). Mean leptin concentration in maternal serum at birth was 20.0 +/- 13.2 ng/mL and was higher (P < 0.002) than in arterial cord blood (9.7 +/- 9.4 ng/mL) and venous cord blood (8.9 +/- 8.6 ng/mL). Mean amniotic fluid leptin concentration was 3.6 +/- 2.8 ng/mL. Placental weight correlated inversely with leptin levels in maternal serum at birth (r = -0.49, P < 0.01). In addition, leptin concentrations in venous cord blood correlated significantly with the levels in arterial cord blood (r = 0.98, P < 0.0001), and leptin levels in cord blood correlated positively with birth weight (r = 0.57, P = 0.03) and placental weight (r = 0.50, P < 0.01). In contrast, there was no correlation between maternal serum leptin levels and birth weight. Thus, leptin levels are high in the fetus and in the mother at term. We hypothesize that high leptin levels could represent an important feed-back modulator of substrate supply and subsequently for adipose tissue status during late gestation.

356 citations


Journal ArticleDOI
TL;DR: The study shows that the expression profile of the two ERs is different, and ER-beta is expressed in a variety of tissues during human fetal development, suggesting different, organ-specific roles for the two receptors.
Abstract: We compared the expression profiles of the mRNAs of both estrogen receptors, ER-alpha and the recently cloned ER-beta, in the midgestational human fetus by semiquantitative RT-PCR. ER-alpha was most abundant in the uterus, and smaller quantities were detected in the ovary, testis, skin and gut. High amounts of ER-beta mRNA were present in fetal ovaries, testes, adrenals and spleen. In these tissues, the levels of ER-beta mRNA were higher than ER-alpha. In the uterus, however, ER-alpha mRNA was more abundant, and ER-beta mRNA was expressed only moderately. ER-beta mRNA was present at moderate to low levels in the thymus, pituitary gland, skin, lung, kidney and brain cortex. In the course of our work, using the ER-beta primers on genomic DNA, an intron of 2468 bp in length, located between nt 222 and 223 in the A/B domain of ER-beta cDNA, was detected, cloned and sequenced. The study shows that the expression profile of the two ERs is different, and ER-beta is expressed in a variety of tissues during human fetal development, suggesting different, organ-specific roles for the two receptors.

340 citations


Journal ArticleDOI
06 Nov 1997-Nature
TL;DR: It is shown that morphological changes resulting in closure of theDA in mice are virtually identical to those observed in larger mammals, including humans, and that maintenance of the DA in the open, or patent, state in fetal mice is dependent on prostaglandin synthesis.
Abstract: Survival of newborn placental mammals depends on closure of the ductus arteriosus (DA), an arterial connection in the fetus which directs blood away from the pulmonary circulation and towards the placenta where oxygenation occurs1. Here we show that morphological changes resulting in closure of the DA in mice are virtually identical to those observed in larger mammals, including humans2, and that maintenance of the DA in the open, or patent, state in fetal mice is dependent on prostaglandin synthesis. This requirement is absent in mice lacking the prostaglandin E2 EP4 receptor (EP4(−/−) mice). In EP4(−/−) mice of the 129 strain, remodelling of the DA fails to occur after birth, resulting in a left-to-right shunt of blood and subsequently in death. This suggests that the neonatal drop in prostaglandin E2 (refs 3,4,5,6,7) that triggers ductal closure is sensed through the EP4 receptor. In contrast, 5% of EP4(−/−) mice of mixed genetic background survive, and selective breeding of these mice leads to a 21% survival rate, suggesting that alleles at other loci can provide an alternative mechanism for ductal closure.

332 citations


Journal ArticleDOI
01 Jan 1997-Steroids
TL;DR: Feto-placental 11 beta-HSD2, by regulating fetal exposure to maternal glucocorticoids, crucially determines fetal growth and the programming of later disorders.

Journal ArticleDOI
TL;DR: It is indicated that E2 beta acutely stimulates eNOS activity in fetal PAEC via the activation of endothelial ER and increases in intracellular Ca2+.
Abstract: Estrogen (E) has nitric oxide (NO)-mediated effects in certain vascular beds, and fetal E levels rise acutely with parturition, suggesting that E may be involved in NO-mediated pulmonary vasodilati...

Journal ArticleDOI
TL;DR: Estrogen upregulates eNOS gene expression in fetal PAECs through the activation of PAEC estrogen receptors, thereby optimizing the capacity for NO-mediated pulmonary vasodilation at birth.
Abstract: NO, produced by endothelial NO synthase (eNOS), is a key mediator of pulmonary vasodilation during cardiopulmonary transition at birth. The capacity for NO production is maximal at term because pulmonary eNOS expression increases during late gestation. Since fetal estrogen levels rise markedly during late gestation and there is indirect evidence that the hormone enhances nonpulmonary NO production in adults, estrogen may upregulate eNOS in fetal pulmonary artery endothelium. Therefore, we studied the direct effects of estrogen on eNOS expression in ovine fetal pulmonary artery endothelial cells (PAECs). Estradiol-17beta caused a 2.5-fold increase in NOS enzymatic activity in PAEC lysates. This effect was evident after 48 hours, and it occurred in response to physiological concentrations of the hormone (10(-10) to 10(-6) mol/L). The increase in NOS activity was related to an upregulation in eNOS protein expression, and eNOS mRNA abundance was also enhanced. Estrogen receptor antagonism with ICI 182,780 completely inhibited estrogen-mediated eNOS upregulation, indicating that estrogen receptor activation is necessary for this response. In addition, immunocytochemistry revealed that fetal PAECs express estrogen receptor protein. Furthermore, transient transfection assays with a specific estrogen-responsive reporter system have demonstrated that the endothelial estrogen receptor is capable of estrogen-induced transcriptional transactivation. Thus, estrogen upregulates eNOS gene expression in fetal PAECs through the activation of PAEC estrogen receptors. This mechanism may be responsible for pulmonary eNOS upregulation during late gestation, thereby optimizing the capacity for NO-mediated pulmonary vasodilation at birth.

Journal ArticleDOI
TL;DR: Repetitive 7-d interval exposures of fetal lambs to glucocorticoids progressively enhanced postnatal lung function and resulted in growth and endocrine abnormalities.
Abstract: We evaluated the effects of multiple fetal exposures to glucocorticoids on postnatal lung function and growth. Ewes were randomized to receive 1 to 4 doses of 0.5 mg/kg betamethasone or saline placebo at 7 d intervals from 104 d to 118 d and at 124 d gestation. All lambs were delivered preterm at 125 d gestation, and postnatal lung function was evaluated. There were sequential improvements in compliance, ventilation efficiency, and lung volumes for two, three, and four doses of betamethasone. The maximal effect was a 150% increase in compliance and a 4-fold increase in lung volume after fetal exposure to four doses of betamethasone. However, birth weights decreased (15% after one dose, 19% after two doses, and 27% after three and four doses). There were no changes in lung to body weight ratios, lung dry to wet weight ratios, lung protein to body weight ratios, or lung hyaluronan content. Prenatal glucocorticoid exposure also altered postnatal cortisol, thyroid, and catecholamine plasma levels. Repetitive 7-d interval exposures of fetal lambs to glucocorticoids progressively enhanced postnatal lung function and resulted in growth and endocrine abnormalities.

Journal Article
TL;DR: Observations are consistent with the idea that FasL at the maternal-fetal interface protects the placenta against a maternal leukocytic influx that reduces fertility.
Abstract: Despite intimate juxtaposition of maternal and fetal tissues during mammalian pregnancy, reciprocal migration of cells is limited. To evaluate the postulate that cell traffic is restricted by expression of Fas ligand (FasL) in the uterus and placenta, FasL mRNA was identified by using reverse transcription-PCR, and FasL protein was identified by Western blotting and immunohistology. FasL mRNA and protein were detected at all stages tested (gestation days (g.d.) 6-18). At g.d. 6 to 10, immunoreactive FasL was prominent in glandular epithelial cells and decidual cells. Between g.d. 12 and 14, expression shifted to placental trophoblast cells bordering maternal blood spaces and fetal placental endothelial cells. Thus, FasL is appropriately positioned, first in the uterus and then in the placenta, to deter trafficking of activated Fas+ immune cells between the mother and the fetus. To test whether the absence of functional FasL affects pregnancy, uteroplacental units from homozygous matings of gld mice, a mutant strain lacking functional FasL, were examined. Extensive leukocytic infiltrates and necrosis at the decidual-placental interface were observed from day 10 onward, resorption sites were common, and small litters were delivered by gld mice. These observations are consistent with the idea that FasL at the maternal-fetal interface protects the placenta against a maternal leukocytic influx that reduces fertility.

Journal ArticleDOI
TL;DR: Minimally invasive fetal surgery appears to constitute a feasible approach to nonlethal fetal malformations that result in progressive and disabling organ damage.

Journal ArticleDOI
TL;DR: These studies are the first to suggest a vital role for large granulated lymphocytes in the promotion of fetal survival and pregnancy success in mice that carried immune-competent fetuses to term.
Abstract: Strategies of cell depletion were pursued to extend understanding of the functions of natural killer (NK) cell-like large granulated lymphocytes found in the rodent uterus during pregnancy. Repeated infusions of antibody to Ly-49G2, a surface marker thought to be expressed by the progenitor forms of these cells, removed Ly-49G2+ cells from the virgin but not the pregnant uterus. Large granulated uterine lymphocytes also differentiated during pregnancy in transgenic mice that carried a deletion in the IL-2 gene. This cell population was absent in two strains of mice, p56lck-/lck-.IL-2Rbeta-/IL-2Rbeta- and TgE26. Implantation sites in both of these strains had histopathological anomalies in the zone of decidualization. In TgE26 mice, a sudden onset of fetal loss began at Day 10 of gestation. Fetal death was associated with progressive changes in the maternal uterine arterioles, suggestive of localized arteriosclerosis associated with hypertension. TgE26 females carried immune-competent fetuses to term, apparently through preventive or compensatory mechanisms that may modify the uterine vasculature after the onset of vascular pathology. These studies are the first to suggest a vital role for large granulated lymphocytes in the promotion of fetal survival and pregnancy success.

Journal ArticleDOI
TL;DR: Findings suggest that bone lead might be a better biomarker than blood lead for birth weight, because mobilization of bone lead during pregnancy may pose a significant fetal exposure with health consequences, long after maternal external lead exposure has declined.
Abstract: Objectives Birth weight predicts infant survival, growth, and development. Previous research suggests that low levels of fetal lead exposure, as estimated by umbilical cord blood-lead levels at birth, may have an adverse effect on birth weight. This report examines the relationship of lead levels in cord blood and maternal bone to birth weight. Methods Umbilical cord and maternal venous blood samples and anthropometric and sociodemographic data were obtained at delivery and 1-month postpartum. Blood-lead levels were analyzed by atomic absorption spectrophotometry. Maternal tibia and patella lead levels were determined at 1-month postpartum with use of a spot-source 109Cd K-X-ray fluorescence instrument. The relationship between birth weight and lead burden was evaluated by multiple regression with control of known determinants of size at birth. Results Data on all variables of interest were obtained for 272 mother-infant pairs. After adjustment for other determinants of birth weight, tibia lead was the only lead biomarker clearly related to birth weight. The decline in birth weight associated to increments in tibia lead was nonlinear and accelerated at the highest tibia lead quartile. In the upper quartile, neonates were on average, 156 grams lighter than those in the lowest quartile. Other significant birth weight predictors included maternal nutritional status, parity, education, gestational age, and smoking during pregnancy. Conclusions Our results indicate that bone-lead burden is inversely related to birth weight. Taken together with other research indicating that lead can mobilize from bone into plasma without detectable changes in whole blood lead, these findings suggest that bone lead might be a better biomarker than blood lead. Because lead remains in bone for years to decades, mobilization of bone lead during pregnancy may pose a significant fetal exposure with health consequences, long after maternal external lead exposure has declined.

Journal ArticleDOI
TL;DR: There is the possibility that each of the HPA products evaluated, even though correlated (e.g., ACTH and beta E), may be linked to unique and specific outcomes.
Abstract: Preliminary conclusions from our research include the possibility that each of the HPA products evaluated, even though correlated (e.g., ACTH and beta E), may be linked to unique and specific outcomes. Maternal stress during the 28-30 weeks of gestation is associated with birth outcome. Increased levels of psychosocial stress were significantly related to gestational age at birth and infant birth weight. Maternal stress during the third trimester was associated with increased maternal plasma levels of ACTH and cortisol. This finding is consistent with possible mechanisms whereby psychosocial stress influences birth outcome. CRH controls the timing of labor and delivery. Precocious elevation of CRH is related to the risk of preterm delivery. This system may be "stress-sensitive." Even though pregnant women may be immunized from stress, the stress signal that is transmitted (release of ACTH and cortisol) is amplified by the placental release of CRH. This possibility has at least two consequences: (1) influencing the timing of delivery and (2) desensitization of hypophyseal corticotrophs and further "protection" of the pregnant women from the results of stress (i.e., release of ACTH and beta E). Beta E appears to influence fetal learning and perhaps the developing nervous system.

Journal ArticleDOI
TL;DR: Evidence is provided that in addition to the Ah receptor complex, other cell-specific factors modulate the response of CYP1B1 and CyP1A1 to Ah receptor ligands.
Abstract: Expression of the Ah receptor-regulated cytochrome P4501B1 (CYP1B1) gene was studied in human adult and fetal tissues and cells in culture by reverse transcriptase-coupled polymerase chain reaction (RT-PCR). In adults, CYP1B1 mRNA was detected in liver, lymphocytes, cells of bronchoalveolar lavage samples and uterine endometrium, but not in lung. The level of expression was very low in adult liver and only three out of six fetal livers expressed CYP1B1. Extrahepatic fetal tissues, especially brains and kidneys, expressed high levels of CYP1B1. CYP1B1 mRNA was constitutively detected at a low level in first trimester and full-term placental samples. A competitive RT-PCR assay was developed to assess the regulation of CYP1B1. CYP1B1 mRNA was not induced in placenta by maternal cigarette smoking. Inducibility of CYP1B1 in cells in culture by the Ah receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin was studied in primary fibroblasts and chorion carcinoma cell line JEG-3 having different CYP1A1 induction properties. Inducibility of CYP1B1 was found to be regulated independently from CYP1A1. In JEG-3 cells CYP1A1 mRNA was induced up to 9000-fold, while the expression of CYP1B1 was not affected. Expression of Ah receptor and Ah receptor nuclear translocator (regulators of the CYP1 family) was determined in human placenta and in the JEG-3 cell line. Expression of these transcription factors was found neither to be co-regulated nor affected by Ah receptor ligands. This study provides evidence that in addition to the Ah receptor complex, other cell-specific factors modulate the response of CYP1B1 and CYP1A1 to Ah receptor ligands.

Journal ArticleDOI
TL;DR: IL-1 in amniotic fluid in preterm labor may promote lung maturation and thus be part of a host-defense mechanism that prepares the fetus for extrauterine life.
Abstract: Intraamniotic infection is associated with increased IL-1 activity in amniotic fluid, increased incidence of preterm labor, and with decreased incidence of respiratory distress syndrome in infants born prematurely. We hypothesized that an elevated IL-1 in amniotic fluid promotes fetal lung maturation. On day 23 or 25 of gestation (term 31 d), either IL-1alpha (150 or 1,500 ng per fetus) or its antagonist IL-1 receptor antagonist (IL-1ra, 20 microg) was injected to the amniotic fluid sacs in one uterine horn, whereas the contralateral amniotic sacs were injected with vehicle. Within 40 h, IL-1alpha caused a dose-dependent increase in surfactant protein-A (SP-A) and SP-B mRNAs (maximally, fivefold), without affecting lung growth or increasing inflammatory cells in the lung. Both genders, and upper and lower lung lobes were similarly affected. IL-1ra did not modify SP-A, -B, or -C mRNA. IL-1 increased the intensity of staining of alveolar type II cells for SP-B, and the concentrations of SP-B, -A, and disaturated phosphatidylcholine in bronchoalveolar lavage. The dynamic lung compliance and the postventilatory expansion of lungs were increased two- to fourfold after IL-1alpha treatment. In fetal lung explants, IL-1alpha increased the expression of SP-A mRNA. IL-1 in amniotic fluid in preterm labor may promote lung maturation and thus be part of a host-defense mechanism that prepares the fetus for extrauterine life.

Journal ArticleDOI
01 Jun 1997-Diabetes
TL;DR: The findings further corroborate the notion that an imbalance in the metabolism of free oxygen radicals is involved in the embryonic maldevelopment of diabetic pregnancy, and suggest a direction for prophylactic treatment in the future.
Abstract: An association between excess oxygen radical activity and disturbed embryogenesis in diabetic pregnancy has been suggested. In the present study, the protective capacity of vitamin E with different treatment regimens was investigated in early and late pregnancy of streptozotocin-induced diabetic rats. Daily gavaging of 0.2 g/kg or 0.8 g/kg of vitamin E exerted moderate protective effects. In contrast, treatment with a diet enriched with 2% (wt/wt) of vitamin E, yielding an approximate daily dosage of 2 g/kg of vitamin E, clearly restored both embryonic and fetal morphology. High-performance liquid chromatography measurement showed that maternal diabetes decreased embryonic content of vitamin E. When pregnant diabetic animals were supplemented with vitamin E, increased concentrations of the vitamin were found in maternal, embryonic, and fetal tissues. Thus, despite marked accumulation of vitamin E in maternal tissues, the compound apparently reached the conceptus. Thiobarbituric acid reactive substances (TBARS) were estimated as a measure of lipid peroxidation, and no changes were observed in maternal tissue, embryonic tissue, placenta, and fetal brain in the untreated diabetic group. In contrast, a fivefold increase of TBARS was found in fetal liver, a rise that was reduced with vitamin E treatment of the diabetic pregnant rats and completely normalized with 2% vitamin E in the diet. Congenital malformations caused by experimental diabetes can be prevented by antioxidants in vivo. These findings further corroborate the notion that an imbalance in the metabolism of free oxygen radicals is involved in the embryonic maldevelopment of diabetic pregnancy, and suggest a direction for prophylactic treatment in the future.

Journal ArticleDOI
TL;DR: The data suggest that leptin is synthesized in utero, and that the circulating leptin concentration relates to the intrauterine growth pattern.
Abstract: Leptin is an adipocyte-derived peptide hormone regulating energy balance in experimental animals. Although the physiological function of leptin in humans is still unclear, its secretion is closely related to fat mass in adult humans. To examine how fetal growth correlates with leptin levels at birth, an umbilical cord venous blood sample was obtained at the delivery from 50 term newborn infants. Twenty-eight of the newborn infants had birth weights appropriate for gestational age (AGA; mean +/- SEM, 3362 +/- 90 g; relative birth weight, -0.08 +/- 0.2 SD), 9 were large for gestational age (birth weight, 4655 +/- 165 g; relative birth weight, 3.2 +/- 0.3 SD; P < 0.001 vs. AGA newborn infants), and 13 were small for gestational age (SGA; birth weight, 2385 +/- 69 g; relative birth weight, -2.2 +/- 0.08 SD; P < 0.001 vs. AGA newborn infants). Leptin concentrations were higher in large for gestational age (35.7 +/- 8.0 micrograms/L; P < 0.005), but lower in SGA (3.3 +/- 0.5 micrograms/L; P < 0.001) than in AGA infants (14.5 +/- 2.8 micrograms/L). When adjusted for differences in body weight, mean leptin levels were similar in the three newborn groups. Leptin concentration correlated closely with both absolute and relative birth weights (r = 0.71; P < 0.001 in both), with cord blood insulin concentration (r = 0.67; P < 0.001), and with placental weight (r = 0.60; P < 0.001). These data suggest that leptin is synthesized in utero, and that the circulating leptin concentration relates to the intrauterine growth pattern.

Journal ArticleDOI
TL;DR: There is a striking difference in the tissue localization of 11 beta HSD1 and 11beta HSD2 expression in the late gestation human placenta and fetal membranes, which may discretely determine the accessibility of bioactive glucocorticoid to specific cell types.
Abstract: Two isoforms of 11β-hydroxysteroid dehydrogenase (11βHSD) are present in mammals. 11βHSD1 interconverts biologically active cortisol and inactive cortisone, whereas 11βHSD2 only converts cortisol to cortisone. Placental 11βHSD has been proposed to protect the fetus from high level of maternal glucocorticoids. Although bidirectional activity of 11βHSD has been demonstrated in homogenized human placental tissues, the tissue and cellular distribution of 11βHSD1 has not been resolved. In this study, the cellular localization of 11βHSD1 protein and levels of its messenger ribonucleic acid (mRNA) in human placenta and fetal membranes were determined by immunohistochemistry and Northern blot analysis, respectively. We found that 11βHSD1 immunoreactivity was present in the placental extravillous intermediate trophoblasts, chorion trophoblasts, amnion epithelial cells, and stromal cells of the decidua vera. Positive staining was also observed in the endothelium of the blood vessels in both placental villous tissue...

Journal Article
TL;DR: It is found that migrating fetal cells were cleared by the maternal immune system and the mother is not continuously exposed to circulating fetal cells and, in fact, has the capacity to eliminate them without eliminating the fetus.
Abstract: Although female mice readily reject organs from allogeneic or semiallogeneic male donors, they do not reject the fetuses sired by those same donors An explanation for this that has been made in the past is that the fetus influences its mother's immune response by sending fetal cells into the maternal circulation To determine the frequency and magnitude of fetal to maternal cell migration, we employed a sensitive quantitative PCR technique to assess the numbers of male cells in the thymus, spleen, liver, lymph nodes, and peripheral blood of normal mice undergoing their first pregnancy We found that fetal cell migration is not universal but occurs in only a fraction of pregnancies Using a kinetic analysis of normal mice mated to syngeneic or allogeneic males, a comparison of normal and SCID mice, and testing of multiparous mice for CTL against fetal Ags, we found that migrating fetal cells were cleared by the maternal immune system Thus the mother is not continuously exposed to circulating fetal cells and, in fact, has the capacity to eliminate them without eliminating the fetus

Journal ArticleDOI
TL;DR: A dramatic yet reversible increase in the incidence of indomethacin-induced ductal constriction occurs at 31 weeks' gestation, however, ductalconstriction can occur at any gestational age.

Journal ArticleDOI
TL;DR: Fetal hypothyroidism in pregnant women with high titers of thyroid stimulating autoantibody is possible by judicious administration of antithyroid drugs to the mother, and management of the hyperthyroid state in the neonate also is essential.
Abstract: The fetal hypothalamic-pituitary-thyroid axis develops independently of the maternal axis, but it is dependent on the maternal-placental system for adequate supply of iodide substrate. This iodide is supplied by direct transfer of maternal plasma iodide and by placental deiodination of T4. In addition, although placental transport of iodothyronines is limited, significant maternal-fetal transfer of T4 occurs, accounting for approximately 30% of the average 10 ug/dL serum-T4 concentration in fetal-cord blood at term. Current information suggests that this maternal contribution to the fetal-T4 levels is important for normal fetal maturation, particularly of the central nervous system. Combined maternal-fetal hypothyroxinemia can lead to irreversible fetal central nervous system damage. The timing of this fetal T4 dependency is not clear. It may be important in the first half of gestation, before the fetal thyroid gland is capable of T4 production, as well as the latter half of gestation when thyroid hormone effects on multiple organ systems are developing. Management of fetal thyroid dysfunction requires normalization of maternal serum T4 concentrations, avoidance or careful monitoring of potentially goitrogenic drug effects in the fetus, and in some instances, direct or indirect fetal therapy. In most cases fetal hypothyroidism is sporadic and undetected, and prognosis for normal growth and development is excellent if the mother is euthyroid and the hypothyroid state is detected and adequately treated at birth. Fetal treatment by intraamniotic thyroxine injection has been provided in cases of inadvertent maternal radioiodine treatment of Graves' disease between 10 and 20 weeks gestation and for fetal goiter detected by ultrasound. Effective treatment of fetal hyperthyroidism in pregnant women with high titers of thyroid stimulating autoantibody is possible by judicious administration of antithyroid drugs to the mother. Management of the hyperthyroid state in the neonate also is essential.

Journal ArticleDOI
TL;DR: The hepatic content in CYP2C8, 2C9 and 2C18 RNA displayed the same profile of evolution, which suggested a coregulation of their synthesis during the neonatal period, enabling dating of the onset of CYP1C proteins to the first weeks after birth, which is of considerable clinical importance in pediatric pharmacology.
Abstract: Experiments were performed in vivo and in vitro to date the onset of hepatic CYP2C isoforms and CYP2C-dependent activities during the perinatal period in humans. Proteins were not detected by immunoblotting in fetal livers and developed in the first few weeks after birth, irrespective of the gestational age at birth. Similarly, the hydroxylation of tolbutamide, a marker for CYP2C9 was undetected in fetal liver microsomes and rose in the first month after birth. In adult liver preparations, the hydroxylation of diazepam correlated well with the CYP3 A content of microsomes (r = 0.858, p < 0.01) and with the 6 beta hydroxylation of testosterone (r = 0.830, p < 0.005), whereas demethylation was related to the bulk of CYP2C proteins (r = 0.865, p < 0.005). In fetal liver microsomes, hydroxylation and demethylation activities accounted for less than 5% of the adult activities and both increased immediately after birth to reach adult activities at 1 year of age. When diazepam was given for sedative purpose in neonates and infants, the in-vivo urinary excretion of desmethyl diazepam, temazepam and oxazepam was extremely low in 1-2 day newborns (less than 5 nmol metabolites excreted in 24 h per kg body weight) and developed in the first week after birth. In newborns, barbiturates and to a lesser extent steroids, acted as inducers of CYP2C isoforms and increased tolbutamide hydroxylation, diazepam demethylation and diazepam hydroxylation by 2 to 10-fold. The surge of CYP2C proteins was caused by an accumulation of RNAs occurring in the first week after birth. The hepatic content in CYP2C8, 2C9 and 2C18 RNA displayed the same profile of evolution, which suggested a coregulation of their synthesis during the neonatal period. Taken together, these biochemical and clinical data enable dating of the onset of CYP2C proteins to the first weeks after birth, which is of considerable clinical importance in pediatric pharmacology.

Journal ArticleDOI
TL;DR: Findings indicate that serum level of leptin correlates with fetal body weight gain.
Abstract: The serum leptin concentration reflects the amount of adipose tissue in the body. Although fat deposition in the fetus in the third trimester markedly increases, the role of leptin during pregnancy has not been clarified. In the present study, whether or not the serum leptin concentration correlates with growth in utero was investigated, in addition to how leptin levels change in the first few days after birth. One hundred sixteen Japanese infants were divided into term (n = 91) and preterm groups (n = 25). Term infants were divided into 3 subgroups: birth weight appropriate for gestational age (AGA) (n = 44), birth weight large for gestational age (LGA) (n = 28), and birth weight small for gestational age (SGA) (n = 19). Longitudinal changes in the concentration of serum leptin after birth were examined in 48 infants. The serum leptin concentration was determined by RIA. No significant difference in leptin levels between cord sera and infants’ sera obtained within the first 6 h of life (n = 28) was obser...

Journal ArticleDOI
TL;DR: A consideration of the binding properties and distribution of these proteins suggests that the neonated Fc receptor (FcRn) transports IgG across the syncytiotrophoblast, and possibly the fetal blood vessel endothelium.