Antenatal Dexamethasone Treatment Research Articles

Antenatal dexamethasone treatment and long-term programming

Antenatal dexamethasone treatment and long-term programming

Effect of antenatal dexamethasone therapy on hearing screening in premature infants: A retrospective case-control study

PurposeHearing impairment has a great impact on children's auditory language development, which causes serious socio-economic burden. Existing data showed the effect of antenatal dexamethasone treatment on hearing of premature infants is controversial, which may be caused by different treatment courses. Therefore, this study explored the effects of different courses of antenatal dexamethasone treatment on hearing of premature infants. MethodAll premature infants born in West China Second University Hospital, Sichuan University from 2018 to 2020 with abnormal hearing screening were included. We matched premature infants who passed the hearing screening according to the gestational age (±1 week) at a ratio of 1:1. Antenatal dexamethasone information, hearing screening results, and postnatal diagnosis related to hearing were available. ResultsA total of 299 premature infants failed hearing screening. In the final logistic model, antenatal use of 4 doses of dexamethasone reduced the hearing screening failure rate of premature infants (OR 0.39; 95 % CI: 0.22–0.69). Excessive exposure (OR 1.01; 95 % CI: 0.45–2.23) and incomplete exposure (OR 1.03; 95 % CI: 0.59–1.80) had no effect on the hearing screening of premature infants. ConclusionAntenatal dexamethasone therapy has a dose-dependent protective effect on hearing loss in premature infants.

Effect of dexamethasone on newborn survival at different administration-to-birth intervals: A secondary analysis of the WHO ACTION (Antenatal CorticosTeroids for Improving Outcomes in Preterm Newborn)-I trial.

The WHO ACTION-I trial demonstrated that dexamethasone significantly reduced neonatal mortality when administered to women at risk of early preterm birth in low-resource countries. We conducted a secondary analysis to determine how these benefits can be optimised, by evaluating the effect of dexamethasone compared to placebo on newborn mortality and severe respiratory distress outcomes at different administration-to-birth intervals, and identifying the interval with the greatest benefits. The WHO ACTION-I trial was a multi-country, individually-randomised, parallel-group, double-blind, placebo-controlled trial. It was conducted in 29 hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan. Women with a viable singleton or multiple pregnancy who presented to participating hospitals at a gestational age of 26 weeks 0 days-33 weeks 6 days and who were at risk of imminent preterm birth were eligible. In this secondary analysis, 2638 women and their newborns treated with single course of dexamethasone or placebo were analysed. Multivariate logistic regression was used to assess the effect of dexamethasone versus placebo on neonatal death, stillbirth or neonatal death, and severe respiratory distress at 24h and at 168h, by administration-to-birth interval (from 0 through 28 days), adjusting for gestational age at first dose. We used relative risks to identify the administration-to-birth interval with the greatest benefits of dexamethasone compared to placebo on the newborn outcomes. Between 24 December 2017 and 21 November 2019, 2852 women and their 3070 babies were enrolled in the WHO ACTION-I trial; 1332 women (1464 babies) in the dexamethasone group and 1306 women (1440 babies) in the placebo group were included in this secondary analysis. Neonatal mortality risk was lower with increasing time between initiating dexamethasone and birth, achieving peak mortality reduction by days 13 and 14 and then diminishing as the interval approached 28 days, regardless of gestational age at administration. For other outcomes, the overall pattern of risk reduction extending into the second week was consistent with that of neonatal death. In women at risk of preterm birth prior to 34 weeks' gestation, the neonatal benefits of antenatal dexamethasone appear to increase with longer administration-to-birth intervals than previously thought. This knowledge can support clinical assessment and estimation of the risks of adverse preterm newborn outcomes at the time of birth, and the potential benefits of antenatal dexamethasone treatment for a known administration-to-birth interval. Bill and Melinda Gates Foundation; World Health Organization.

Antenatal dexamethasone retarded fetal long bones growth and development by down-regulating of insulin-like growth factor 1 signaling in fetal rats.

Dexamethasone (DEX), a synthetic glucocorticoid, has been widely used as a medication for premature delivery. However, the side effects of antenatal DEX treatment on fetal bone development, as well as the underlying mechanisms still remain to be elucidated. Here, we aimed to explore the effects and the related mechanisms of antenatal DEX exposure during late pregnancy on fetal bone growth and development. Pregnant Sprague-Dawley rats were randomly divided into DEX group and vehicle group from gestational day 14 (GD14). Pregnant rats in DEX group were intraperitoneally injected once with DEX (200µg/kg body weight) on GD14, 16, 18, and 20. The vehicle group rats were administered the same amount of normal saline at the same time. Pregnant rats were anesthetized at GD21 to harvest fetal femurs for analysis. Antenatal DEX treatment delayed fetal skeletal growth via inhibiting extracellular matrix (ECM) synthesis and downregulating insulin-like growth factor 1 (IGF1) signaling. Several components of IGF1 signaling pathway, including IGF1 receptor, insulin receptor substrate, as well as serine-threonine protein kinase, were down-regulated in fetal growth plate chondrocytes following DEX treatment. This study indicated that antenatal DEX treatment-retarded fetal skeletal growth was associated with the down-regulation of IGF1 signaling in growth plate chondrocytes, providing important information about the impact of antenatal DEX application four courses on premature infant.

Antenatal Dexamethasone Treatment Induces Sex-dependent Upregulation of NTPDase1/CD39 and Ecto-5'-nucleotidase/CD73 in the Rat Fetal Brain.

Dexamethasone (DEX) is frequently used to treat women at risk of preterm delivery, but although indispensable for the completion of organ maturation in the fetus, antenatal DEX treatment may exert adverse sex-dimorphic neurodevelopmental effects. Literature findings implicated oxidative stress in adverse effects of DEX treatment. Purinergic signaling is involved in neurodevelopment and controlled by ectonucleotidases, among which in the brain the most abundant are ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) and ecto-5'-nucleotidase (e5'NT/CD73), which jointly dephosphorylate ATP to adenosine. They are also involved in cell adhesion and migration, processes integral to brain development. Upregulation of CD39 and CD73 after DEX treatment was reported in adult rat hippocampus. We investigated the effects of maternal DEX treatment on CD39 and CD73 expression and enzymatic activity in the rat fetal brain of both sexes, in the context of oxidative status of the brain tissue. Fetuses were obtained at embryonic day (ED) 21, from Wistar rat dams treated with 0.5mg DEX/kg/day, at ED 16, 17, and 18, and brains were processed and used for further analysis. Sex-specific increase in CD39 and CD73 expression and in the corresponding enzyme activities was induced in the brain of antenatally DEX-treated fetuses, more prominently in males. The oxidative stress induction after antenatal DEX treatment was confirmed in both sexes, although showing a slight bias in males. Due to the involvement of purinergic system in crucial neurodevelopmental processes, future investigations are needed to determine the role of these observed changes in the adverse effects of antenatal DEX treatment.

Concomitant deletion of HRAS and NRAS leads to pulmonary immaturity, respiratory failure and neonatal death in mice

We reported previously that adult (HRAS−/−; NRAS−/−) double knockout (DKO) mice showed no obvious external phenotype although lower-than-expected numbers of weaned DKO animals were consistently tallied after crossing NRAS-KO and HRAS-KO mice kept on mixed genetic backgrounds. Using mouse strains kept on pure C57Bl/6 background, here we performed an extensive analysis of the offspring from crosses between HRAS-KO and NRAS-KO mice and uncovered the occurrence of very high rates of perinatal mortality of the resulting DKO littermates due to respiratory failure during the first postnatal 24–48 h. The lungs of newborn DKO mice showed normal organ structure and branching but displayed marked defects of maturation including much-reduced alveolar space with thick separating septa and significant alterations of differentiation of alveolar (AT1, AT2 pneumocytes) and bronchiolar (ciliated, Clara cells) cell lineages. We also observed the retention of significantly increased numbers of undifferentiated progenitor precursor cells in distal lung epithelia and the presence of substantial accumulations of periodic acid-Schiff-positive (PAS+) material and ceramide in the lung airways of newborn DKO mice. Interestingly, antenatal dexamethasone treatment partially mitigated the defective lung maturation phenotypes and extended the lifespan of the DKO animals up to 6 days, but was not sufficient to abrogate lethality in these mice. RNA microarray hybridization analyses of the lungs of dexamethasone-treated and untreated mice uncovered transcriptional changes pointing to functional and metabolic alterations that may be mechanistically relevant for the defective lung phenotypes observed in DKO mice. Our data suggest that delayed alveolar differentiation, altered sphingolipid metabolism and ceramide accumulation are primary contributors to the respiratory stress and neonatal lethality shown by DKO mice and uncover specific, critical roles of HRAS and NRAS for correct lung differentiation that are essential for neonatal survival and cannot be substituted by the remaining KRAS function in this organ.

Structural and transcriptomic response to antenatal corticosteroids in an Erk3-null mouse model of respiratory distress

Neonatal respiratory distress syndrome in preterm infants is a leading cause of neonatal death. Pulmonary insufficiency-related infant mortality rates have improved with antenatal glucocorticoid treatment and neonatal surfactant replacement. However, the mechanism of glucocorticoid-promoted fetal lung maturation is not understood fully, despite decades of clinical use. We previously have shown that genetic deletion of Erk3 in mice results in growth restriction, cyanosis, and early neonatal lethality because of pulmonary immaturity and respiratory distress. Recently, we demonstrated that the addition of postnatal surfactant administration to antenatal dexamethasone treatment resulted in enhanced survival of neonatal Erk3-null mice. To better understand the molecular underpinnings of corticosteroid-mediated lung maturation, we used high-throughput transcriptomic and high-resolution morphologic analysis of the murine fetal lung. We sought to examine the alterations in fetal lung structure and function that are associated with neonatal respiratory distress and antenatal glucocorticoid treatment. Dexamethasone (0.4 mg/kg) or saline solution was administered to pregnant dams on embryonic days 16.5 and 17.5. Fetal lungs were collected and analyzed by microCT and RNA-seq for differential gene expression and pathway interactions with genotype and treatment. Results from transcriptomic analysis guided further investigation of candidate genes with the use of immunostaining in murine and human fetal lung tissue. Erk3(-/-) mice exhibited atelectasis with decreased overall porosity and saccular space relative to wild type, which was ameliorated by glucocorticoid treatment. Of 596 differentially expressed genes (q < 0.05) that were detected by RNA-seq, pathway analysis revealed 36 genes (q<0.05) interacting with dexamethasone, several with roles in lung development, which included corticotropin-releasing hormone and surfactant protein B. Corticotropin-releasing hormone protein was detected in wild-type and Erk3(-/-) lungs at E14.5, with significantly temporally altered expression through embryonic day 18.5. Antenatal dexamethasone attenuated corticotropin-releasing hormone at embryonic day 18.5 in both wild-type and Erk3(-/-) lungs (0.56-fold and 0.67-fold; P< .001). Wild type mice responded to glucocorticoid administration with increased pulmonary surfactant protein B (P= .003). In contrast, dexamethasone treatment in Erk3(-/-) mice resulted in decreased surfactant protein B (P= .012). In human validation studies, we confirmed that corticotropin-releasing hormone protein is present in the fetal lung at 18 weeks of gestation and increases in expression with progression towards viability (22 weeks of gestation; P < .01). Characterization of whole transcriptome gene expression revealed glucocorticoid-mediated regulation of corticotropin-releasing hormone and surfactant protein B via Erk3-independent and-dependent mechanisms, respectively. We demonstrated for the first time the expression and temporal regulation of corticotropin-releasing hormone protein in midtrimester human fetal lung. This unique model allows the effects of corticosteroids on fetal pulmonary morphologic condition to be distinguished from functional gene pathway regulation. These findings implicate Erk3 as a potentially important molecular mediator of antenatal glucocorticoid action in promoting surfactant protein production in the preterm neonatal lung and expanding our understanding of key mechanisms of clinical therapy to improve neonatal survival.

Multiple Antenatal Dexamethasone Treatment Alters Brain Vessel Differentiation in Newborn Mouse Pups.

Antenatal steroid treatment decreases morbidity and mortality in premature infants through the maturation of lung tissue, which enables sufficient breathing performance. However, clinical and animal studies have shown that repeated doses of glucocorticoids such as dexamethasone and betamethasone lead to long-term adverse effects on brain development. Therefore, we established a mouse model for antenatal dexamethasone treatment to investigate the effects of dexamethasone on brain vessel differentiation towards the blood-brain barrier (BBB) phenotype, focusing on molecular marker analysis. The major findings were that in total brains on postnatal day (PN) 4 triple antenatal dexamethasone treatment significantly downregulated the tight junction protein claudin-5, the endothelial marker Pecam-1/CD31, the glucocorticoid receptor, the NR1 subunit of the N-methyl-D-aspartate receptor, and Abc transporters (Abcb1a, Abcg2 Abcc4). Less pronounced effects were found after single antenatal dexamethasone treatment and in PN10 samples. Comparisons of total brain samples with isolated brain endothelial cells together with the stainings for Pecam-1/CD31 and claudin-5 led to the assumption that the morphology of brain vessels is affected by antenatal dexamethasone treatment at PN4. On the mRNA level markers for angiogenesis, the sonic hedgehog and the Wnt pathway were downregulated in PN4 samples, suggesting fundamental changes in brain vascularization and/or differentiation. In conclusion, we provided a first comprehensive molecular basis for the adverse effects of multiple antenatal dexamethasone treatment on brain vessel differentiation.

Astroglial Plasticity Is Implicated in Hippocampal Remodelling in Adult Rats Exposed to Antenatal Dexamethasone.

The long-term effects of antenatal dexamethasone treatment on brain remodelling in 3-month-old male Sprague Dawley rats whose mothers had been treated with dexamethasone were investigated in the present study. Dorsal hippocampus, basolateral amygdala and nucleus accumbens volume, cell numbers, and GFAP-immunoreactive astroglial cell morphology were analysed using stereology. Total brain volume as assessed by micro-CT was not affected by the treatment. The relative volume of the dorsal hippocampus (% of total brain volume) showed a moderate, by 8%, but significant reduction in dexamethasone-treated versus control animals. Dexamethasone had no effect on the total and GFAP-positive cell numbers in the hippocampal subregions, basolateral amygdala, and nucleus accumbens. Morphological analysis indicated that numbers of astroglial primary processes were not affected in any of the hippocampal subregions analysed but significant reductions in the total primary process length were observed in CA1 by 32%, CA3 by 50%, and DG by 25%. Mean primary process length values were also significantly decreased in CA1 by 25%, CA3 by 45%, and DG by 25%. No significant astroglial morphological changes were found in basolateral amygdala and nucleus accumbens. We propose that the dexamethasone-dependent impoverishment of hippocampal astroglial morphology is the case of maladaptive glial plasticity induced prenatally.

293: Transcriptomic analysis reveals potential roles for ERK3 in fetal lung maturation via surfactant protein B and corticotropin releasing hormone

The mechanism by which prenatal glucocorticoid treatment promotes fetal lung maturation remains poorly understood despite decades of clinical use. In an Erk3-/- murine model of neonatal respiratory distress syndrome (RDS), we showed partial abrogation of the pulmonary immaturity phenotype through antenatal dexamethasone (dex) treatment. Using transcriptomic analysis, we have previously identified key molecular pathways in lung maturation. In this study, we aimed to determine the interaction of antenatal glucocorticoids with regulatory genes at crucial intervals in lung development employing IPA analysis & immunohistochemistry validation.

Antenatal Glucocorticoid Treatment Affects Hippocampal Development in Mice

Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg) was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function.

Antenatal Dexamethasone Treatment in Midgestation Reduces System A-Mediated Transport in the Late-Gestation Murine Placenta

Clinically, approximately 30% of women who receive synthetic glucocorticoids (sGC) for risk of preterm labor carry to term. In vitro studies have shown that sGC acutely regulate the placental system A amino acid transporter, but there are no comparable data in vivo. Hence, the objective of our study was to examine the acute [embryonic day (E)15.5] and longer-term (E17.5 and E18.5) consequences of midgestation antenatal sGC [dexamethasone (DEX); 0.1 mg/kg on E13.5 and E14.5] on placental system A-mediated transfer in the mouse (measured in vivo as maternal-fetal unidirectional (14)C-methylaminoisobutyric acid transfer per gram of placenta). System A transfer and Slc38a mRNA expression significantly increased from E12.5 to E18.5 (P < 0.05), corresponding to increased fetal growth. DEX treatment had no acute effect at E15.5 or longer-term effect at E17.5 but significantly decreased system A-mediated transfer before term (E18.5; P < 0.05) in placentae of male and female fetuses. There was no effect of DEX on Slc38a gene expression. Administration of DEX in this regime had no effect on birth weight. We conclude that sGC treatment in midgestation leads to a substantial decrease in placental system A-mediated transport in late gestation, suggesting that prenatal sGC therapy may lead to a reduction in availability of neutral amino acids to the fetus if gestation persists to term.

Effects of antenatal dexamethasone treatment on glucocorticoid receptor and calcyon gene expression in the prefrontal cortex of neonatal and adult common marmoset monkeys

BackgroundSynthetic glucocorticoids such as dexamethasone (DEX) are commonly used to promote fetal lung maturation in at-risk preterm births, but there is emerging evidence of subsequent neurobehavioral abnormalities in these children e.g. problems with inattention/hyperactivity. However, molecular pathways mediating effects of glucocorticoid overexposure on motor and cognitive development are poorly understood.MethodsIn this study with common marmoset monkeys, we investigated for neonatal and adulthood effects of antenatal DEX treatment on the expression of the corticosteroid receptors and also calcyon, a risk gene for attention-deficit/hyperactivity disorder, in the prefrontal cortex (PFC). Pregnant marmosets were exposed to DEX (5 mg/kg body weight) or vehicle during early (days 42-48) or late (days 90-96) stages of the 144-day pregnancy.ResultsIn neonates, relative to controls, glucocorticoid receptor (GR) mRNA levels were significantly reduced after the late DEX treatment in the medial, orbital and dorsal PFC and after the early DEX treatment in the dorsal PFC. The early DEX exposure, specifically, resulted in significant reduction in calcyon mRNA expression in the medial, orbital, dorsal and lateral PFC relative to controls. Mineralocorticoid receptor (MR) mRNA levels were not significantly affected by DEX treatment. In adults, PFC GR, calcyon, and MR mRNA levels were not significantly affected by early or late prenatal DEX treatment.ConclusionThese findings indicate that antenatal DEX treatment could lead to short-term alterations in PFC expression of the GR and calcyon genes, with possible neurodevelopmental functional consequences.

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is caused by a defect in any of the 5 enzymes necessary for the synthesis of cortisol. However, in more than 90% of cases, CAH results from a defect in the enzyme 21-hydroxylase. Antenatal dexamethasone for the treatment of fetuses with CAH was introduced in 1978, and has been shown to prevent virilizaton of affected girls. Some researchers have been concerned about the possible long-term side effects of this therapy. A variety of studies have evaluated cognition and behavioral traits as well as metabolic alterations in treated children and in animals, and some investigators have reported adverse effects of antenatal treatment, but no firm conclusions about the potential risks of dexamethasone have been reached. This review summarizes the outcomes of affected children with and without antenatal dexamethasone treatment, and evaluates the benefits of prenatal treatment as well as the potential risks. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader should be able to recall the pathophysiology, broad clinical presentation, differences in prognosis with and without antenatal treatment, and face the importance of the antenatal dexamethasone treatment in congenital adrenal hyperplasia despite the potential adverse effects.

Antenatal Dexamethasone Treatment Leads to Changes in Gene Expression in a Murine Late Placenta

Antenatal steroids like dexamethasone (DEX) are used to augment fetal lung maturity and there is a major concern that they impair fetal growth. If delivery is delayed after using antenatal DEX, placental function and hence fetal growth may be compromised even further. To investigate the effects of DEX on placental function, we treated 9 pregnant C57/BL6 mice with DEX and 9 pregnant mice were injected with saline to serve as controls. Placental gene expression was studied using microarrays in 3 pairs and other 6 pairs were used to confirm microarray results by semi-quantitative RT-PCR, real-time PCR, in situ hybridization, western blot analysis and Oligo ApopTaq assay. DEX-treated placentas were hydropic, friable, pale, and weighed less (80.0 ± 15.1 mg compared to 85.6.8 ± 7.6 mg, p = 0.05) ( n = 62 placentas). Fetal weight was significantly reduced after DEX use (940 ± 32 mg compared to 1162 ± 79 mg, p = 0.001) ( n = 62 fetuses). There was >99% similarity within and between the three gene chip data sets. DEX led to down-regulation of 1212 genes and up-regulation of 1382 genes. RT-PCR studies showed that DEX caused a decrease in expression of genes involved in cell division such as cyclins A2, B1, D2, cdk 2, cdk 4 and M-phase protein kinase along with growth-promoting genes such as EGF-R, BMP4 and IGFBP3. Oligo ApopTaq assay and western blot studies showed that DEX-treatment increased apoptosis of trophoblast cells. DEX-treatment led to up-regulation of aquaporin 5 and tryptophan hydroxylase genes as confirmed by real-time PCR, and in situ hybridization studies. Thus antenatal DEX treatment led to a reduction in placental and fetal weight, and this effect was associated with a decreased expression of several growth-promoting genes and increased apoptosis of trophoblast cells.

Ontogeny of hippocampal corticosteroid receptors: Effects of antenatal glucocorticoids in human and mouse

Women at risk for preterm delivery are treated with synthetic glucocorticoids (GCs) to enhance fetal lung maturation. GCs can bind to two intracellular receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which function as transcription factors. Both are highly expressed in the hippocampus. Several studies have focused on adverse side effects of antenatal GC treatment. However, relatively little is known about the ontogeny of GR and MR, especially in human. Therefore, we studied the ontogeny of both receptors in the human and mouse hippocampus and investigated the effects of antenatal dexamethasone (dex) treatment, a synthetic glucocorticoid, on MR and GR mRNA levels during hippocampal development. The results demonstrate that MR mRNA was first expressed in mouse hippocampus at embryonic day (E)15.5, at the timepoint when dex was administered. In contrast, GR mRNA expression was first observed after birth at postnatal day (P)5. However, in the human hippocampus both receptors are expressed at 24 weeks of gestation, when antenatal GCs are administered in clinical practice. Quantitative in situ hybridization demonstrated that MR mRNA levels were reduced only shortly after dex treatment at E16, but were unaffected from E18 onwards. These findings indicate that a single antenatal dex administration at E15.5 transiently affects MR mRNA levels in the mouse hippocampus. No effect of antenatal dex treatment was found on the human hippocampus at the third trimester of pregnancy. These data on the prenatal ontogeny of both corticosteroid receptors in the human hippocampus is important for understanding the significance of fetal glucocorticoid or stress exposure and its potential effects on health and disease.

Skeletal muscle glucose transporter protein responses to antenatal glucocorticoids in the ovine fetus

We investigated the effects of maternal antenatal dexamethasone (Dex) treatment given as a single course (4 doses) or multiple courses (20 doses) on fetal skeletal muscle glucose transporter (GLUT) protein concentrations at 70% of gestation (106 to 107 days with term being 145 to 150 days) in the ovine fetus. Antenatal corticosteroid administration was associated with a decrease in endogenous fetal plasma cortisol concentrations (P < 0.05), fetal hyperglycemia (P < 0.02) and hyperinsulinemia (P < 0.05). These metabolic/hormonal changes were associated with a decrease in fetal body weight (P < 0.05) in the multiple course Dex group compared with the multiple course placebo group. These perturbations were associated with an increase in fetal skeletal muscle GLUT 1 concentrations that mediate basal glucose transport in the extensor digitorum lateralis and extensor digitorum longus muscles (P < 0.05) 18 h after the last dose of Dex was given in the single course group. However, in the multiple course Dex group, a small increase in GLUT 1 was observed only in the biceps femoris. In contrast, both single and multiple courses of antenatal Dex were associated with an increase in the extensor digitorum lateralis and biceps femoris muscle GLUT 4 (insulin-responsive) concentrations (P < 0.05). We conclude that antenatal corticosteroids perturb fetal glucose/insulin homeostasis, which is associated with increases in fetal skeletal muscle glucose transporters to compensate for and attenuate the associated catabolic fetal state. These changes consist of an increase in proteins that mediate basal glucose transport (GLUT 1) to meet immediate energy requirements of the fetal skeletal muscle with an increase in basal insulin sensitivity (GLUT 4) to compensate for the Dex-induced catabolic state after exposure to multiple courses of Dex.

Exogenous antenatal glucocorticoid treatment reduces susceptibility for hippocampal kindled and maximal electroconvulsive seizures in infant rats

Dexamethasone (DEX) and betamethasone (BETA) are synthetic glucocorticoids used clinically to reduce morbidity and mortality in infants at risk of premature birth. While their main role is to facilitate lung development, their effect on the developing nervous system and seizure susceptibility is unclear. The present study tested the hypothesis that antenatal DEX or BETA treatment would alter seizure thresholds and spread of epileptiform activity in the brains of infant offspring. Pregnant dams received once daily injections with DEX, BETA, or vehicle on gestation days 15 to 18. Physical appearance, litter size, and weight of the pups were assessed postnatally. Seizure thresholds were determined on postnatal day 14 using electroconvulsive shock delivered through ear clips (i.e., generalized seizure) or kindling stimulation of the left hippocampus through indwelling electrodes (i.e., partial seizure). The rate of acquisition of kindled seizures was determined on postnatal days 14 and 15. Pups from dams treated with DEX and BETA were growth restricted. Antenatal BETA treatment increased seizure threshold for both models. Antenatal DEX treatment increased kindling threshold, but not electroconvulsive shock threshold. Kindling rate was unaffected by either antenatal treatment. In summary, repeated glucocorticoid treatments had adverse effects on weight, skin and litter size, raised seizure thresholds, and reduced seizure vulnerability. Although these effects are seemingly desirable with respect to seizure susceptibility, they suggest that the functional organization of the nervous system is altered with antenatal synthetic glucocorticoid treatment.

Antenatal glucocorticoids blunt the functioning of the hypothalamic-pituitary-adrenal axis of neonates and disturb some behaviors in juveniles

Antenatal glucocorticoids are highly effective in preventing respiratory distress of premature babies but can induce physiological and behavioral disturbances in young infants as well as in animals. Therefore, the hypothalamic-pituitary-adrenal (HPA) axis of rat neonates, and the consequences on behavioral development of offspring have been studied after five antenatal injections of dexamethasone (DEX) or vehicle. DEX decreased offspring body weight at birth, and significantly delayed the normal growth for the first 3 weeks of life. This paralleled diminished behavioral performances measured on postnatal day 3 (righting reflex) and postnatal day 10 (grasping test). Circulating levels of adrenocorticotrophin (ACTH) and corticosterone were significantly decreased on postnatal day 1 and this was related to a diminution of HPA axis activity shown by the decrease of central expression of corticotropin releasing hormone (CRH) mRNA, immunoreactive content in paraventricular neurons (PVN) and in the median eminence endings were significantly decreased. On the other hand, expression of another secretagogue of ACTH, arginine vasopressin (AVP), was differently affected in the PVN parvocellular neurons of offspring of the DEX group since AVP mRNA increased whereas immunoreactive content of the PVN parvocellular neurons was lowered. Simultaneously, the co-production of AVP and CRH in PVN neurons was stimulated. This can support the view that antenatal DEX reached the fetus and produced some damage which did not parallel that induced by prenatal stress of the pregnant females, especially the low body weight of offspring. The harmful consequence of antenatal DEX treatment was not restrictively due to the blunting of the HPA axis but also to the low body weight, which disturbed behavioral performances for the first weeks of life and could participate in other disorders in adult life.

Decreased expression of voltage-gated K+ channels in pulmonary artery smooth muscles cells in nitrofen-induced congenital diaphragmatic hernia in rats.

The newborn with congenital diaphragmatic hernia (CDH) is at high risk of developing persistent pulmonary hypertension (PPH). Recently, smooth muscle K(+) channels have been implicated in hypoxic pulmonary vasoconstriction in adults. We hypothesized that the hyperreactivity of the newborn pulmonary vasculature in CDH might reflect a relatively low level of smooth muscle K(+) channel activity because of hypoxemia, which could give rise to excessive smooth muscle cell depolarisation and lead to failure of the pulmonary vasculature to adapt to extrauterine life. We therefore investigated K(+) channel subunits in pulmonary artery smooth muscle cells (PASMC) in the nitrofen-induced CDH lung in rats. The CDH model was induced in pregnant rats after administration of 100 mg nitrofen on day 9.5 of gestation (term = 22 days). Dexamethasone (0.25 mg/kg) was given on days 18.5 and 19.5 of gestation. Cesarean section was performed on day 21. Fetuses were divided into three groups: group I, normal control; group II, nitrofen-induced CDH; and group III, nitrofen-induced CDH with antenatal dexamethasone treatment. Reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate the relative amount of the potassium channels Kv1.2, Kv2.1, and KvCa mRNA. Indirect immunohistochemistry was performed using a laser scanning confocal microscope with anti-Kv1.2, -Kv2.1, and -KvCa antibodies. In the CDH lung, Kv1.2, Kv2.1, and KvCa immunoreactivity was markedly decreased in PASMC compared with controls. Relative mRNA levels of potassium channel anti-Kv1.2, -Kv2.1, and -KvCa were significantly decreased in the CDH lung compared with controls (p<0.05). Dexamethasone treatment increased Kv1.2, Kv2.1, and KvCa immunoreactivity and mRNA levels in the CDH lung. Changes in voltage-gate K(+) channel subunits expression in the CDH lung suggest that potassium channels may play an important role in the development of pulmonary hypertension. Antenatal dexamethasone may modulate pulmonary vascular tone in the CDH hypoplastic lung by selectively upregulating local expression of Kv1.2, Kv2.1, and KvCa.