Effects Of Prenatal Dexamethasone Treatment Research Articles

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.

Sex difference in adrenal developmental toxicity induced by dexamethasone and its intrauterine programming mechanism

Dexamethasone is widely used to treat preterm labor and related diseases. However, prenatal dexamethasone treatment (PDT) can cause multiorgan developmental toxicities in offspring. Our previous study found that the occurrence of fetal-originated diseases was associated with adrenal developmental programming alterations in offspring. Here, we investigated the effects of PDT on adrenal function in offspring and its intrauterine programming mechanism. A rat model of PDT was established to observe the alterations of adrenal steroidogenesis in offspring. Furthermore, we confirmed the sex differences of adrenal steroidogenesis and its molecular mechanism combined with in vivo and in vitro experiments. PDT caused a decrease in adrenal steroidogenic function in fetal rats, but it was decreased in males and increased in females after birth. Meanwhile, the adrenal H3K14ac level and expression of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) in PDT offspring were decreased in males and increased in females, suggesting that 11β-HSD2 might mediate sex differences in adrenal function. We further confirmed that dexamethasone inhibited the H3K14ac level and expression of 11β-HSD2 through the GR/SP1/p300 pathway. After bilateral testectomy or ovariectomy of adult PDT offspring rats, adrenal 11β-HSD2 expression and steroidogenic function were both reduced. Using rat primary fetal adrenal cells, the differential expression of AR and ERβ was proven to be involved in regulating the sex difference in 11β-HSD2 expression. This study demonstrated the sex difference in adrenal steroidogenic function of PDT offspring after birth and elucidated a sex hormone receptor-dependent epigenetically regulating mechanism for adrenal 11β-HSD2 programming alteration.

Early and late effects of prenatal corticosteroid treatment on the microRNA profiles of lung tissue in rats.

Glucocorticoids have been administered to mothers at risk of premature delivery to induce maturation of preterm fetal lungs and prevent the development of respiratory distress syndrome. Micro (mi)RNAs serve various crucial functions in cell proliferation, differentiation and organ development; however, few studies have demonstrated an association between miRNAs and lung development. The aim of the present study was to investigate alterations in the miRNA profiles of rat lung tissue following prenatal glucocorticoid therapy for fetal lung development. The differences in miRNA expression profiles were compared between postnatal days 7 (D7) and 120 (D120) rat lung tissues, followed by validation using reverse transcription-quantitative polymerase chain reaction. The miRNA profiles of rat lung tissues following prenatal dexamethasone (DEX) therapy were also investigated. miRNAs with 2-fold changes were selected for further analysis. At D120, 6 upregulated and 6 downregulated miRNAs were detected, compared with D7. Among these differentially expressed miRNAs, miR-101-3p and miR-99b-5p were associated with the lowest and highest expressions of miRNA at D7, respectively. A limited impact on the miRNA profiles of rat lung tissues was observed following prenatal DEX treatment, which may help to further clarify the mechanisms underlying normal lung development. However, the results of the present study cannot entirely elucidate the effects of prenatal DEX treatment on the lung development of premature infants, and further studies investigating the impact of prenatal corticosteroids on fetal lung miRNA profiles are required.

Gender-dependent effect of prenatal dexamethasone treatment on the concentration of selected hormones, bone alkaline phosphatase, osteocalcin and insulin-like growth factor-1 in serum obtained from male and female piglets at the age of 35 days

Gender-dependent effect of prenatal dexamethasone treatment on the concentration of selected hormones, bone alkaline phosphatase, osteocalcin and insulin-like growth factor-1 in serum obtained from male and female piglets at the age of 35 days

Prenatal Dexamethasone Exposure Does Not Alter Blood Pressure and Nephron Number in the Young Adult Marmoset Monkey

The influence of prenatal factors on the development of arterial hypertension has gained considerable interest in recent years. Prenatal dexamethasone exposure was found to induce hypertension and to alter nephron number and size in rodents and sheep. However, it is not clear whether these findings are applicable to nonhuman primates. Thus, we examined the effects of prenatal dexamethasone treatment on blood pressure (BP) and nephron number in marmoset monkeys. Fifty-two marmosets were allotted to 3 groups according to the gestational stage during which their mothers were exposed to oral 5-mg/kg dexamethasone for 7 days (gestation period: 20 weeks): (1) the early dexamethasone group at week 7; (2) the late dexamethasone group at week 13; and (3) the control group. BP was determined by telemetric (n=12) or cuff measurements (n=30), along with cystatin C, proteinuria, and body weight. All of the animals were euthanized at the age of 24 months, and glomerular number and volume were determined. Prenatal exposure to dexamethasone did not lead to a significant difference between the groups with regard to BP, kidney morphology and function, or body weight. BP correlated significantly with body weight, relative kidney weight, and mean glomerular volume and the body weight with the glomerular volume regardless of dexamethasone treatment. In conclusion, prenatal exposure to dexamethasone in marmosets does not, in contrast to other mammals studied, result in hypertension or changes in kidney morphology. Our data support the role of body weight as a predictor of elevated glomerular volume and BP development rather than prenatal dexamethasone exposure.

Effects of Prenatal Dexamethasone Treatment on Physical Growth, Pituitary-Adrenal Hormones, and Performance of Motor, Motivational, and Cognitive Tasks in Juvenile and Adolescent Common Marmoset Monkeys

Synthetic glucocorticoids such as dexamethasone (DEX) are commonly used to prevent respiratory distress syndrome in preterm infants, but there is emerging evidence of subsequent neurobehavioral abnormalities (e.g. problems with inattention/hyperactivity). In the present study, we exposed pregnant common marmosets (Callithrix jacchus, primates) to daily repeated DEX (5 mg/kg by mouth) during either early (d 42-48) or late (d 90-96) pregnancy (gestation period of 144 days). Relative to control, and with a longitudinal design, we investigated DEX effects in offspring in terms of physical growth, plasma ACTH and cortisol titers, social and maintenance behaviors, skilled motor reaching, motivation for palatable reward, and learning between infancy and adolescence. Early DEX resulted in reduced sociability in infants and increased motivation for palatable reward in adolescents. Late DEX resulted in a mild transient increase in knee-heel length in infants and enhanced reversal learning of stimulus-reward association in adolescents. There was no effect of either early or late DEX on basal plasma ACTH or cortisol titers. Both treatments resulted in impaired skilled motor reaching in juveniles, which attenuated in early DEX but persisted in late DEX across test sessions. The increased palatable-reward motivation and decreased social motivation observed in early DEX subjects provide experimental support for the clinical reports that prenatal glucocorticoid treatment impairs social development and predisposes to metabolic syndrome. These novel primate findings indicate that fetal glucocorticoid overexposure can lead to abnormal development of motor, affective, and cognitive behaviors. Importantly, the outcome is highly dependent upon the timing of glucocorticoid overexposure.

Prenatal corticosteroid exposure affects hippocampal plasticity and reduces lifespan

Synthetic corticosteroids, such as dexamethasone, are frequently administered to pregnant women at risk for preterm delivery. Endogenous corticosteroids are essential for normal development, but exposure to therapeutic doses at critical developmental stages may have adverse effects on the central nervous system. Major concern has arisen about long-term effects of corticosteroid treatment on brain plasticity, particularly in the hippocampus. Therefore, we analyzed the molecular, cellular, and behavioral effects of prenatal dexamethasone treatment on the adult hippocampus. Pregnant mice were treated at embryonic day 15.5 with a single dose of dexamethasone or saline. Adult offspring was analyzed for hippocampal neuron loss, cell proliferation, and NMDA receptor subunit expression. Hippocampal function was assessed in the Morris water maze and synaptic plasticity in the CA1 field by determining frequency dependence of LTP and LTD in hippocampal slices. Prenatal dexamethasone treatment decreased hippocampal cell proliferation in the dentate gyrus. Treated mice showed reduced LTD, impaired spatial learning, and a marked reduction in lifespan. Our data show long-term adverse effects of prenatal dexamethasone treatment on hippocampal function in mice and suggest accelerated aging. These findings indicate that it is important to be restrictive with corticosteroid administration during fetal development because of the lifelong consequences.

Effects of Prenatal Dexamethasone Treatment on Postnatal Physical, Endocrine, and Social Development in the Common Marmoset Monkey

The prophylactic treatment of diagnosed preterm delivery with synthetic glucocorticoids, such as dexamethasone (DEX), is commonplace. Long-term effects of such treatment are not well understood. In the present study, we exposed pregnant common marmosets (Callithrix jacchus), small-bodied monkeys that are therefore advantageous for long-term primate studies, to daily repeated DEX (5 mg/kg orally) either during early (d 42-48) or late (d 90-96) pregnancy (gestation period of 144 d). Relative to control, we investigated DEX effects in terms of maternal endocrinology (plasma cortisol and estrogen titers) and offspring physical growth, plasma and urinary ACTH and cortisol titers, and social and maintenance behaviors from birth to weaning. Both DEX treatments resulted in markedly reduced maternal plasma cortisol titers during treatment and reduced estimated gestation period. Both treatments were without effects on neonate morphometric measurements and basal hypothalamic-pituitary-adrenal axis activity. Early DEX treatment resulted in increased infant body weight at postnatal d 56 and 84, co-occurring at the behavioral level with increased time spent in eating solid food, a mobile state, solitary play, and exhibiting tail hair piloerection. The constellation of physical and behavioral effects of early DEX suggests interesting parallels with the human metabolic syndrome, providing primate support that the latter is causally associated with the fetal environment, including prenatal programming. This novel primate in vivo evidence for postnatal effects of prenatal synthetic glucocorticoid exposure indicates the importance of improved understanding of this acute clinical treatment in terms of its long-term effects on offspring well-being.

Prenatal dexamethasone exposure, postnatal development, and adulthood prepulse inhibition and latent inhibition in Wistar rats

Prenatal stress is an important risk factor in schizophrenia, and the aetiological factors mediating this relationship are central to the neurodevelopmental hypothesis of schizophrenia. The glucocorticoid receptor (GR) agonist dexamethasone (DEX) is commonly prescribed for prenatal conditions, and results in GR activation, which is part of the stress response. To investigate animal evidence for whether prenatal DEX leads to development of schizophrenia-like phenotypes, Wistar rats were prenatally exposed to DEX (0.1 mg/kg/day) between the gestational days 15 and 21, and tested in two paradigms known to be disrupted in schizophrenia patients: prepulse inhibition (PPI) and latent inhibition (LI). A cross-fostering design was used to allow dissociation of any direct prenatal effects on offspring from effects dependent on DEX exposure of the rearing dam. Pup birth weight was reduced by prenatal DEX treatment. DEX-treated dams demonstrated increased pup-directed behaviour. There were additive effects of prenatal DEX treatment and DEX treatment of rearing dam in terms of reduced body weight in adulthood. In one of two replications, PPI was increased by prenatal DEX in males only and specific to the highest prepulse intensity. There was no evidence that LI was disrupted by prenatal DEX treatment. This study does not provide support for the hypothesis that prenatal DEX exposure leads to schizophrenia-like deficits in PPI or LI, suggesting that GR prenatal programming is not a mechanism of direct relevance to the neurodevelopmental hypothesis of schizophrenia.

Prenatal programming of hepatocyte nuclear factor 4α in the rat: a key mechanism in the ‘foetal origins of hyperglycaemia’?

Prenatal glucocorticoid exposure causes lifelong hyperglycaemia in rat offspring, associated with permanently increased hepatic phosphoenolpyruvate carboxykinase 2 (PCK2), the rate-controlling enzyme of gluconeogenesis. To elucidate the mechanisms underlying the 'programming' of PCK2, this study examined the effect of prenatal dexamethasone treatment on expression of transcription factors that regulate Pck2. Real-time RT-PCR and in situ hybridisation were used to measure and localise hepatic mRNA transcribed from the genes for PCK2, hepatocyte nuclear factor 4, alpha (HNF4A), transcription factor 1 (TCF1), CCAAT/enhancer binding protein, alpha (CEBPA), CEBPB, the glucocorticoid receptor (NR3C1) and peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (PPARGC1A) in foetal and adult offspring of dams treated with dexamethasone or vehicle during the last week of gestation. Prenatal dexamethasone exposure significantly elevated Hnf4a mRNA expression in foetal and adult liver. This resulted from increased expression of isoforms derived from the 'adult' (P1) Hnf4a promoter. In contrast, isoforms from the 'foetal' (P2) promoter were markedly suppressed by dexamethasone. Like Pck2, the increase in hepatic Hnf4a mRNA occurred exclusively in the periportal zone. Foetal Tcf1 expression was also increased by dexamethasone treatment, but this did not persist into adulthood. Prenatal dexamethasone did not affect the amounts of foetal and/or adult Cebpa, Cebpb, Nr3c1 or Ppargc1a mRNA. Prenatal dexamethasone exposure caused a permanent increase in hepatic Hnf4a mRNA. This increase, which was associated with a premature switch from foetal to adult promoter predominance, was congruent with changes in Pck2 expression. These data suggest that HNF4A might mediate Pck2 overexpression and subsequent hyperglycaemia.

Programming effects of short prenatal exposure to dexamethasone in sheep.

Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of the present study were to see whether prenatal dexamethasone administered intravenously to the ewe between 26 to 28 days of gestation (1) resulted in high blood pressure in male and female offspring and whether hypertension in males was modulated by testosterone status, and (2) altered gene expression for angiotensinogen and angiotensin type 1 (AT1) receptors in the brain in late gestation and in the adult. Basal mean arterial pressure (MAP) at 2 years of age was significantly higher in wethers exposed to prenatal dexamethasone (group D; 106+/-5 mm Hg, n=9) compared with the control group (group S; 91+/-3 mm Hg, n=8; P<0.01). Infusion of testosterone for 3 weeks had no effect on MAP in either treatment group. At 130 days of gestation, dexamethasone administered between 26 to 28 days of gestation (group DF; n=8), resulted in an increased expression of angiotensinogen in hypothalamus (in arbitrary units: 2.5+/-0.3 versus 1.3+/-0.3 in the saline group [group SF], n=10; P<0.05). In addition, there was higher expression of the AT1 receptors in medulla oblongata in group DF (2.6+/-0.6 versus 1.1+/-0.2 in group SF; P<0.01). This effect of prenatal dexamethasone treatment was still evident in females at 7 years of age (group DA; n=5; 2.6+/-0.5 versus 1.1+/-0.2 in group SA; n=6, P<0.05). In conclusion, brief prenatal exposure of the pregnant ewe to dexamethasone leads to hypertension in adult animals of both sexes. Most interestingly, the mechanism leading to programming of hypertension might be linked with the brain angiotensin system.

Indicators of delayed maturation of rat heart treated prenatally with dexamethasone.

We investigated the effects of prenatal dexamethasone treatment on indicators of cardiac maturation: heart weight/body weight ratios, myosin heavy chain (MHC) expression, cell proliferation, and extracellular matrix. We administered dexamethasone, a synthetic glucocorticoid (approximately 48 microg/d, 3-wk slow release pellets), to pregnant rats (n = 8) beginning at 17 d postconception. Control dams were unmanipulated (n = 8). After approximately 4-5 d of dexamethasone exposure, hearts were collected from neonatal rats (12-24 h after birth). The prenatal dexamethasone treatment produced smaller pups with larger heart/body weight ratios, accompanied by a higher proliferative index and a reduction in extracellular matrix in the ventricles (with lowest values in the septal region) compared with control pups. We also report that, although there were no sex differences in body mass or heart and heart/body weight ratios, females had a greater proportion of cells synthesizing DNA in the heart. In addition, ventricles of male pups treated with dexamethasone contained lower levels of alpha-MHC mRNA, as reflected in a sex by treatment interaction. The changes in each parameter are consistent with delayed maturation. Our findings suggest that exposure to excess glucocorticoids in utero can affect cardiac development in potentially detrimental ways and that assessment of cardiac function should be closely monitored when such circumstances arise.

Prenatal dexamethasone administration to premature rats exposed to prolonged hyperoxia: A new rat model of pulmonary fibrosis (bronchopulmonary dysplasia)

Objective: To evaluate the postnatal effects of prenatal dexamethasone treatment of preterm rats and to test the hypothesis that prenatal dexamethasone treatment protects against pulmonary oxygen toxicity in the preterm rats and stimulates lung antioxidant enzyme levels in response to hyperoxia. Study design: We administered dexamethasone (0.4 mg/kg, intraperitoneally), or equivolume saline solution to pregnant rats at 48 and 24 hours before premature delivery at gestation day 21. Both groups of prematurely delivered rat pups were randomly assigned to either >95% O 2 or room air immediately after birth and brief resuscitation. Results: The hyperoxic survival rates from day 1 through day 14 were similar in both dexamethasone-treated and control preterm O 2 groups. At 7 days of hyperoxia, the preterm pups demonstrated similar lung antioxidant enzyme activity and surfactant content responses to high O 2 in the dexamethasone-treated and control groups. Lung quantitative morphometry changes were similar (equal degree of inhibition of normal alveolar development) in both groups. Unexpectedly, the lungs of the preterm O 2 control rats showed evidence of septal fibrosis and the pups that received dexamethasone-O 2 showed even greater severity of septal fibrosis and a greater increase (+50%) of lung hydroxyproline compared with the O 2 group control rats. Conclusions: In preterm animals, prenatal dexamethasone administration does not show any of the hypothesized protective effects against hyperoxia or protective biochemical lung changes during prolonged O 2 exposure. However, prenatal dexamethasone administration with prolonged exposure of the preterm rat to hyperoxia results in a pulmonary pathologic picture quite similar to bronchopulmonary dysplasia. (J Pediatr 1997;130:409-16)

Fetal dexamethasone exposure sensitizes neonatal rat brain to hypoxia: effects on protein and DNA synthesis

Fetal exposure to glucocorticoids is known to produce long-term alterations in cell development within the central nervous system. The current study examines whether some of the adverse effects of prenatal dexamethasone treatment on brain development represent sensitization to hypoxia-induced damage. Pregnant rats were given 0.2 or 0.8 mg/kg of dexamethasone on gestational days 17, 18 and 19 and their offspring were challenged by exposure to 7% O 2 on postnatal days 1 and 8. In control rats at 1 day of age, hypoxia evoked an acute decrease in protein synthesis, assessed by [ 3H]leucine incorporation, in both the midbrain + brainstem and forebrain. The decrease was also seen in animals receiving the low dose of dexamethasone, but was of smaller magnitude in the midbrain + brainstem than in the control cohort. At the higher dose of dexamethasone, hypoxia failed to evoke a decrease in protein synthesis; instead, protein synthesis was significantly increased. By 8 days of age, the animals receiving the lower dose of dexamethasone also displayed the anomalous increment in [ 3H]leucine incorporation during hypoxic challenge, whereas the effect in the high dose group was less notable. Similarly, parallel examination of incorporation of [ 3H]thymidine into DNA on postnatal day 1 indicated that control animals would reduce their macromolecule synthetic rate in a hypoxic environment, but that animals exposed to the high dose of dexamethasone would not; unlike the case with protein synthesis, however, the dexamethasone group never showed an increase in DNA synthesis during hypoxia. By 8 days of age, the interaction between the high dose of dexamethasone and hypoxia was no longer apparent for DNA synthesis. A reduction in macromolecule synthesis represents a conservative strategy for cell survival during restricted energy availability, and thus the repercussions of fetal dexamethasone exposure are maladaptive and likely to contribute to increased cell death during hypoxia. The selective enhancement of protein synthesis seen in dexamethasone-treated animals exposed to hypoxia, as opposed to the more moderate effects on DNA synthesis, suggests that specific proteins are being induced, perhaps those involved in the cellular shock response or programmed cell death.

Effect of dexamethasone or fetal lung 15-hydroxy-prostaglandin dehydrogenase: Possible mechanism for the prevention of patent ductus arteriosus by maternal dexamethasone therapy

Prenatal maternal glucocorticoid treatment has been reported to reduce the incidence of patent ductus arteriosus in prematurely born infants. Patency of the ductus arteriosus is thought to be maintained primarily by the vasodilatory effect of PGE, both in utero and in prematurely born infants, and lung is a major source of PGE, in fetuses and neonates. 15-Hydroxy-prostaglandin dehydrogenase (15-PGDH) catalyzes the initial reaction in converting biologically active PGE, to its inactive analogue, 15-keto-PGE 2. In the present study, effect of prenatal dexamethasone treatment on the activity of fetal rat lung 15-PGDH was studied at 20, 21 and 22 days of gestation. Activity of fetal lung 15-PGDH more than doubled from 20 to 22 days of gestation. Dexamethasone treatment at 0.4 mg/kg and 0.8 mg/kg significantly increased the activity of 15-PGDH in both 20- and 21-day fetuses but had no effect on 2 22-day fetuses. We speculate that the clinical observation that prenatal glucocorticoid treatment reduces the incidence of patent ductus arteriosus in premature infants say in part be due to the stimulatory effect of glucocorticoid-on the activity of 15-PGDH in fetal and neonatal lung and possibly other organs.

The Effect of Prenatal Dexamethasone Treatment on Oxygen Toxicity in the Newborn Rat

To determine whether prenatal corticosteroid therapy had adverse effects on the tolerance of the newborn lung to prolonged high O2 exposure, pregnant rats were given injections of dexamethasone (0.2 mg/kg) at 48 and 24 hours prior to parturition, and the newborn pups were placed in 96% to 98% O2 for the first seven days of life. Dexamethasone treatment resulted in significant decreases in body weight (-17%), lung weight (-30%), lung weight/body weight (-22%), and lung DNA (-18%) compared to untreated rat pups. Despite this growth inhibition, the dexamethasone-treated pups had improved survival in hyperoxia (36/48 = 75% vs 29/48 = 60% for untreated rats, P = .055). In addition, substantial "catch-up" lung growth had occurred by seven days and was complete in 28-day-old rats. Dexamethasone did not interfere with normal pulmonary antioxidant enzyme responses to hyperoxia. Thus, prenatal dexamethasone did not compromise the relative tolerance of the newborn to pulmonary O2 toxicity.