Prenatal Dexamethasone Administration Research Articles

Potential teratogenic effect of prenatal dexamethasone administration on palate development: Experimental study in rats

BackgroundThe interaction of cell populations and synchronization of cell signaling pathways during craniofacial development can cause malformations such as facial clefts when interrupted by teratogenic agents including synthetic corticosteroids. Therefore, this study aimed to determine the potentially disturbing dexamethasone (Dex) effect on palatal shelf development in rat embryos and the possible reasons for this teratogenic potential in relation to fibroblast growth factor 10 (FGF10) as well as FGF10 receptor2 (FGFR2) signaling. MethodsThirty pregnant rats were used, which were then randomly categorized into three groups of ten animals each: the control group, where pregnant rats received no treatment, Sham group in which pregnant rats were injected subcutaneously with saline (0.4 mg/kg body weight) during the mid-pregnancy period at gestational day 9–14, and Dex-treated group, where pregnant rats received 0.4 mg/kg of Dex at mid-gestational period. Pregnant animals from all groups were sacrificed on day 20 of gestation before birth and the fetuses were removed for examination of the palatal shelves using a light microscope (LM). In addition, a real-time polymerase chain reaction and a reverse transcription-polymerase chain reaction (RT-PCR) were done to evaluate FGF10 and its receptor FGFR2 gene expression. ResultsThe cleft palate incidence rates in the groups of embryos were determined. Only the offspring in the Dex group showed a cleft palate. Moreover, the cleft palate incidence rate in the Dex group was significantly different compared to controls. Moreover, a significant decrease in FGF10 and FGFR2 expression levels was reported in the Dex group than in the controls. ConclusionsDex treatment in mid-gestation may increase the incidence of cleft palate development, which may be due to modulation of FGF signaling. This calls for caution when using this medication in the first half of pregnancy unless absolutely necessary and under close medical supervision.

The influence of prenatal dexamethasone administration before scheduled full-term cesarean delivery on short-term adverse neonatal outcomes: a retrospective single-center cohort study.

There has been a gradual increase in the prevalence of cesarean section deliveries and more healthcare professionals are considering the prophylactic use of corticosteroids before planned full-term cesarean sections. However, the association between dexamethasone administration before full-term cesarean delivery and short-term adverse neonatal outcomes is unclear. This study analyzed the disparities in short-term adverse neonatal effects in neonates born via full-term elective cesarean delivery with or without antenatal dexamethasone treatment. This single-center retrospective cohort study involved neonates aged 37-39 weeks. The primary neonatal outcomes included various short-term adverse events, including neonatal admission to the neonatal intensive care unit, neonatal access to the special care baby unit, transient neonatal respiratory distress, respiratory distress syndrome, and the requirement of intravenous antibiotics or ventilatory support. Multiple logistic regression analysis was used to assess the association between these outcomes and dexamethasone exposure while adjusting for covariates. Of the 543 neonates included in the study, 121 (22.2%) had been exposed to prenatal dexamethasone. When compared with the control group, the dexamethasone-exposed group exhibited significantly higher rates of transient neonatal respiratory distress, respiratory distress syndrome, administration of intravenous antibiotics, the need for ventilatory support, and longer duration of neonatal hospitalization (P < 0.05). The association between dexamethasone exposure and short-term adverse neonatal outcomes remained significant after adjusting for potential confounders (odds ratio: 12.76, 95% confidence interval: 6.9-23.62, P < 0.001). The dexamethasone-exposed group had a higher likelihood of experiencing short-term adverse outcomes when compared with non-exposed neonates, suggesting that dexamethasone may have detrimental effects on infants delivered at full term. This implies the importance of exercising caution when contemplating the use of antenatal corticosteroids.

Contribution of changes in the orexin system and energy sensors in the brain in depressive disorder - a study in an animal model

BackgroundMaternal elevated glucocorticoid levels during pregnancy can affect the developing fetus, permanently altering the structure and function of its brain throughout life. Excessive action of these hormones is known to contribute to psychiatric disorders, including depression.MaterialsThe study was performed in a rat model of depression based on prenatal administration of dexamethasone (DEX) in late pregnancy (0.1 mg/kg, days 14–21). We evaluated the effects of prenatal DEX treatment on the cognition and bioenergetic signaling pathways in the brain of adult male rats, in the frontal cortex and hippocampus, and in response to stress in adulthood, using behavioral and biochemical test batteries.ResultsWe revealed cognitive deficits in rats prenatally treated with DEX. At the molecular level, a decrease in the orexin A and orexin B levels and downregulation of the AMPK-SIRT1-PGC1α transduction pathway in the frontal cortex of these animals were observed. In the hippocampus, a decreased expression of orexin B was found and changes in the MR/GR ratio were demonstrated. Furthermore, an increase in HDAC5 level triggered by the prenatal DEX treatment in both brain structures and a decrease in MeCP2 level in the hippocampus were reported.ConclusionsOur study demonstrated that prenatal DEX treatment is associated with cognitive dysfunction and alterations in various proteins leading to metabolic changes in the frontal cortex, while in the hippocampus adaptation mechanisms were activated. The presented results imply that different pathophysiological metabolic processes may be involved in depression development, which may be useful in the search for novel therapies.

Features of the expression of Fox-1 in rat’s thyroid after prenatal dexamethasone action

The purpose of the work was to establish the features of Fox-1 expression and distribution in the parenchyma of the thyroid gland of rats in the postnatal period of ontogeny in the norm and after intrauterine action of dexamethasone.Material and methods: thyroid gland of rats (162 animals) of the Wistar line at the age from 1 to 14 days of postnatal development. Experimentally, the animals were injected intrauterinely with a solution of dexamethasone at a dose of 0.05 ml at a dilution of 1:40 on the 18th day of the dated pregnancy. The material was examined using a set of methods of morphological studies (production of histological serial sections, survey microscopy, morphometry, immunohistochemistry and statistical processing).Results of the research. In the thyroid glands of neonatal prenatal dexamethasone, the parenchyma was well developed and consisted of hollow colloid-type follicles and single colloid-type microfollicles, and a bright cytoplasmic reaction with Fox-1 antibodies was observed throughout the organ parenchyma. In the thyroid glands of animals of the 3rd day of life, morphological changes occurred in all groups of the experiment. In animals of the experimental group, hollow follicles of colloidal type of small, medium and large diameter were chaotically visualized throughout the body, and large follicles of irregular shape with immunohistochemical weak or negative reaction with Fox-1 antibodies in thyrocytes and lumen without colloidal evidence, which detected a decrease in the specific synthetic activity in these thyrocytes. On day 7 in the experimental group in the flattened thyrocytes of overstretched follicles, the expression of Fox-1 was present only in the apical part. On days 11-14 of postnatal development in the thyroid glands of rats experimentally prenatally exposed to dexamethasone in the wall of large follicles with flattened epithelium began extrafollicular proliferation of thyrocytes on the background of visualization in the lumen of these follicles desquamated cells. Intensive perinuclear and cytoplasmic Fox-1 positive reaction was present in extrafollicular proliferating thyrocytes.Conclusions. 1. The detected changes in the first day of life in the thyroid gland of rats indicated that prenatal administration of dexamethasone affects the intensification of differentiation not only structural and functional units - follicles, but also a specific synthetic intracellular apparatus of thyrocytes, judging by the intensification of Fox-1. Thus, immature pre-mRNA is converted into mature mRNA, from which thyroid proteins, in particular thyroglobulin, are translated. By the time of birth, this process in the experimental group reaches a significant development, covering the entire parenchyma of the gland. 2. In rats prenatally receiving dexamethasone, the period of lactation was characterized by intense structural changes in the thyroid gland, in particular intracellularly in thyrocytes of monolayer flattened epithelium, the expression of Fox-1 antibodies was sharply reduced, which was then replaced by a bright cytoplasmic reaction in proliferative clusters and follicles of colloidal type of secretion, which is an adaptive-compensatory mechanism of intracellular enhancement of proliferation of synthesizing organelles in response to the restructuring of a significant number of existing follicles by hypofunctional type, aimed at maintaining normal levels of thyroid function.

Role of curcumin in ameliorating hazards caused by prenatal dexamethasone administration on development of the neonates suprarenal glands in albino rats ,( Light microscopic study).

AAbstract: Introduction: The dexamethasone (Dx) is a synthetic glucocorticoid that pass through placental barrier especially in late gestation and affects the growth and maturation of most of fetal tissues so that The Dx is commonly used drug in preterm delivery to promote fetal lung growing, lowering the postnatal deaths from respiratory distress diseases.Aim of work: This study was carried out to study the effects of dexamethasone on the development of neonates suprarenal gland and possible protective effect of curcumin against this. Material & Methods: In this study a total of 12 adult pregnant female albino rats were included. The animals were subdivided into 3 groups, five rats for each group. the offspring were scarified at birth. The suprarenal glands were processed for light microscope studies . Results: Variable pathological changes were observed in adrenal cortex of the dexamethasone treated group compared to the control one and these changes become little or not present on the curcumin and dexamethasone treated group. conclusion: prenatal dexamethasone administration has enormous destructive effects on both the structure and fine structure of the developing adrenal gland. Therefore, it is highly recommended that its use must be restricted to the urgent necessity and in such case, curcumin as a potent antioxidant, can be utilized to ameliorate these adverse effects. Keywords: development, adrenal gland, Dexamethasone, curcumin.

Immunohistochemical features of expression and distribution of antibodies to thyroglobulin in the thyroid glands of newborn rats after prenatal exposure of dexamethasone

In clinical practice, synthetic glucocorticoids, such as dexamethasone, are used to accelerate fetal maturation in pregnant women at risk of preterm birth. Increasing the concentration of cortisol in humans and other mammals often causes structural and functional changes in fetal tissues, preparing it for childbirth and extrauterine life, but they can have long-term consequences in the structural organization of organs postnatally. Despite the large number of studies on the effect of glucocorticoids on the fetus, there are almost no data on the prenatal effect of dexamethasone on the processes of synthesis and resorption of thyroglobulin by thyroid thyrocytes in the postnatal period of life. Therefore, the aim of the study was to determine the immunohistochemical features of expression and distribution of antibodies to thyroglobulin in the thyroid glands of newborn rats in normal and after prenatal exposure to dexamethasone. The study material was the thyroid gland of Wistar rats aged 1 to 7 days of postnatal development (54 animals): I group - intact animals (norm); ІІ group - control, animals which were injected with 0.9% NaCl solution at a dose of 0.05 ml to each fetus on the 18th day of dated pregnancy; III group - experimental animals, which were administered a solution of dexamethasone at a dilution of 1:40 at a dose of 0.05 ml to each fetus on the 18th day of the date of pregnancy operatively during laparotomy, by intrauterine, transdermal subcutaneous injection into the interscapular area (Ukrainian patent №112288). Thyroglobulin Antibody (2H11) monoclonal antibodies: sc-51708 from Santa Cruz Biotechnology, Inc. were used for immunohistochemical study. Photo documentation of the studied objects was performed using a “Primo Star” microscope (Carl Zeiss, Germany) using an AxioCam camera using the Zeiss Zen program (2011). Analysis of micropreparations of thyroid glands of intact and control rats showed invariance of thyroglobulin synthesis and its accumulation, which was expressed by sufficient immunohistochemical expression of antibodies to thyroglobulin (ТgAb+). Prenatal administration of dexamethasone leads to intensification of the processes of morphological development of hormone-producing structures (follicles and follicular epithelium), production, resorption and iodination of thyroglobulin. This is evidenced by immunohistochemical studies found in 1-3 days of the neonatal period. It should be noted that on the 7th day of life the newborn was found intense changes in the structure of the parenchyma of the thyroid gland of animals of the experimental group: increased relative percentage of follicle cavity due to increased number of large and medium, some follicles had no resorption vacuoles which was accompanied by a slowdown in the excretion of hormones into the bloodstream and led to overstretching of the follicles and, as a consequence, to the flattening of the thyroid epithelium. Intrauterine administration of dexamethasone leads to prenatal acceleration of structure formation, folliculogenesis and enhancement of hormone-producing function, which is confirmed by the peculiarities of immunohistochemical expression of TgAb. By the end of the neonatal period in rats prenatally exposed to dexamethasone, the thyroid gland is depleted of compensatory-reactive internal reserves, which is morphologically and immunohistochemically manifested by signs of hypofunction and hypertrophy. Thus, detected in the thyroid glands of animals prenatally exposed to dexamethasone, aberration of cytoplasmic expression of ТgAb+, intensification of colloidal expression of ТgAb+, flattening of thyroid epithelium, and the absence of resorption vacuoles are signs of impaired hormone-forming function, which is the morphological basis for the development of hypofunctional states and requires further study.

Protection of Male Rat Offspring against Hypertension Programmed by Prenatal Dexamethasone Administration and Postnatal High-Fat Diet with the Nrf2 Activator Dimethyl Fumarate during Pregnancy.

Hypertension can originate from early-life exposure to oxidative stress. As reported, dimethyl fumarate (DMF) activates nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and protects against oxidative stress damage. We examined whether maternal DMF therapy protects adult offspring against hypertension programmed by prenatal dexamethasone (DEX) and postnatal high-fat (HF) diet exposure. We examined male Sprague Dawley rat offspring at 4 months of age from five groups (n = 11–13/group): control, DEX (0.1mg/kg i.p. from gestational day 16 to 22), HF (D12331 diet from weaning to 16 weeks of age), DEX+HF, and DEX+HF+DMF (50mg/kg/day via gastric gavage for 3 weeks during pregnancy). Maternal DMF therapy prevented male offspring against hypertension programmed by combined DEX and HF exposures. The protective effects of maternal DMF include reduced oxidative stress, decreased plasma asymmetric dimethylarginine (ADMA) levels, downregulated the renin-angiotensin system (i.e. Ren, Agt, Ace, and Agtr1a), increased renal protein levels of certain nutrient-sensing signals, and promoted autophagy. In conclusion, maternal Nrf2 activation by DMF protects male adult offspring against hypertension programmed by combined DEX and HF exposures. Our results cast a new light on the therapeutic potential of targeting Nrf2 signaling pathway as reprogramming strategies to prevent programmed hypertension in children exposed to antenatal corticosteroids and postnatally excessive consumption of fat.

Prenatal Administration of Dexamethasone Leads to Decreased Lysine 24 Acetylation of Histone H3 in the Neocortex and Hippocampus of Adult Rats

Dexamethasone, as well as other synthetic glucocorticoids, is widely employed in general obstetric practice. The principal indication for glucocorticoid treatment is a risk of miscarriage. However, certain data suggest that glucocorticoid administration during pregnancy may lead to aberrations of brain development and behavior in the offspring. Current research suggests that such aberrations are frequently mediated by epigenetic mechanisms. The goal of the present work was to investigate the patterns of histone H3 acetylation at lysine 24 (acH3K24) in neurons of the hippocampus and the neocortex of adult rats following administration of dexamethasone (0.8 mg/kg) in the beginning and the end of week 3 of their prenatal development. Immunohistochemical analysis was used to describe changes in the acH3K24 content in the cells of the hippocampus and the neocortex of adult rats after exposure to dexamethasone on gestation days 14–16 and 17–19. The principal differences concerned the number of cells strongly stained with acH3K24-specific antibodies. In particular, exposure to dexamethasone led to a decrease in the number of cells with a high acH3K24 content in the CA1 field and the dentate gyrus of the hippocampal formation, Specifically, this decrease constituted 53.5 and 76% in CA1 and 39.7 and 87.8% in the dentate gyrus following dexamethasone administration on gestation days 14–16 and 17–19, respectively. In cortical layer 5, the abundance of acH3K24 decreased (to 55% of the control level) following dexamethasone administration on gestation days 17–19, but not on days 14–16. The observed modifications of the epigenetic status of brain cells of rats exposed to dexamethasone may underlie the long-lasting changes in behavior and learning capacity described in our previous studies.

Effects of Late Gestational Fetal Exposure to Dexamethasone Administration on the Postnatal Hypothalamus-Pituitary-Adrenal Axis Response to Hypoglycemia in Pigs

Background: Prenatal glucocorticoid administration alters the activity of the fetal hypothalamic-pituitary-adrenocortical axis (HPAA), and correspondingly the adenocorticotropic hormone (ACTH) and cortisol levels after birth. The dosages required for these effects are critically discussed. Activation of the HPAA is related to metabolic syndrome and diabetes mellitus. Hypoglycemia is the classic side effect of antidiabetic treatment. We hypothesized that a low dosage of dexamethasone in late pregnancy alters the HPAA response to hypoglycemia in pigs. Methods: 12 pregnant sows were randomly assigned to two groups which received either a low-dose intramuscular injection (99th and 100th day of gestation) of dexamethasone (0.06 μg/kg body weight) or vehicle. Three months after birth, 18 dexamethasone-treated anaesthetized offspring and 12 control offspring underwent a 75 min hypoglycemic clamp (blood glucose below 4 mmol/L) procedure. Heart rate (HR), blood pressure, ACTH and cortisol levels and body weight (at birth and after three months) were recorded. Results: Dexamethasone-treated animals exhibited significantly elevated ACTH (139.9 ± 12.7 pg/mL) and cortisol (483.1 ± 30.3 nmol/L) levels during hypoglycemia as compared to the control group (41.7 ± 6.5 pg/mL and 257.9 ± 26.7 nmol/L, respectively), as well as an elevated HR (205.5 ± 5.7 bpm) and blood pressure (systolic: 128.6 ± 1.5, diastolic: 85.7 ± 0.7 mmHg) response as compared to the control group (153.2 ± 4.5 bpm; systolic: 118.6 ± 1.6, diastolic: 79.5 ± 1.4 mmHg, respectively; p < 0.001). Conclusions: Low-dose prenatal administration of dexamethasone not only exerts effects on the HPAA (ACTH and cortisol concentration) and vital parameters (HR and diastolic blood pressure) under baseline conditions, but also on ACTH, HR and systolic blood pressure during hypoglycemia.

High glucocorticoid levels during gestation activate the inflammasome in hippocampal oligodendrocytes of the offspring.

Exposure to high levels of glucocorticoids (GCs) during early life induces long-lasting neuroinflammation. GCs induce rapid degranulation of mast cells, which release proinflammatory molecules promoting activation of microglia and astrocytes. The possible involvement of oligodendrocytes, however, remains poorly understood. It was studied whether high GC levels during gestation activates the inflammasome in hippocampal oligodendrocytes of mouse offspring. Oligodendrocytes of control pups showed expression of inflammasome components (NLRP3, ACS, and caspase-1) and their levels were increased by prenatal administration of dexamethasone (DEX), a synthetic GC. These cells also showed high levels of IL-1β and TNF-α, revealing activation of the inflammasome. Moreover, they showed increased levels of the P2X7 receptor and pannexin1, which are associated to inflammasome activation. However, levels of connexins either were not affected (Cx29) or reduced (Cx32 and Cx47). Nonetheless, the functional states of pannexin1 and connexin hemichannels were elevated and directly associated to functional P2X7 receptors. As observed in DEX-treated brain slices, hemichannel activity first increased in hippocampal mast cells and later in microglia and macroglia. DEX-induced oligodendrocyte hemichannel activity was mimicked by urocortin-II, which is a corticotropin-releasing hormone receptor (CRHR) agonist. Response to DEX and urocortin-II was inhibited by antalarmin (a CRHR blocker) or by mast cells or microglia inhibitors. The increase in hemichannel activity persisted for several weeks after birth and cross-fostering with a control mother did not reverse this condition. It is proposed that activation of the oligodendrocyte inflammasome might be relevant in demyelinating diseases associated with early life exposure to high GC levels. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 625-642, 2017.

Role of renal sympathetic nerve activity in prenatal programming of hypertension.

Prenatal insults, such as maternal dietary protein deprivation and uteroplacental insufficiency, lead to small for gestational age (SGA) neonates. Epidemiological studies from many different parts of the world have shown that SGA neonates are at increased risk for hypertension and early death from cardiovascular disease as adults. Animal models, including prenatal administration of dexamethasone, uterine artery ligation and maternal dietary protein restriction, result in SGA neonates with fewer nephrons than controls. These models are discussed in this educational review, which provides evidence that prenatal insults lead to altered sodium transport in multiple nephron segments. The factors that could result in increased sodium transport are discussed, focusing on new information that there is increased renal sympathetic nerve activity that may be responsible for augmented renal tubular sodium transport. Renal denervation abrogates the hypertension in programmed rats but has no effect on control rats. Other potential factors that could cause hypertension in programmed rats, such as the renin-angiotensin system, are also discussed.

Prenatal Dexamethasone Exposure Increases the Susceptibility to Autoimmunity in Offspring Rats by Epigenetic Programing of Glucocorticoid Receptor.

Objective. Prenatal glucocorticoids (GC) can induce long term effects on offspring health. However, reports and related studies regarding the prolonged effects of prenatal GC on the development of autoimmunity are limited. Here, we aimed to explore the immunological effects of dexamethasone (DEX) exposure on young adults and whether glucocorticoid receptor (GR) is involved in this process. Methods. Wistar rats were given DEX during pregnancy. Susceptibility to autoimmunity in offspring was assessed using experimental autoimmune encephalomyelitis (EAE) and adjuvant-induced arthritis (AIA) animal models. To reveal the possible mechanism, glucocorticoid response, GR expression, and methylation status were measured in peripheral blood mononuclear cells (PBMCs). Results. Our results showed that the DEX-treated rats had greater susceptibility to EAE (100% versus 62.5%, P < 0.05) and AIA (63.6% versus 0%, P < 0.05) than saline control group. Glucocorticoid response and GR expression were decreased in DEX rats. Significant difference was also found in the methylation levels of GR exon 1-10 to exon 1-11 region. Conclusions. Prenatal DEX administration increases the susceptibility to autoimmune diseases, which is potentially mediated by programming GR methylation status and glucocorticoid sensitivity.

Prenatal glucocorticoid exposure in rats: programming effects on stress reactivity and cognition in adult offspring

Human epidemiological studies have provided compelling evidence that prenatal exposure to stress is associated with significantly increased risks of developing psychiatric disorders in adulthood. Exposure to excessive maternal glucocorticoids may underlie this fetal programming effect. In the current study, we assessed how prenatal dexamethasone administration during the last week of gestation affects stress reactivity and cognition in adult offspring. Stress reactivity was assessed by evaluating anxiety-like behavior on an elevated plus maze and in an open field. In addition, to characterize the long-term cognitive outcomes of prenatal exposure to glucocorticoids, animals were assessed on two cognitive tasks, a spatial reference memory task with reversal learning and a delayed matching to position (DMTP) task. Our results suggest that prenatal exposure to dexamethasone had no observable effect on anxiety-like behavior, but affected cognition in the adult offspring. Prenatally dexamethasone-exposed animals showed a transient deficit in the spatial reference memory task and a trend to faster acquisition during the reversal-learning phase. Furthermore, prenatally dexamethasone-treated animals also showed faster learning of new platform positions in the DMTP task. These results suggest that fetal overexposure to glucocorticoids programs a phenotype characterized by cognitive flexibility and adaptability to frequent changes in environmental circumstances. This can be viewed as an attempt to increase the fitness of survival in a potentially hazardous postnatal environment, as predicted by intrauterine adversity. Collectively, our data suggest that prenatal exposure to dexamethasone in rats could be used as an animal model for studying some cognitive components of related psychiatric disorders.

Prepubertal exposure to glucocorticoid delays puberty independent of the hypothalamic Kiss1-GnRH system in female rats

Secretion of glucocorticoids is widely known as a key endocrine response to stresses. Prenatal dexamethasone administration induces intrauterine growth retardation and delayed onset of puberty in female rats independent of the hypothalamic Kiss1-gonadotropin-releasing hormone (GnRH) system. The aim of this study was to evaluate the influence of chronic intracerebroventricular (central, CD) or subcutaneous (peripheral, PD) dexamethasone administration to prepubertal female rats on the onset of puberty and body weight change. Rats administered dexamethasone from day 25 to day 34 (CD and PD) showed significantly reduced body weight gain throughout the experimental period and delayed onset of vaginal opening compared with rats administered saline centrally (CS) or peripherally (PS). At 34 days old, hypothalamic Kiss1r mRNA levels were significantly lower with CD than with CS. No significant differences were seen between rats administered saline and rats administered dexamethasone with regard to hypothalamic Kiss1, GnRH and NPY mRNA levels or serum LH levels. Serum leptin concentrations were higher in CD and PD than in the controls (CS and PS). These results suggest that the delayed onset of puberty induced by prepubertal dexamethasone administration occurs independent of the hypothalamic Kiss1-GnRH system.

Prenatal administration of dexamethasone during early pregnancy negatively affects placental development and function in mice1

Prenatal treatment of dexamethasone, a synthetic stress hormone, leads to low birth weight and affects adult pathophysiology. Because fetal growth and survival are critically dependent on successful placental development, we aimed to investigate the effects of prenatal dexamethasone exposure on placental growth and function, particularly focusing on issues surrounding the time of stress exposure in a developmental context. Dexamethasone was administered at a dosage of 1 mg/kg BW (DEX1) or 10 mg/kg BW (DEX10) intraperitoneally at gestational d 7.5, 8.5, and 9.5 in pregnant mice. Placentas were then dissected at gestational d 11.5 and 18.5. Placental size and weight were reduced at d 11.5 in a dose-dependent manner (P = 0.11 for saline vs. DEX1 and P < 0.001 for DEX1 vs. DEX10 in size; P = 0.34 for saline vs. DEX1 and P < 0.01 for DEX1 vs. DEX10 in weight). In contrast, a considerable heterogeneity was shown at d 18.5, especially in DEX10-treated mice. Some placentas were small and malformed whereas some were enlarged with structural abnormalities in spongiotrophoblasts and labyrinth layers. Although placental overgrowth under such condition seemed to compromise fetal demand for nutrient supply, disorganized cell structure with reduced fetal vasculature observed in large placentas suggests that prenatal stress exposure during the early gestational period negatively affects placental development and efficiency.

Maternal treatment with dexamethasone at minimal therapeutic doses inhibits neonatal bone development in a gender-dependent manner

The structural quality of bone is genetically determined, and remains under the influence of hormonal modification. A gender-dependent effect of prenatal treatment with multiple therapeutic minimal doses of dexamethasone (DEX) on the growth and mineralisation of the skeletal system of piglets at weaning was considered in undertaking this study. Sows were treated i.m. with DEX at the dose of 0.03mgkg−1 body weight every second day during the last 45 days of pregnancy. Prenatal treatment with DEX resulted in decreased weight, length, geometric parameters and histomorphometry of limb bones and influenced bone quality which was expressed by decreased values of bone mineral density (BMD), ultimate and maximum elastic strengths about 40%, 60% and 40%, respectively. Prenatal DEX administration to male piglets via their mothers significantly enhanced the concentration of leptin and decreased the concentration of GH and insulin. Additionally, the negative effect of DEX treatment on bone tissue was connected with changes of the free amino acid pool of male piglets. In addition, female pigs had unaffected mass and length of bones. This result showed that maternal DEX action was multifactorial and differently influenced postnatal bone development in the female and male piglets.

The Effects of Dexamethasone Treatment in Early Gestation on Hypothalamic–Pituitary–Adrenal Responses and Gene Expression at 7 Months of Postnatal Age in Sheep

We determined the effects of prenatal dexamethasone administration in early gestation on development of the hypothalamic-pituitary-adrenal (HPA) axis up to 7 months of postnatal age with measurements of hormone levels and gene expression. Plasma adrenocorticotropic hormone and cortisol levels after corticotropin-releasing hormone (CRH)/arginine vasopressin challenge were lower in treatment females than in control females and treatment males. Calculation of cortisol to adrenocorticotropic hormone ratios indicated however that the adrenals of treatment females were more responsive to adrenocorticotropic hormone than control females or treatment males. Effects of treatment and sex dependence at 7 months of age were observed in levels of hypothalamic CRH messenger RNA (mRNA), hypothalamic arginine vasopressin mRNA, pituitary proopiomelanocortin mRNA, pituitary prohormone convertase 1 and prohormone convertase 2, glucocorticoid receptor and mineralocorticoid receptor in the hypothalamus and hippocampus, adrenal adrenocorticotropic hormone receptor, steroidogenic acute regulatory, 3β hydroxysteroid dehydrogenase, and 11β hydroxysteroid dehydrogenase type 2 mRNA. The results indicate that exposure to glucocorticoids in early pregnancy produces persisting and sex-dependent effects on the hypothalamic-pituitary-adrenal axis at 7 months of age.

Comparison of effects of prenatal administration of dexamethasone and ambroxol on expression of Toll-like receptor 4 of fetal and neonatal rats

Objective To investigate the role of prenatal single-dose administration of dexamethasone and ambroxol on the expression of Toll-like receptor 4 (TLR4) of fetal and neonatal rats. Methods Fifty-four pregnant rats were randomly divided into three groups with eighteen rats in each group:rats treated with 0.2 mg/kg dexamethasone (group 1),0.2 mg/kg dexamethasone and 100 mg/kg ambroxol (group 2),or saline(controls) on the 17th day of gestation.The lung tissues of the offsprings were harvest independently on the 19th day of gestation,the postnatal 3 days and 7 days.The expressions of TLR4 in fetal/neonatal rat lungs of each pregnant rat were analyzed by reverse transcription-polymerase chain reaction(RT-PCR),immunohistochemistry stain,and Western blot. ANOVA and two independent samples t-test were applied. Results On the 19th day of pregnancy,TLR4 mRNA expression was up-regulated in lungs of the two treatment groups compared with controls(controls:0.26 ± 0.18,group 1:0.39 ± 0.21,t =5.866,P＜ 0.05 ; control:0.27 ± 0.22,group 2:0.46 ± 0.13,t =9.572,P＜ 0.01 ).TLR4 mRNA expression was up-regulated in group 2 compared with controls on the postnatal 3 days and 7 days(postnatal 3 d:0.59 ± 0.23 and 0.47 ±0.24,t=2.295,P＜0.05;postnatal 7 d:0.52±0.12 and 0.35±0.17,t=4.219,P＜0.05),while no significant difference was found in group 1 compared with the controls(postnatal 3 d:0.45±0.22 and 0.44±0.14,t=0.128,P＞0.05; postnatal 7 d:0.40±0.16 and 0.36 ±0.12,t=1.365,P＞0.05).Results of the immunohistochemistry demonstrated that on the 19th day of pregnancy,the protein expression of TLR4 was significantly increased in the two treatment groups (controls:0.20 ± 0.29,group 1:0.35±0.32,t=7.179,P＜0.05 ;controls:0.20±0.29,group 2:0.39±0.25,t=10.764,P＜0.01).The protein expression of TLR4 was significantly increased in group 2 on the postnatal 3 days and 7 days(postnatal 3 d:0.55±0.32 and 0.37±0.18,t=7.121,P＜0.05;postnatal 7 d:0.41±0.29and 0.25±0.24,t=6.355,P＜0.05),while no notable difference was found between group 1 and the control (postnatal 3 d:0.40±0.21 and 0.37±0.18,t=0.683,P＞0.05 ;postnatal 7 d:0.28±0.31 and 0.25±0.24,t=0.462,P＞0.05).Results of the Western blot demonstrated that on the 19th day of pregnancy,the protein expression of TLR4 was significantly increased in the two treatment groups (controls:0.15 ± 0.12,group 1:0.27± 0.20,t =7.835,P＜0.05; controls:0.16 ± 0.18,group 2:0.34±0.16,t=10.470,P＜0.01).The protein expression of TLR4 was significantly increased in lungs of the combination administration group on the postnatal 3 days and 7 days(postnatal 3 d:group 2:0.37±0.20 and 0.25±0.22,t=6.379,P＜0.05; postnatal 7 d:0.35±0.15 and 0.24±0.13,t=5.152,P＜0.05),while no notable difference could be found between group 1 and the control (postnatal3 d:0.32±0.26 and 0.25±0.16,t=1.167,P＞0.05; postnatal 7 d:0.29±0.19 and 0.24±0.10,t =1.248,P ＞ 0.05 ). Conclusions Prenatal single-dose administration of dexamethasone may up-regulate the expression of TLR4 in the rat fetal lung.The up-regulation of TLR4 might be one of the critical factors for glucocorticoid-induced maturity of fetal lung.Prenatal single-dose administration of dexamethasone and ambroxol may have effects on the regulation of TLR4 not only in fetal rats,but also in neonatal rats. Key words: Dexamethasone; Ambroxol; Lung; Toll-like receptor 4; Fetal organ maturity; Rats

Prenatal programming of rat cortical collecting tubule sodium transport

Prenatal insults have been shown to lead to elevated blood pressure in offspring when they are studied as adults. Prenatal administration of dexamethasone and dietary protein deprivation have demonstrated that there is an increase in transporter abundance for a number of nephron segments but not the subunits of the epithelial sodium channel (ENaC) in the cortical collecting duct. Recent studies have shown that aldosterone is elevated in offspring of protein-deprived mothers when studied as adults, but the physiological importance of the increase in serum aldosterone is unknown. As an indirect measure of ENaC activity, we compared the natriuretic response to benzamil in offspring of mothers who ate a low-protein diet (6%) with those who ate a normal diet (20%) for the last half of pregnancy. The natriuretic response to benzamil was greater in the 6% group (821.1 ± 161.0 μmol/24 h) compared with the 20% group (279.1 ± 137.0 μmol/24 h), consistent with greater ENaC activity in vivo (P < 0.05). In this study, we also directly studied cortical collecting tubule function from adult rats using in vitro microperfusion. There was no difference in basal or vasopressin-stimulated osmotic water permeability. However, while cortical collecting ducts of adult offspring whose mothers ate a 20% protein diet had no sodium transport (-1.9 ± 3.1 pmol·mm(-1)·min(-1)), the offspring of rats that ate a 6% protein diet during the last half of pregnancy had a net sodium flux of 10.7 ± 2.6 pmol·mm(-1)·min(-1) (P = 0.01) in tubules perfused in vitro. Sodium transport was measured using ion-selective electrodes, a novel technique allowing measurement of sodium in nanoliter quantities of fluid. Thus we directly demonstrate that there is prenatal programming of cortical collecting duct sodium transport.

Postnatal administration of 2-oxoglutaric acid improves the intestinal barrier affected by the prenatal action of dexamethasone in pigs

ObjectiveThe potential effects of the prenatal administration of dexamethasone and the postnatal treatment with 2-oxoglutaric acid on postnatal development of the small intestine of farm animals have not been examined experimentally. The aim of this study was to establish the changes in morphologic parameters of the small intestine damaged by the prenatal action of dexamethasone in piglets supplemented with 2-oxoglutaric acid. MethodsThree milligrams dexamethasone was administered intramuscularly every second day from day 70 of pregnancy to parturition and then piglets were supplemented with 2-oxoglutaric acid for 35 d of postnatal life (0.4 g/kg of body weight). The histomorphometry of the pig duodenum and jejunum was determined. Immunohistochemical staining with anti–Ki-67, CD3, null T cells, cadherin, claudin, and neurofilament antibodies was performed. ResultsMaternal treatment with dexamethasone decreased and limited the expression of claudin and cadherin in the epithelium. Dexamethasone led to thinning of the myenteron of the duodenum and the middle part of the jejunum in weaned piglets and influenced duodenal glands that became more elongated compared with control glands. Moreover, 2-oxoglutaric acid increased cell proliferation and the amount and maturity of peripheral blood lymphocytes in the duodenum and jejunum. It supported epithelial integrity and changed the circularity of the nerve plexuses. ConclusionThe 2-oxoglutaric acid administered to piglets while suckling induced a complete recovery from intestinal damage caused by the prenatal action of dexamethasone.