Showing papers on "Fetus published in 1995"

Fetal origins of coronary heart disease

Abstract: The fetal origins hypothesis states that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease. Animal studies have shown that undernutrition before birth programmes persisting changes in a range of metabolic, physiological, and structural parameters. Studies in humans have shown that men and women whose birth weights were at the lower end of the normal range, who were thin or short at birth, or who were small in relation to placental size have increased rates of coronary heart disease. We are beginning to understand something of the mechanisms underlying these associations. The programming of blood pressure, insulin responses to glucose, cholesterol metabolism, blood coagulation, and hormonal settings are all areas of active research.

Cardiac malformation in neonatal mice lacking connexin43

Abstract: Gap junctions are made up of connexin proteins, which comprise a multigene family in mammals. Targeted mutagenesis of connexin43 (Cx43), one of the most prevalent connexin proteins, showed that its absence was compatible with survival of mouse embryos to term, even though mutant cell lines showed reduced dye coupling in vitro. However, mutant embryos died at birth, as a result of a failure in pulmonary gas exchange caused by a swelling and blockage of the right ventricular outflow tract from the heart. This finding suggests that Cx43 plays an essential role in heart development but that there is functional compensation among connexins in other parts of the developing fetus.

Growth in full-term small-for-gestational-age infants : from birth to final height

Abstract: Intrauterine growth retardation, or being small for gestational age (SGA), has a life-long impact on a fetus's potential for development and survival. The incidence and relative risk of short stature in children born SGA were studied using a Swedish healthy full-term (37-43 wk of gestation) singleton birth cohort (n = 3650) from Goteborg, followed from birth to final height at about 18 y of age. Most infants, defined as SGA on the basis of a birth length less than -2 standard deviation scores (SDS) below the mean (SGAL infants), showed catch-up growth during the first 6 mo after birth, and by 1 y only 13.4% of the SGAL infants were below -2 SDS in height. This percentage decreased further during childhood to reach a value of 7.9% at 18 y of age. Although most SGAL infants have catch-up growth in early life, those who do not constitute 21% of short, prepubertal children. At 18 y of age, 22% of the total short population were short at birth ( 86%) of "healthy" full-term singleton SGAL infants will achieve catch-up in height during the first 6-12 mo of life, and that this is almost independent of whether birth weight or birth length is used to define SGA. Of the remaining, non-catch-up SGA infants, about 50% remain short in final height, and thus constitute a high risk group for persistent short stature.

Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis.

Abstract: GATA-3 is one member of a growing family of related transcription factors which share a strongly conserved expression pattern in all vertebrate organisms. In order to elucidate GATA-3 function using a direct genetic approach, we have disrupted the murine gene by homologous recombination in embryonic stem cells. Mice heterozygous for the GATA3 mutation are fertile and appear in all respects to be normal, whereas homozygous mutant embryos die between days 11 and 12 postcoitum (p.c.) and display massive internal bleeding, marked growth retardation, severe deformities of the brain and spinal cord, and gross aberrations in fetal liver haematopoiesis.

Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death

Abstract: The low-affinity receptor for leukemia inhibitory factor (LIFR) interacts with gp130 to induce an intracellular signal cascade. The LIFR-gp130 heterodimer is implicated in the function of diverse systems. Normal placentation is disrupted in LIFR mutant animals, which leads to poor intrauterine nutrition but allows fetuses to continue to term. Fetal bone volume is reduced greater than three-fold and the number of osteoclasts is increased six-fold, resulting in severe osteopenia of perinatal bone. Astrocyte numbers are reduced in the spinal cord and brain stem. Late gestation fetal livers contain relatively high stores of glycogen, indicating a metabolic disorder. Hematologic and primordial germ cell compartments appear normal. Pleiotropic defects in the mutant animals preclude survival beyond the day of birth.

An adjustable fetal weight standard

Abstract: The monitoring of fetal weight is an important aspect of antenatal care. To construct an individually adjustable standard, we developed a model to link the predicted birth weight to a fetal weight curve which outlines how this weight is to be reached in an uncomplicated pregnancy. A formula was derived which describes the median fetal weight at each gestation as a proportion of the optimal term weight, and also defines the 90th and 10th centile curves as normal limits. We analyzed a birth weight database of 38,114 singleton, routine ultrasound-dated pregnancies resulting in term deliveries. By stepwise multiple regression analysis, we derived coefficients for the factors that act as variables on term birth weight in our population. Apart from gestational age and sex, the maternal height, weight at first visit, ethnic group, parity and smoking all have significant and independent effects on birth weight. The variation due to ethnic group appears to be physiological in this population. Smoking is associated with a reduction in birth weight, which is independent of maternal physique and related to the number of cigarettes per day as reported at the first visit. We have developed a software program which calculates, on the basis of pregnancy variables entered at the first visit, an adjusted normal range for fetal size. This can be printed out as a chart and used for antenatal surveillance of growth.

Actions of Placental and Fetal Adrenal Steroid Hormones in Primate Pregnancy

Abstract: It is clear that steroid hormones of placental and fetal adrenal origin have critically important roles in regulating key physiological events essential to the maintenance of pregnancy and development of the fetus for extrauterine life Thus, progesterone has suppressive actions on lymphocyte proliferation and activity and on the immune system to prevent rejection of the developing fetus and placenta (see Fig 9) Progesterone also suppresses the calcium-calmodulin-MLCK system and thus activity of uterine smooth muscle, thereby promoting myometrial quiescence to ensure the maintenance of pregnancy Estrogen enhances uteroplacental blood flow and possibly placental neovascularization to provide optimal gas exchange and the nutrients required for the rapidly developing fetus and placenta In turn, estrogen has specific stimulatory effects on the receptor-mediated uptake of LDL by, and P-450scc activity within, syncytiotrophoblasts, thus promoting the biosynthesis of progesterone Moreover, there is an estrogen-dependent developmental regulation of expression of the LDL receptor and NAD-dependent 11 beta-HSD in the placenta, processes reflecting functional/biochemical differentiation of the trophoblast cells with advancing gestation The increase in 11 beta-HSD causes a change in transplacental corticosteroid metabolism, which results in activation of the HPAA in the fetus As a result of this cascade of events, there is an increase in expression of pituitary POMC/ACTH and key enzymes, eg 3 beta-HSD and P-450 17 alpha-hydroxylase, important for de novo cortisol formation by, and consequently maturation of, the fetal adrenal gland In turn, cortisol has well defined actions on surfactant biosynthesis and consequently fetal lung maturation, as well as effects on placental CRH/POMC release, which may be important to the initiation of labor At midgestation, estrogen also selectively feeds back on the fetal adrenal to suppress DHA and maintain physiologically normal levels of estrogen Preparation of the breast for lactation and nourishment of the newborn appears to involve a multifactorial system of regulation that includes estrogen It is apparent, therefore, that autocrine/paracrine, as well as endocrine, systems of regulation are operative within the fetoplacental unit during primate pregnancy A major goal of this review has been to illustrate the critically close functional communication existing between the developing placenta and fetus in the biosynthesis and the actions of steroid hormones during primate pregnancy The functional interaction of the human fetal adrenal and placenta with respect to the biosynthesis of estrogen was demonstrated many years ago However, the recent studies presented in this review show that the endocrine interaction between the fetus and placenta is more extensive, involving complex physiological regulatory mechanisms Thus, as illustrated in Fig 9, estrogen, acting via its receptor within the placenta and other reproductive tissues, orchestrates the dynamic interchange between the placenta and fetus responsible for the developmental regulation of the biosynthesis of the various steroid and peptide hormones and their receptors necessary for the maintenance of pregnancy and development of a live newborn It would appear, therefore, that the immediate and long range challenges in this area of reproductive endocrinology are to employ in vitro molecular and in vivo experimental approaches simultaneously to elucidate the nature of these complex interactions and define the cellular and molecular mechanisms underlying these important regulatory events

Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth

Abstract: Insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and insulin are believed to be important in the regulation of fetal and neonatal growth. We previously reported that the profiles of IGFBPs in fetal cord serum (FCS) were dependent on the growth/metabolic status of the fetus. The goals of the current study were to examine the IGF system in FCS from term fetuses with normal growth, those with intrauterine growth retardation (IUGR), and those who were large for gestational age (LGA) and in FCS from normal weight preterm (25-37 weeks) and term fetuses in the neonatal period from the day of birth (day 0) until 7 days of age (day 7). Western ligand blotting (WLB) of term FCS revealed IGFBPs with mol wt of 43 and 38 kilodaltons (kDa; IGFBP-3), 34 kDa (IGFBP-2), 28 kDa (IGFBP-1 and glycosylated IGFBP-4), and 24 kDa (IGFBP-4). In IUGR FCS, there was a 50% decrease in IGFBP-3 detected by WLB, which was shown not to be due to an IGFBP-3 protease in IUGR sera. In LGA FCS, IGFBP-3 levels were elevated 2-fold by densitometric analysis of ligand blots. In normal term FCS, the following levels (+/- SE) were present: IGF-I, 76 +/- 16; IGF-II, 401 +/- 38; IGFBP-3, 700 +/- 112; IGFBP-1, 77 +/- 10 ng/mL; and insulin, 3.8 +/- 1.6 microU/mL. In IUGR FCS, IGF-I, IGF-II, and IGFBP-3 were significantly reduced, and IGFBP-1 was 7-fold higher than in FCS from normal weight fetuses. In LGA FCS, IGF-I, insulin, and IGFBP-3 were significantly increased, whereas IGFBP-1 was significantly decreased. During the neonatal period, IGF-I levels on day 0 were 4-fold higher in FCS from term (38-40 weeks) compared to preterm (25-31 weeks) newborns. FCS IGF-II levels did not change significantly on day 0 between 25-40 weeks gestation. In the first 7 days of postnatal life, IGF-I levels were unchanged in preterm newborns, whereas in term neonates, IGF-I levels decreased precipitously on day 1, remained low during the first 3 days of life, and returned to birth levels by the end of the first week. In contrast, IGF-II and IGFBP-3 levels did not significantly change during the first week of life in preterm or term newborns.(ABSTRACT TRUNCATED AT 400 WORDS)

Utero-placental vascular development and placental function.

Abstract: The rate of fetal growth and subse- quent birth weight are major determinants of postna- tal survival and growth. Because the placenta is the organ through which respiratory gases, nutrients, and wastes are transported between the maternal and fetal systems, its primary function is to supply the metabolic substrates necessary to support fetal growth. Placental growth and development, therefore, are critical for normal fetal growth and development. During the last half of gestation in mammals, growth of the fetus is exponential, whereas utero-placental growth slows or ceases. Nevertheless, unless placental transport capacity keeps pace with the continually increasing demands of the fetus, fetal growth will be compromised. Studies over the last two decades have shown that placental transport capacity does indeed keep pace with fetal growth. This increase in placental function can be accounted for primarily by continual increases in placental (uterine and umbilical) blood flows, associated with increased placental vascularity. Placental vascular growth and development, in turn, are probably regulated by angiogenic factors produced by the placental tissues themselves. These placental angiogenic factors are produced primarily by the maternal placental tissues, are heparin-binding, and seem to be related to the fibroblast growth factor family. Further elucidation of the factors responsible for placental growth and vascular development is critical for an improved understanding of utero- placental-fetal interactions, which result in delivery of a healthy offspring.

Type 2 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal adrenal steroidogenesis.

Abstract: Two isoforms of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) have been described which catalyze the interconversion of cortisol (F) to cortisone (E). 11 beta HSD activity has previously been reported in placenta and fetal membranes, where its role may be to protect the developing fetus from glucocorticoid excess. Furthermore, in the rat, an association between placental 11 beta HSD activity and the subsequent development of hypertension in the offspring has been reported. We have characterized the isoforms of 11 beta HSD in human fetal membranes and dissected placental tissue at term and investigated the relationship between placental 11 beta HSD activity and fetal and placental weights. 11 beta HSD activity studies in the presence of 0.1 mumol/L F and NAD (indicative of type 2 isoform activity) revealed high levels of activity in trophoblast dissected free of vessels (561 +/- 87 pmol E/h.mg protein; n = 4) > undissected placenta > cotyledenous vessels dissected away from trophoblast > placental and reflected amnion. In contrast, in the presence of 2.5 mumol/L F and NADP (indicative of type 1 isoform activity), only decidua and chorion demonstrated significant levels of 11 beta HSD activity. Type 1 11 beta HSD activity in chorion was probably due to decidual contamination, in that it was absent in decidua-free fused chorion obtained from a twin pregnancy. In keeping with these data, type 1 11 beta HSD messenger ribonucleic acid (1.5 kilobases) was detected in decidua, but in no other tissue, and high levels of type 2 11 beta HSD messenger ribonucleic acid (1.9 kilobases) were found in undissected placenta and trophoblast. In 27 term placentas, 11 beta HSD activity varied from 194-448 pmol E/h.mg protein. There was a weak, but significant, positive correlation between term placental 11 beta HSD activity and fetal weight (r = 0.408; P = 0.034), but no correlation with placental weight. Thus, in man, the reported association of a small fetus and a large placenta predisposing to adult hypertension cannot be explained on the basis of defective 11 beta HSD activity. However, the placenta offers an immense reservoir for F clearance (1.73-7.95 mumol/min.placenta) and may be a principal factor driving fetal ACTH secretion and, hence, fetal adrenal steroidogenesis.

Nutrition and fetal growth

Abstract: Nutrient supply to the fetus is a key factor in the regulation of fetal growth. However, the direct supply of nutrients to provide building blocks for tissue growth is likely to be only a minor component of this regulation. The indirect effects of nutrition on fetal endocrine and metabolic status, and on the interaction between the fetus, placenta and mother all of which must be coordinated to allow fetal growth are also important. Maternal undernutrition may alter the growth of the fetus and its different component tissues in a way which cannot be explained solely on the basis of reduced substrate supply during the rapid growth phase of the tissues involved. Adaptation to altered substrate supply, during both undernutrition and refeeding, involves sequential changes in the metabolic and endocrine interactions between the fetus and the placenta. In addition, undernutrition has long-term consequences for the fetus. There is evidence for nutritional programming of fetal endocrine and cardiovascular systems before birth. Nutritional effects may also persist over more than one generation. The effects of nutrition on fetal growth are far more complex than simply those of substrate deprivation.

Apoptosis (Programmed Cell Death) in Arteries of the Neonatal Lamb

Abstract: We have examined whether cell death contributes to postnatal remodeling of arteries in lambs First, abdominal aortic smooth muscle cell proliferation rates fell from 287 +/- 008% per day at 3 days of age to 175 +/- 015% per day at 21 days These proliferation rates would yield a 50% increase in DNA content in the absence of cell death No increase in DNA content was observed (P < 05 for predicted versus measured accumulation); therefore, significant cell death was inferred The same analysis did not indicate high cell-death rates in the carotid, renal, or iliac arteries; however, cell death was detected in situ by end-labeling partially degraded DNA with terminal deoxynucleotidyl transferase or by nuclear labeling with propidium iodide, a fluorescent dye that permeates only nonviable cells Nuclei were labeled in all arteries, although labeling was most frequent in the abdominal aorta, a vessel that regresses substantially after birth Cell death was apoptotic because DNA extracted from arteries and end-labeled with [32P]dCTP produced a series of low molecular weight bands (DNA ladder) on an agarose gel, a hallmark of apoptosis The ladder was strong for neonatal abdominal aorta but weak for other arteries Only weak laddering was observed for fetal abdominal aortas in late gestation, confirming that high apoptosis rates in this vessel were initiated after birth Intense DNA ladders and frequent in situ labeling indicated high rates of apoptosis in the postnatal intra-abdominal umbilical artery, another vessel that regresses after birth We conclude that apoptosis contributes to postpartum arterial remodeling This contribution is greatest in arteries that regress after birth

Exogenous Transforming Growth Factor-Beta Amplifies Its Own Expression and Induces Scar Formation in a Model of Human Fetal Skin Repair

Abstract: OBJECTIVE: Fetal skin wounds heal without scarring To determine the role of TGF-beta 1 in fetal wound healing, mRNA expression of TGF-beta 1 was analyzed in human fetal and adult skin wounds METHODS: Human fetal skin transplanted to a subcutaneous location on an adult athymic mouse that was subsequently wounded heals without scar, whereas human adult skin heals with scar formation in that location In situ hybridization for TGF-beta 1 mRNA expression and species-specific immunohistochemistry for fibroblasts, macrophages, and neutrophils were performed in human adult wounds, fetal wounds, and fetal wounds treated with a TGF-beta 1 slow release disk RESULTS: Transforming growth factor-beta 1 mRNA expression was induced by wounding adult skin No TGF-beta 1 mRNA upregulation was detected in human fetal skin after wounding However, when exogenous TGF-beta 1 was added to human fetal skin, induction of TGF-beta 1 mRNA expression in human fetal fibroblasts occurred, an adult-like inflammatory response was detected, and the skin healed with scar formation CONCLUSIONS: Transforming growth factor-beta 1 is an important modulator in scar formation Anti-TGF-beta 1 strategies may promote scarless healing in adult wounds

Clinical review 68: The endocrine regulation of fetal growth in late gestation: the role of insulin-like growth factors.

Abstract: I NTRAUTERINE growth retardation (IUGR) remains a dominant cause of perinatal morbidity and mortality. More recently, it has been suggested that IUGR has longerterm effects on morbidity and mortality. A causal association between IUGR and the subsequent development of maturityonset diabetes mellitus and cardiovascular disease in adulthood has been suggested; one postulated mechanism to explain this association is that IUGR may lead to altered programming of endocrine development (1). The causes of IUGR can be considered in three major groupings. It may be secondary to the effects of toxins affecting fetal or placental cell division (e.g. fetal infection), to genetic abnormalities (e.g. trisomy 21), or to disturbance of the supply of nutrients from mother to fetus (e.g. maternal cardiovascular disease, placental pathology, hypertension of pregnancy, and maternal undernutrition). The latter group represents the group in which the greatest potential for clinical intervention may lie. Strategies aimed at coordinately enhancing placental function are the only potential therapeutic approaches to in utero therapy at a gestational age before safe premature delivery by cesarean section. However, such strategies remain theoretical, as little is known of the factors that might regulate nutrient transfer across the placenta. It is well established that the maternal phenotype is a major determinant of fetal growth in late gestation. Under most circumstances, the limited capacity of the placenta to transfer nutrients to the fetus constrains the growth of the fetus; for example, transfer of an embryo of a small breed into the uterus of a larger breed will overcome this constraint and lead to a larger birth size than observed within the homologous breed (2). This phenomenon of maternal constraint is reflected in the smaller average birth size of multiple pregnancies. It is assumed to reflect several mechanisms, including limitations on uterine blood flow and the limited capacity of placental transfer mechanisms. Thus, the endocrine regulation of fetal growth in late gestation is determined by hormones that influence the parti-

Regulation of Pulmonary Vascular Tone in the Perinatal Period

Abstract: In the fetus, gas exchange occurs in the placenta and not in the lung. Conse­ quently, pulmonary vascular resistance is high, pulmonary blood flow is low (about 35 ml/minlkg fetal body wt in near-term fetal lambs), and right ven­ tricular output is thereby directed through the ductus arteriosus toward the placenta for gas exchange. At the time of birth and the onset of ventilation, pulmonary vascular resistance falls, and pulmonary blood flow rapidly in­ creases approximately tenfold (31). Failure of the pulmonary circulation to undergo this transition at birth results in persistent pulmonary hypertension of the newborn (PPHN), a condition that can result in significant morbidity and mortality. Many factors regulate pulmonary blood flow in this critical perinatal period: These include mechanical influences and the release of a variety of vasoactive substances. Recent evidence suggests that vasoactive mediators produced-and released by the pulmonary vascular endothelium, either locally or into the circulation (paracrine or endocrine function), are central to many of these phenomena. This review discusses current knowledge dealing with the regulation of blood flow in the normal fetal, transitional, and postnatal pulmonary circulations, and possible aberrations in these regulatory mecha­ nisms associated with PPHN. We place particular emphasis on newer infor­ mation relating to the role of the pulmonary vascular endothelium in regulation

In Utero Placement of Aortopulmonary Shunts A Model of Postnatal Pulmonary Hypertension With Increased Pulmonary Blood Flow in Lambs

Abstract: Background The development of pulmonary hypertension and its associated increased vascular reactivity is a common accompaniment of congenital heart disease with increased pulmonary blood flow. Although the morphology of the pulmonary vascular changes is well described, the mechanisms of vascular remodeling and increased reactivity remain incompletely understood. Methods and Results To elucidate these mechanisms, we established an accurate and reliable experimental model of pulmonary hypertension with increased pulmonary blood flow. An aortopulmonary shunt was created with an 8.0-mm expanded polytetrafluoroethylene vascular graft in 11 late-gestation fetal lambs. At 1 month of age, shunted lambs had a pulmonary–to–systemic blood flow ratio of 2.2±1.2. Compared with 11 age-matched control lambs, mean pulmonary arterial pressure (44.8±11.7 versus 16.2±2.9 mm Hg) and the ratio of pulmonary to systemic arterial pressure were significantly increased (P<.05). Pulmonary vascular resistance was not significantly i...

Hypoxia selectively induces proliferation in a specific subpopulation of smooth muscle cells in the bovine neonatal pulmonary arterial media.

Abstract: Medial thickening of the pulmonary arterial wall, secondary to smooth muscle cell (SMC) hyperplasia, is commonly observed in neonatal hypoxic pulmonary hypertension. Because recent studies have demonstrated the existence of multiple phenotypically distinct SMC populations within the arterial media, we hypothesized that these SMC subpopulations would differ in their proliferative responses to hypoxic pulmonary hypertension and thus contribute in selective ways to the vascular remodeling process. Expression of meta-vinculin, a muscle-specific cytoskeletal protein, has been shown to reliably distinguish two unique SMC subpopulations within the bovine pulmonary arterial media. Therefore, to assess the proliferative responses of phenotypically distinct SMC subpopulations in the setting of neonatal pulmonary hypertension, we performed double immunofluorescence staining on pulmonary artery cryosections from control and hypertensive calves with antibodies against meta-vinculin and the proliferation-associated nuclear antigen, Ki-67. We found that, although neonatal pulmonary hypertension caused significant increases in overall cell replication, proliferation occurred almost exclusively in one, the meta-vinculin-negative SMC population, but not the other SMC population expressing meta-vinculin. We also examined fetal pulmonary arteries, where proliferative rates were high and meta-vinculin expression again reliably distinguished two SMC subpopulations. In contrast to the hypertensive neonate, we found in the fetus that the relative proliferative rates of both SMC subpopulations were equal, thus suggesting the existence of different mechanisms controlling proliferation and expression of cytoskeletal proteins in the fetus and neonate. We conclude that phenotypically distinct SMC populations in the bovine arterial media exhibit specific and selective proliferative responses to neonatal pulmonary hypertension. Distinct SMC subpopulations may, thus, contribute in unique ways to vascular homeostasis under both normal and pathologic conditions.

In utero ethanol exposure elicits oxidative stress in the rat fetus.

Abstract: Prior studies in our laboratory have shown that exposure of cultured fetal rat hepatocytes to ethanol (E) blocks epidermal growth factor-dependent replication and that this is paralleled by cell membrane damage, mitochondrial dysfunction, membrane lipid peroxidation (LP), and enhanced generation of reactive oxygen species. These measures of E-mediated oxidative stress (OS) were mitigated by treatment with antioxidants, and cell replication could be normalized by maintaining cell glutathione (GSH) pools. We have now extended these studies to an in vivo model. Rats were administered E (4 g/kg, po) at 12-hr intervals on days 17 and 18 of gestation and killed on day 19, 1 hr following a final dose of E (a total of 5 doses). Fetal and maternal brain and liver were assayed for signs of OS. The 2-day in utero E exposure increased membrane LP in fetal brain as evidenced by increased malondialdehyde (MDA) levels from 1.76 ± 0.12 SE (nMol/mg protein) to 2.00 ± 0.08 (p 0.05), whereas maternal liver α-tocopherol content was reduced by 31% (p < 0.05) by E treatment. It is concluded that maternal E consumption can induce an OS in fetal tissues that may contribute to the fetotoxic effects of E.

CIC-2: a developmentally dependent chloride channel expressed in the fetal lung and downregulated after birth.

Abstract: Growth and differentiation of the fetal lung are dependent on chloride and fluid secretion, yet the specific molecular identities of fetal chloride channels have not been fully determined In this study, we demonstrate mRNA expression of the volume-activated chloride channel, CIC-2, in fetal rat lung using reverse-transcriptase polymerase chain reaction (RT-PCR) and ribonuclease (RNase) protection assay By RNase protection assay, CIC-2 mRNA expression is most abundant in fetal lung and diminishes after birth until it is almost undetectable in adult rat lung To confirm this result at the protein level, a C-terminal fragment of CIC-2 cDNA derived from 19-day fetal rat lung was cloned into an expression plasmid The truncated 33-kD CIC-2 protein was expressed in Escherichia coli and purified by column chromatography Polyclonal antibodies to this antigen were raised in chickens, and the antisera detected a 94-kD protein in fetal rat lung homogenates by Western blotting Protein expression of CIC-2 was most abundant in mid and late gestation and decreased significantly shortly after birth, as would be predicted by the RNase protection data CIC-2 protein was localized along the apical surface of fetal airway epithelium by immunocytochemistry The abundant fetal expression of CIC-2 RNA and protein supports the hypothesis that CIC-2 is important to fetal lung development, and its apical location suggests that it may be involved in fluid secretion during normal lung morphogenesis

The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency

Abstract: The role of thyroid hormone in the human fetus is uncertain; a significant amount of T4 is transferred from the maternal to the fetal circulation. A mother-infant pair was found to be heterozygotic for a point mutation in codon 271 of the gene encoding Pit-1, a pituitary-specific transcription factor regulating somatotrope, lactotrope, and thyrotrope function. At birth, serum T4 was undetectable in mother and infant. The newborn presented with a striking delay of respiratory, cardiovascular, neurological, and bone maturation. Despite replacement therapy since birth, neurological development of the infant is impaired. Fetomaternal Pit-1 deficiency resulted in unmitigated fetal hypothyroidism that unmasked thyroid hormone as a potent endogenous drive of fetal maturation and revealed placental transfer of maternal T4 as a rescue mechanism for infants with congenital hypothyroidism, preventing fetal and neonatal symptoms of thyroid deficiency and safeguarding developmental potential.

Pre-eclampsia-like conditions produced by nitric oxide inhibition: effects of L-arginine, D-arginine and steroid hormones

Abstract: The aim of this study was to establish that inhibiting nitric oxide (NO) production with NG-nitro-L-arginine methyl ester (L-NAME) results in high blood pressure conditions in chronically treated pregnant rats. To validate the model, the effects of L-arginine (the substrate for NO) and D-arginine (the stereoisomer of L-arginine which is not a substrate for NO synthesis) were studied on blood pressure and fetal weights. The effects of a progesterone agonist, promegestone (R5020) and 17 beta-oestradiol were also explored. The NO synthase inhibitor L-NAME was chronically infused s.c. into pregnant rats from day 17 of gestation, either alone or with the simultaneous infusion of L-arginine and injections of sex steroid hormones (promegestone and oestradiol), compounds that may act in the pathogenic pathways of pre-eclampsia. Systolic blood pressure was measured daily. Weight and mortality of pups were recorded immediately after delivery. Blood pressure was elevated significantly in rats treated with L-NAME for only 1 day following infusion; there was a consistent decline during the next 3 days of pregnancy followed by a dramatic and significant rise just prior to delivery and post-partum. Fetal weights were reduced significantly in the L-NAME-treated rats. Co-treatment of L-NAME-infused rats with L-arginine reversed both the increase in blood pressure and the decrease in fetal weights observed with L-NAME alone. R5020, but not oestradiol, also reduced blood pressure and increased fetal weights in the L-NAME-treated animals. NO appears to play essential roles in the regulation of blood pressure during pregnancy, as well as in fetal perfusion and fetal weights at delivery. This study also indicates that progesterone, and not oestrogen, may regulate the vascular adaptations during normal pregnancy. L-Arginine and progesterone agonists like promegestone may have beneficial effects on the high blood pressure levels and reduced fetal weights associated with pre-eclampsia.

Enriching and identifying fetal cells in maternal blood for in situ hybridization

Abstract: Fetal cells may be obtained from amniocentesis, chorionic villus sampling, percutaneous umbilical cord sampling or in vitro fertilization embryos or products of conception, but are preferably from maternal peripheral blood. Fetal cells may be enriched by density gradient centrifugation. Fetal cells may also be enriched by removing maternal cells with an antibody to a cell surface antigen, e.g. anti-CD45, either immobilized or by fluorescence-activated cell sorting. Fetal cells are also distinguishable from maternal cells by staining, e.g. with a labeled antibody to cytokeratin or to fetal hemoglobin, or for fetal hemoglobin by hematoxylin/eosin, or by in situ hybridization to detect one or more fetal mRNAs, e.g., of fetal hemoglobin or fetoprotein. Amplification may be used in conjunction with the in situ hybridization. Fetal cells circulating in maternal blood may be separated by flow cytometry, sorting on their intrinsic light scattering properties. Fetal nucleated erythrocytes may be identified by a label for fetal hemoglobin. Fetal cells may be treated to determine genetic characteristics or abnormalities, infectious agents or other properties by nucleic acid hybridization. Genetic abnormalities may include deletions, additions, amplifications, translocations or rearrangements. Multiple abnormalities may also be detected simultaneously, and they may be visually distinguished by color. Kits are provided for the disclosed procedures.