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Dexamethasone in the Last Week of Pregnancy Attenuates Hippocampal Glucocorticoid Receptor Gene Expression and Elevates Blood Pressure in the Adult Offspring in the Rat
Abstract
Human epidemiological data show a strong association between low birth weight and hypertension in adulthood, an effect that has been ascribed to ‘fetal programming’. In rats, fetoplacental exposure to maternally administered dexamethasone throughout gestation reduces birth weight and produces hypertensive adult offspring, though the mechanism is unclear. Pre- and postnatal stress programmes hypothalamic-pituitary-adrenal (HPA) axis responses throughout the lifespan, an effect thought to be mediated via permanent effects on glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) gene expression in the hippocampus. Corticosteroids also have specific central effects on blood pressure control mediated by GR and MR. This study investigated corticosterone (CORT) responses to restraint stress and GR and MR gene expression in areas of the brain postulated to mediate the central effects of corticosteroids on (i) HPA axis suppression (hippocampus), and (ii) blood pressure (organ vasculosum of the lamina terminalis (OVLT), sub-commissural organ, area postrema and nucleus tractus solitarius). Pregnant Wistar rats received dexamethasone (100 µg/kg·day–1) or vehicle on days 15–20 of gestation. This reduced birth weight by 11 %. When the offspring were 16 weeks old, blood pressure was recorded directly and plasma CORT measured basally (AM) and after 30 min restraint. GR and MR mRNA expression were determined by in situ hybridization. Blood pressure was significantly elevated in the adult offspring of dexamethasone-treated pregnancies (dexamethasone 144 ± 2/125 ± 2 mm Hg vs. control 133 ± 2.7/ 112 ± 2.8 mm Hg; both p
... Increasing significance has been placed on the fetal environment in the pathophysiology of the disease. Of particular interest is the role of GCs in fetal development and programming [1]. GCs can stimulate tissue maturation and fetal development; however, in times of stress, excess production of maternal GCs can negatively impact the fetus, promoting premature tissue development and programing for disease [1]. ...
... Of particular interest is the role of GCs in fetal development and programming [1]. GCs can stimulate tissue maturation and fetal development; however, in times of stress, excess production of maternal GCs can negatively impact the fetus, promoting premature tissue development and programing for disease [1]. As outlined in our previous paper, understanding how these changes in the fetal environment affect adult gene expression has been the key to unravelling the mechanisms involved in the fetal programming of hypertension [2]. ...
... VPA mediates HDACi and thus gene activation by reducing protein activity, potentially via binding to the catalytic centre [21]. VPA exhibits HDACi across several classes of HDACs including class 1 and some class 2 HDACs [1][2][3][4][5]7] and is a more potent inhibitor of class IIb HDACs [6, 10] [22]. VPA also displays some activity outside of HDACi, and HDACs can deacetylate proteins other than histones to alter activity. ...
The causes of hypertension are complex and involve both genetic and environmental factors. Environment changes during fetal development have been linked to adult diseases including hypertension. Studies show that timed in utero exposure to the synthetic glucocorticoid (GC) dexamethasone (Dex) results in the development of hypertension in adult rats. Evidence suggests that in utero stress can alter patterns of gene expression, possibly a result of alterations in the topology of the genome by epigenetic markers such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). The objective of this study was to determine the effects of epigenetic regulators in the fetal programming and the development of adult hypertension. Specifically, this research examined the effects of the HDAC inhibitor valproic acid (VPA) and the DNMT inhibitor 5-aza-2′-deoxycytidine (5aza2DC) on blood pressure (BP) and gene expression in prenatal Dex-programmed rats. Data suggest that both VPA and 5aza2DC attenuated the Dex-mediated development of hypertension and restored BP to control levels. Epigenetic DNMT inhibition (DNMTi) or HDAC inhibition (HDACi) also successfully attenuated elevations in the majority of altered catecholamine (CA) enzyme expression, phenylethanolamine N-methyltransferase (PNMT) protein, and elevated epinephrine (Epi) levels in males. Although females responded to HDACi similar to males, DNMTi drove increased glucocorticoid receptor (GR) and PNMT expression and elevations in circulating Epi in females despite showing normotensive BP.
... These studies suggest that increased fetal exposure to maternal glucocorticoids, due to reduced placental 11β-HSD-2 activity, may contribute to the reduction in birth weight . Furthermore, animal experiments using maternal low-protein diet (Langley & Jackson, 1994;Langley-Evans et al., 1996;Bertram et al., 2001), synthetic glucocorticoid administration Levitt et al., 1996;Celsi et al., 1998;Wyrwoll et al., 2006) or 11β-HSD-2 ...
... increased blood pressure (Levitt et al., 1996;Ortiz et al., 2001;Ortiz et al., 2003) in adult offspring. Antenatal glucocorticoid therapy in humans has been associated with higher systolic and diastolic blood pressures in adolescents who were born pre-term (Doyle et al., 2000); however, the effect on nephron number is unknown. ...
... Hence, factors that reduce fetal growth may permanently alter the structure and/or function of organs that program the individual for adult-onset diseases. Data from animal studies have demonstrated that increased fetal glucocorticoid exposure restricts growth and induces programming that predisposes the animal to disease later in life Levitt et al., 1996;Langley-Evans, 1997a;Dodic et al., 1998;Edwards et al., 2001;Nyirenda et al., 2001;Aghajafari et al., 2002;Ortiz et al., 2003). Late-gestation dexamethasone administration to pregnant rats reduced birth weight and programmed hypertension in adult offspring (Levitt et al., 1996;Ortiz et al., 2001;Ortiz et al., 2003;O'Regan et al., 2004). ...
... This may imply a reduction in the sensitivity to corticosterone-negative feedback. Similar effects have been observed in the progeny of rats administered dexamethasone during pregnancy, which indicates that excess glucocorticoid transfer to the fetus may be the underlying factor (Levitt et al. 1996). Thus, dexamethasone administration during the last week of pregnancy attenuated GR mRNA expression in the hippocampus of the 16 week-old male offspring and was associated with increased plasma corticosterone concentrations. ...
... Thus, dexamethasone administration during the last week of pregnancy attenuated GR mRNA expression in the hippocampus of the 16 week-old male offspring and was associated with increased plasma corticosterone concentrations. Therefore, overexposure of the fetus to high plasma glucocorticoid concentrations of maternal origin may programme increased HP A activity in the offspring due to the persistent loss of GR in central sites that mediate glucocorticoid feedback control (Levitt et al. 1996). ...
p>The expression of TH and PNMT mRNA was analysed by Northern-blotting in the adrenal of female offspring born to dams fed either a diet mildly restricted in protein content (9% casein), but otherwise isocaloric, or fed a control diet (18% casein) throughout gestation. The blood pressure effects (measured by tail-cuff plethysmography) of twice daily, for a 7-day period, intraperitoneal administration of a PNMT inhibitor, versus vehicle, were analysed in low-protein and control male and female offspring. As previously described, offspring from dams fed the low-protein diet had significantly elevated blood pressure in postnatal life compared with the control of offspring. Levels of TH and PNMT mRNA expression in the adrenal of the low-protein offspring were not significantly different from those of the control offspring at either 2, 4, 8 or 12 weeks of age. At 16 weeks of age, low-protein offspring displayed a significantly greater adrenal TH mRNA expression than the controls. Blockade of central and peripheral adrenaline synthesis at 8 weeks of age with the PNMT inhibitor markedly reduced heart rate and tended to lower blood pressure in all offspring after 7 days compared with vehicle-treated offspring. Importantly, the PNMT inhibitor tended to exert a prolonged blood pressure reduction specifically in the low-protein female offspring, up to 3 weeks following withdrawal of the treatment. Adrenal PNMT activity was not different between low-protein and control offspring at 8 weeks of age. Therefore, the greater long-term blood pressure reduction in the low-protein female offspring following PNMT inhibition may be centrally mediated. The data suggest that the mechanisms by which hypertension is initiated may not depend on an increased synthesis of catecholamines from the adrenal. However, increased levels of adrenaline synthesis by PNMT in central adrenergic neurones may play a contributory role. Increased adrenal catecholamine synthesis may, once hypertension is established, participate in its maintenance.</p
... It is important to clarify the characteristics of the developmental changes in the HPA axis of preterm infants. Several reports have suggested that AG therapy modulates the HPA axis for a while after birth [4,[8][9][10]. Based on these findings, we suspected that AG therapy affects the development of the HPA axis. ...
... Exposure to AG was found to be associated with higher blood pressure in adulthood in several animal species [21][22][23]. Seckl et al. reported that prenatal glucocorticoid exposure permanently increases basal plasma corticosterone levels because it induces permanent reductions in the hippocampal density of both glucocorticoid receptors and mineralocorticoid receptors, which attenuate the feedback sensitivity of the HPA axis [10,24]. In addition, they suggested that "HPA programming" occurs relatively frequently after prenatal environmental challenges and may act in part via alterations in placental 11HSD2 activity [8,25]. ...
Background:
Developmental changes in the hypothalamus-pituitary-adrenal (HPA) axis during infancy have been reported in term infants, but those in preterm infants have yet to be elucidated. If developmental changes in the HPA axis of preterm infants are modulated by any factors, it may affect their future health. Few studies have examined the lasting consequences of antenatal glucocorticoids on the development of the HPA axis.
Methods:
We measured pre- and post-palivizumab vaccination salivary cortisol values in two conforming periods of three-months intervals during infancy, and compared cortisol values and the response of cortisol secretion between groups with and without antenatal glucocorticoid (AG) therapy.
Results:
Although the strength of the response of cortisol secretion to palivizumab fell age-dependently (until late infancy) in the Non-AG group, the opposite pattern was exhibited in the AG group. The changes of the delta cortisol values between the 2 groups were significant.
Conclusions:
This study suggests that the HPA axis of preterm infants whose mothers receive AG therapy may be upregulated during infancy, possibly leading to long lasting health problems.
... Glucocorticoid management to pregnant rats at specific times during pregnancy to cause high blood pressure [47], insulin resistance in offspring later in life [48], changes in gene expression in the developing brain of offspring, and increased sensitivity to stress after the birth have been reported. The administration of glucocorticoids to the pregnant rat at specific points during gestation has been reported to cause hypertension [47], insulin resistance in the offspring in later life [49], alterations in gene expression in the developing brain of the offspring, and increased sensitivity to postnatal stress [50]. ...
... Glucocorticoid management to pregnant rats at specific times during pregnancy to cause high blood pressure [47], insulin resistance in offspring later in life [48], changes in gene expression in the developing brain of offspring, and increased sensitivity to stress after the birth have been reported. The administration of glucocorticoids to the pregnant rat at specific points during gestation has been reported to cause hypertension [47], insulin resistance in the offspring in later life [49], alterations in gene expression in the developing brain of the offspring, and increased sensitivity to postnatal stress [50]. ...
... Females were monitored daily for vaginal plugs, and subsequently were housed individually. Pregnant females were administered subcutaneous injections of DEX (prepared in 0.9% NaCl, 4% ethanol) at concentrations of 10, 50 or 100 μg/Kg/day (denoted as 10-DEX, 50-DEX, or 100-DEX, respectively), or a vehicle solution throughout the third trimester; days 15-21 [26]. The naïve group did not receive any injections. ...
... Prenatal exposure to DEX in the third trimester is a paradigm for fetal programming of low birth weight offspring resulting in adulthood hypertension [7,25,26,30]. Low birth weight was observed in offspring prenatally exposed to DEX, and negatively correlated to the dose, where the highest dose resulted in the lowest birth weight compared to controls. ...
Biochemical changes in utero may alter normal fetal development, resulting in disease later in life, a phenomenon known as fetal programming. Recent epidemiological studies link fetal programming to negative health outcomes, such as low birth weight and hypertension in adulthood. Here, we used a WKY rat model and studied the molecular changes triggered by prenatal glucocorticoid (GC) exposure on the development of hypertension, and on the regulation of phenylethanolamine N-methyl transferase (PNMT), the enzyme responsible for biosynthesis of epinephrine, and a candidate gene linked to hypertension. Clinically, high doses of the synthetic GC dexamethasone (DEX) are used to treat infant respiratory distress syndrome. Elevated maternal GCs have been correlated with fetal programming of hypertension. The aim of this study was to determine if lower doses of DEX would not lead to detrimental fetal programming effects such as hypertension. Our data suggests that prenatal stress programs for increased expression of PNMT and altered regulation of PNMT in males and females. Importantly, we identified that DEX mediated programming was more apparent in the male rats, and the lower dose 10μg/kg/day of DEX did not lead to changes in blood pressure (BP) in female rats suggesting that this dose is below the threshold for programming of hypertension. Furthermore, sex-specific differences were observed in regards to programming mechanisms that may account for hypertension in males.
... Studies have shown that this alteration is also caused by stress during fetal life [3][4][5][6]. Fetal stressors include hypoxia, undernutrition, drugs administered to the mother, and intrauterine inflammation [7][8][9][10][11]. Intrauterine inflammation is one of the most common types of fetal stressors, accounting for approximately 60% of preterm births [12], and is associated with severe sequelae such as brain white matter damage [13][14][15][16][17][18], chronic lung disease [19], and retinopathy of prematurity [20][21][22] in preterm infants. ...
Context
Intrauterine inflammation, a representative stressor for the fetus, has been shown to alter the hypothalamus–pituitary–adrenal (HPA) axis reactivity in preterm fetuses and increase postnatal cortisol production. However, the mechanism of this alteration has not yet been elucidated.
Objective
We aimed to clarify the effects of endotoxin-induced intrauterine inflammation on the HPA axis of periviable sheep fetuses.
Methods
Fetal sheep (0.63 term) were divided into 2 groups: (1) the endotoxin group, in which the endotoxin was injected into the amniotic fluid; and (2) the control group, in which the saline solution was injected instead. A corticotropin-releasing hormone (CRH) challenge test was performed on the third day after injection to evaluate the cortisol-producing capacity of each group. Gene expression levels in the fetal adrenal glands of each group were analyzed by RNA-seq.
Results
The cortisol levels were significantly higher in the endotoxin group than in the control group after CRH challenge (P = .02). There were no significant differences in the responsiveness of adrenocorticotropin and cortisone between the 2 groups. Gene expression levels of the following enzymes involved in cortisol synthesis were significantly elevated in the endotoxin group: cytochrome P450 family (CYP) 11 subfamily A member 1 (log2FC 1.75), CYP 17 subfamily A member 1 (log2FC 3.41), 3β-hydroxysteroid dehydrogenase type I (log2FC 1.13), steroidogenic acute regulatory protein (log2FC 1.09), and CYP 21 (log2FC 0.89).
Conclusion
Periviable fetuses exposed to inflammation in utero have altered the responsiveness of the HPA axis with increased expression of enzymes involved in cortisol synthesis in the adrenal gland.
... As glucocorticoids are primarily associated with the maturation of specific fetal tissues during late gestation, in the findings of Liggins [43], dexamethasone administration improved the mortality and morbidity of prema-ture sheep offspring relative to lung maturation. Ovine and rodent models of maternal synthetic glucocorticoid administration (dexamethasone and betamethasone, respectively) during gestation altered GR mRNA expression throughout the adulthood of subsequent offspring [44,45]. Models of maternal undernutrition in sheep reported altered pituitary and adrenal GR, hypothalamic corticotropic-releasing hormone, and adrenocorticotropic hormone mRNA abundance [1,46]. ...
The objective of this study was to determine the effects of exogenous glucocorticoid administration on leptin concentrations and brain development markers, such as protein and hypothalamic gene expression, in dairy bull calves. Within 4 h of parturition, Holstein bulls were intravenously infused with either a low cortisol dose (LC; n = 9, 3.5 µg/kg of body weight (BW)), high cortisol dose (HC; n = 9, 7.0 µg/kg BW), or control (CON; n = 9, saline) dose, with a 2nd infusion 24 h postpartum. Jugular blood was collected prior to infusion and daily until the calves were euthanized (day 5). Cerebrospinal fluid (CSF) from the third ventricle and adipose (omental, perirenal, and mesenteric) and hypothalamic tissue were collected. The blood and CSF samples were analyzed for leptin concentrations. The data were analyzed using SAS. Serum (p = 0.013) and CSF (p = 0.005) leptin concentrations in HC- and LC-treated calves were decreased compared with CON-treated calves. Leptin protein expression was decreased (p < 0.044) in perirenal and omental adipose tissue of LC-treated calves compared with CON-treated calves. Gene abundance of brain-derived neurotrophic factor and fibroblast growth factors 1 and 2 were decreased (p < 0.006) in HC- and LC-treated calves compared with CON-treated calves. In summary, cortisol administered to dairy bull calves reduced leptin concentrations, decreased leptin protein expression in perirenal and omental adipose tissue, and altered gene expression in hypothalamic tissue.
... For instance, studies in rodents reported reduced glucocorticoid receptor levels in the hippocampus, attenuated negative feedback, and increased glucocorticoid response to stress in terms of both peak levels and duration of the response (Henry et al. 1994;Barbazanges et al. 1996;Szuran et al. 2000;Green et al. 2011;Bingham et al. 2013). Studies in rats and primates further showed that high glucocorticoid exposure during prenatal life caused elevated basal glucocorticoid levels later in life (Levitt et al. 1996;de Vries et al. 2007) although other studies found unaffected basal glucocorticoid levels (review: van Bodegom et al. 2017). Increased adult stress reactivity in response to different stress-related treatments have also been experimentally demonstrated in some studied bird species, such as captive zebra finches, domestic chickens, and Japanese quails (e.g., Hayward and Wingfield 2004;Spencer et al. 2009;Banerjee et al. 2012;Haussmann et al. 2012) though, as in mammals, results are quite variable (Henriksen et al. 2011). ...
... The passage of GCs from the mother to the fetus is limited by the placenta which synthesizes 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), an enzyme that converts physiologically active corticosterone into its inactive metabolite 11-dehydrocorticosterone (59, 60, 543). GC concentrations in the fetus are strictly controlled by placental 11β-HSD2, as it may be detrimental to development if concentrations are too high (81,212,270,277,537) or too low (100,289). The placenta rhythmically synthesizes 11β-HSD2 to gate the flow of GCs from the mother to the fetus (71, 498). ...
Circadian rhythms are endogenously generated, daily patterns of behavior and physiology that are essential for optimal health and disease prevention. Disruptions to circadian timing are associated with a host of maladies, including metabolic disease and obesity, diabetes, heart disease, cancer, and mental health disturbances. The circadian timing system is hierarchically organized, with a master circadian clock located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus and subordinate clocks throughout the CNS and periphery. The SCN receives light information via a direct retinal pathway, synchronizing the master clock to environmental time. At the cellular level, circadian rhythms are ubiquitous, with rhythms generated by interlocking, autoregulatory transcription-translation feedback loops. At the level of the SCN, tight cellular coupling maintains rhythms even in the absence of environmental input. The SCN, in turn, communicates timing information via the autonomic nervous system and hormonal signaling. This signaling couples individual cellular oscillators at the tissue level in extra-SCN brain loci and the periphery and synchronizes subordinate clocks to external time. In the modern world, circadian disruption is widespread due to limited exposure to sunlight during the day, exposure to artificial light at night, and widespread use of light-emitting electronic devices, likely contributing to an increase in the prevalence, and the progression, of a host of disease states. The present overview focuses on the circadian control of endocrine secretions, the significance of rhythms within key endocrine axes for typical, homeostatic functioning, and implications for health and disease when dysregulated. © 2022 American Physiological Society. Compr Physiol 12: 1-30, 2022.
... Chronic perinatal exposure to GCs has previously been shown to decrease GR expression in the PVN, raising CRH and endogenous GC production with implications for the development of mood and anxiety disorders [58][59][60]. Another study using similar conditions to those described here reported GR downregulation in the hippocampus of WKY rats that also involved negative feedback of the HPA axis, as suggested by elevated levels of corticosterone in animals born to Dex-treated mothers [61]. Results such as these tend to correspond with increases in circulating endogenous GCs, indicating overactivity of the HPA axis [62]. ...
Fetal programming is the concept that maternal stressors during critical periods of fetal development can alter offspring phenotypes postnatally. Excess glucocorticoids can interact with the fetus to effect genetic and epigenetic changes implicated in adverse developmental outcomes. The present study investigates how chronic exposure to the synthetic glucocorticoid dexamethasone during late gestation alters the expression of genes related to behavior in brain areas relevant to the regulation and function of the hypothalamic–pituitary–adrenal axis. Pregnant Wistar Kyoto rats received subcutaneous injections of dexamethasone (100 μg/kg) daily from gestational day 15–21 or vehicle only as sham controls. The amygdala and paraventricular nucleus (PVN) were micro-punched to extract mRNA for reverse transcription and quantitative polymerase chain reaction for the analysis of the expression of specific genes. In the PVN, the expression of the glucocorticoid receptor NR3C1 was downregulated in female rats in response to programming. The expression of CACNA1C encoding the Cav1.2 pore subunit of L-type voltage-gated calcium channels was downregulated in male and female rats prenatally exposed to dexamethasone. Collectively, the results suggest that prenatal exposure to elevated levels of glucocorticoids plays a role in the dysregulation of the hypothalamic–pituitary–adrenal axis and potentially learning and memory by altering the expression of specific genes within the amygdala and PVN.
... For instance, studies in rodents reported reduced glucocorticoid receptor levels in the hippocampus, attenuated negative feedback, and increased glucocorticoid response to stress in terms of both peak levels and duration of the response (Henry et al. 1994;Barbazanges et al. 1996;Szuran et al. 2000;Green et al. 2011;Bingham et al. 2013). Studies in rats and primates further showed that high glucocorticoid exposure during prenatal life caused elevated basal glucocorticoid levels later in life (Levitt et al. 1996;de Vries et al. 2007) although other studies found unaffected basal glucocorticoid levels (review: van Bodegom et al. 2017). Increased adult stress reactivity in response to different stress-related treatments have also been experimentally demonstrated in some studied bird species, such as captive zebra finches, domestic chickens, and Japanese quails (e.g., Hayward and Wingfield 2004;Spencer et al. 2009;Banerjee et al. 2012;Haussmann et al. 2012) though, as in mammals, results are quite variable (Henriksen et al. 2011). ...
Exposure to challenging experiences during development, such as reduced parental care and food availability, can have profound effects on the adult phenotype with far-ranging consequences for individual performance. Traditionally, such early-life adversities have been assumed to lead to detrimental consequences for health and survival. Growing empirical evidence, however, pin point that early-life stress exposure can also promote adaptive coping mechanisms of resistance and resilience, and have beneficial long-lasting effects. Developmental timing, type, and severity of early-life stress exposure are hypothesized to be key features underlying subsequent phenotypic outcomes. In this book chapter, we provide an overview of the main molecular mechanisms and signals that may be driving the emergence of subsequent stress vulnerability or resilience. We focus on the actions of glucocorticoid hormones in shaping adult physiological stress responses, and in organizing key cellular and molecular mechanisms underlying senescence and life-history evolution, including telomeres, oxidative stress, and epigenetics. Finally, we critically appraise and identify gaps in our current knowledge and provide directions for future research.
... En effet une exposition foetale à la dexaméthasone ou une restriction protéique au cours de la gestation augmente l'expression du GR au niveau du rein, du foie et du tissu adipeux (Nyirenda et al. 1998c;C. Bertram et al. 2001b;Cleasby et al. 2003b;Wyrwoll, Mark, et Waddell 2007a), alors même que celle-ci est diminuée dans l'hippocampe et le muscle squelettique (Levitt et al. 1996;Cleasby et al. 2003b). Des études ultérieures ont identifié que ces modifications d'expression pouvaient être en lien avec des variations de méthylation du promoteur du gène Nr3c1 dans sa région 5'UTR, dont l'organisation génomique est complexe. ...
La prématurité et la restriction de croissance fœtale (RCF) sont deux pathologies néonatales fréquentes, qui ont en commun des difficultés d'adaptation à la naissance, avec le développement d'une tubulopathie chez le prématuré, et le développement d'une hypertension artérielle (HTA) a l'âge adulte. L’objectif de ce travail était d’évaluer l'implication des voies de signalisation corticostéroïdes rénales dans la survenue de ces complications dans un modèle murin de prématurité induite par des lipopolysaccharides, et un modèle de RCF par exposition périnatale a la dexaméthasone. Dans ce travail nous avons montré que ces deux pathologies programment la survenue d’une HTA à l’âge adulte chez les mâles, associée à des altérations franches de la signalisation corticostéroïde rénale en période périnatale et une augmentation de la sensibilité rénale aux glucocorticoïdes à l’âge adulte. Dans le modèle de prématurité, nous avons identifié la transmission transgénérationelle d’anomalies de régulation de la pression artérielle chez les mâles jusqu’à la 3ème génération de souris, associée à une hypométhylation du promoteur de GILZ et une augmentation d’expression de GILZ. Notre étude a permis l’identification de potentiels mécanismes moléculaires impliqués dans la programmation fœtale de l’HTA, sur plusieurs générations, ce qui pourrait aboutir à une meilleure prise en charge des patients nés prématurés ou avec une RCF, et de leurs descendants.
... One metaanalysis of 28 studies including N = 3397 individuals found that childhood adversity is also significantly related to hair cortisol concentrations and this association is moderated by the type and timing of the adversity experienced [55]. Animal work has also shown that early-life adversity/prenatal stress elicits changes in HPAaxis functioning that persists into adulthood (developmental programming), including HPA-axis hyperactivity and glucocorticoid/insulin resistance [56][57][58] and the frequent comorbidity between early-life adversity and MDD may be linked to HPA-axis dysregulation [59]. We build on this preclinical work in humans to show that chronically elevated glucocorticoids were specifically associated with early-life stress, but not contemporaneous stress, and were further specifically associated with childhood physical neglect and emotional abuse, as well as current and lifetime MDD. ...
Abstract Hypothalamic–pituitary–adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (β range = −0.057 to −0.104, all P FDR
... These effects are observed across species and are linked to modifications of important endocrine and physiological processes. Antenatal GCs exposure was associated with high blood pressure in sheep [115] and marmoset [116], a deficit in the HPA axis in sheep [117,118], rat [119], guinea pig [120], and in nonhuman primates [116,121], and abnormalities in carbohydrate metabolism in sheep [122], rat [123] and marmoset [123]. ...
Prematurity, observed in 15 million births worldwide each year, is a clinical condition that is a major cause of neonatal mortality and morbidity in short and long term. Preterm infants are at high risk for developing respiratory problems, sepsis, and other morbidities leading to neurodevelopmental impairment and neurobehavioral disorders. Perinatal glucocorticosteroids have been widely used for the prevention and treatment of adverse outcomes linked to prematurity. However, despite their shortterm benefits due to their maturational properties, some clinical trials have shown an association between steroids exposure and abnormal brain development in infants born preterm. Neuroinflammation has emerged as a preeminent factor for brain injury in preterm infants, and the major role of microglia, the brain resident immune cells, has been recently highlighted. Considering the role of microglia in the modulation of brain development, the aim of this review is to summarize the effects of endogenous and exogenous glucocorticosteroids on brain development and discuss the possible role of microglia as a mediator of these effects.
... The cognitive alterations in PS animals reported in this work can also be attributed to other factors such as the probable deficiencies in the existing neuronal connections in the hippocampus, because PS produces a decrease in the length and complexity of dendritic spines in the hippocampal regions CA1, CA3 and DG (Jia et al., 2010;Martínez-Téllez et al., 2009;Hosseini-sharifabad and Hadinedoushan, 2007;Weinstock, 2011), as well as the high concentrations of corticosterone, which increases due to the exposure to the MWM paradigm. PS induce permanently high corticosterone basal levels during the adult stage when animals are exposed to new environments or stressor situations (de Vries et al., 2007;Levitt et al., 1996;Welberg et al., 2000;Welberg and Seckl, 2001). In this study, hyper reactivity of the adrenal axis in PS females and males may have a role in their deficient performance in cognitive tasks because high corticosterone concentrations may interfere with spatial learning (Schwabe et al., 2010). ...
... In ovo CORT treatment elevated the circulating levels of CORT in hatch time in chickens [81] and at 8 weeks old in Japanese quail [82]. Similar results were reported in rats, revealing that exposure of CORT during gestation period inhibited fetal growth rate in mice [83,84] and permanently increased the plasma CORT levels in adult rats [85,86]. ...
Exposure to excess Glucocorticoids (GCs) during embryonic development influences offspring physiology and behaviors and induces change in Hypothalamic-Pituitary-Adrenal (HPA) axis genes expression and serotonergic system in mammals. Whether prenatal corticosterone (CORT) exposure induces similar effects in avian species remains unclear. In the present study, we injected low (0.2 µg) and high (1 µg) doses of CORT in ovo before incubation and detected changes in aggressive behavior, Tonic Immobility (TI), HPA axis and 5-hydroxytryptamine (serotonin) (5-HT) system gene expression on post hatch chickens of different ages. High dose of CORT significantly (P<0.05) suppressed growth rate, increased the frequency of aggressive behaviors, which was associated with elevated plasma CORT concentration. Likewise, in ovo injection of CORT significantly (P<0.05) increased Tonic Immobility (TI) duration both in chickens from low and high doses of CORT treatments compared to control. In addition, administration of CORT significantly (P<0.05) up-regulated mRNA expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) whereas it down-regulated 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and mineralocorticoid receptor (MR) mRNA expression in the hypothalamus. No significant differences were seen in Glucocorticoid Receptor (GR) and 20-hydroxysteroid dehydrogenase (20-HSD) mRNA levels upon CORT treatment. Moreover, CORT exposure significantly (P<0.05) increased hypothalamic 5-hydroxytryptamine (serotonin) receptor 1A (5-HTR1A) mRNA expression, but not 5-HT receptor 1B (5-HTR1B). In ovo administration of CORT may programs the aggressive behaviors in the chicken through alterations of HPA axis and 5-HT system.
... More so, there are increasing evidences that suggest intrauterine exposure to chemicals and some drugs have an impact on the development of metabolic disorders in offspring (Dalziel et al., 2005). Offspring of rat dams administered glucocorticoid as well as dexamethasone during pregnancy presented reduced birth weight, glucose intolerance (Nyirenda et al., 1998) and increased blood pressure in adulthood (Levitt et al., 1996). As a corollary, it is possible that there may be mechanisms by which in utero programming may prevent metabolic syndrome in later life. ...
Context: Intrauterine and early life environments contribute to adult metabolic phenotype. Use of medicinal plants like Hypoxis hemerocallidea during pregnancy raises the question of whether this species may have epigenetic benefits or detriments due to intrauterine-programming, which is phenotypically expressed in the offspring.
Aims: To evaluate the effect of H. hemerocallidea on selected markers of metabolic syndrome on dams and their pups (offspring).
Methods: Pregnant female Wistar rats (n=18) were divided into three treatment groups (n=6/group): Ethanol extract of H. hemerocallidea at 150 and 300 mg/kg b.w and the control (distilled water) were administered for 21 days. Body weights were monitored and oral glucose tolerance was determined for dams on day 20 of gestation and for pups 28 days postpartum. Serum total antioxidant capacity (TAC), LDL and HDL were determined 28 days postpartum.
Results: H. hemerocallidea had no effect on body and organ weights of the treated dams. Pups born to H. hemerocallidea dams had reduced visceral fat compared to the untreated controls. H. hemerocallidea increased the glucose tolerance of treated dams and their pups compared to untreated controls. H. hemerocallidea extract increased serum HDL in treated dams while it decreased LDL in pups born to treated dams. H. hemerocallidea increased TAC in pups born to treated dams.
Conclusions: H. hemerocallidea protected pregnant dams and their pups from insulin resistance, improved lipid profiles, reduced visceral fat accumulation and boosted total antioxidant capacity in pups. These protective effects of H. hemerocallidea in pups may have resultedfrom intrauterine programming during pregnancy.
... More so, there are increasing evidences that suggest intrauterine exposure to chemicals and some drugs have an impact on the development of metabolic disorders in offspring (Dalziel et al., 2005). Offspring of rat dams administered glucocorticoid as well as dexamethasone during pregnancy presented reduced birth weight, glucose intolerance (Nyirenda et al., 1998) and increased blood pressure in adulthood (Levitt et al., 1996). As a corollary, it is possible that there may be mechanisms by which in utero programming may prevent metabolic syndrome in later life. ...
Context: Intrauterine and early life environments contribute to adult metabolic phenotype. Use of medicinal plants like Hypoxis hemerocallidea during pregnancy raises the question of whether this species may have epigenetic benefits or detriments due to intrauterine-programming, which is phenotypically expressed in the offspring.
Aims: To evaluate the effect of H. hemerocallidea on selected markers of metabolic syndrome on dams and their pups (offspring).
Methods: Pregnant female Wistar rats (n=18) were divided into three treatment groups (n=6/group): Ethanol extract of H. hemerocallidea at 150 and 300 mg/kg b.w and the control (distilled water) were administered for 21 days. Body weights were monitored and oral glucose tolerance was determined for dams on day 20 of gestation and for pups 28 days postpartum. Serum total antioxidant capacity (TAC), LDL and HDL were determined 28 days postpartum.
Results: H. hemerocallidea had no effect on body and organ weights of the treated dams. Pups born to H. hemerocallidea dams had reduced visceral fat compared to the untreated controls. H. hemerocallidea increased the glucose tolerance of treated dams and their pups compared to untreated controls. H. hemerocallidea extract increased serum HDL in treated dams while it decreased LDL in pups born to treated dams. H. hemerocallidea increased TAC in pups born to treated dams.
Conclusions: H. hemerocallidea protected pregnant dams and their pups from insulin resistance, improved lipid profiles, reduced visceral fat accumulation and boosted total antioxidant capacity in pups. These protective effects of H. hemerocallidea in pups may have resultedfrom intrauterine programming during pregnancy.
... A survey in 359 institutions of 29 countries showed that, the average rate of using synthetic glucocorticoids as a preventive treatment before birth of preterm infants at 22-36 weeks of gestation is 54 %, even up to 91 % in some countries (Vogel et al., 2014). However, some research suggested that dexamethasone can decrease maternal serum TBA levels in ICP patients by reducing the placental estrogen level (Hirvioja et al., 1992;Levitt et al., 1996). Even though it has been commonly used in clinic, the effect of dexamethasone exposure during pregnancy on maternal bile acid metabolism has not been well defined. ...
As important members in steroids related signal pathways, bile acids are very important in regulating substance metabolism and immune homeostasis. However, bile acids are highly cytotoxic, and the excessive accumulation can induce several abnormalities such as cholestatic liver injury. It is known that the bile acid metabolism alters during pregnancy and mostly will not result in pathologies. However, the effect of dexamethasone exposure during pregnancy on bile acid metabolism is still unknown. In this study, pregnant Wistar rats were subcutaneously administered dexamethasone (0.2 mg/kg.d) or saline from gestation day 9 to 21, while virgin rats were given the same treatment for 13 days. We found that, physiological pregnancy or dexamethasone exposure during non-pregnancy did not affect maternal serum TBA level and liver function. Nevertheless, dexamethasone exposure during pregnancy increased serum TBA level and accompanied with liver injury. Furthermore, we discovered that the conservation of bile acid homeostasis under pregnancy or dexamethasone exposure was maintained through compensatory pathways. However, dexamethasone exposure during pregnancy tipped the balance of liver bile acid homeostasis by increasing classical synthesis and decreasing efflux and uptake. In addition, dexamethasone exposure during pregnancy also increased serum estrogen level and nuclear receptors mRNA expression levels. Finally, two-way ANOVA analysis showed that dexamethasone exposure during pregnancy could induce or facilitate maternal cholestasis and liver injury by up-regulating ERα and CYP7A1 expression. This study confirmed that dexamethasone exposure during pregnancy was related to maternal intrahepatic cholestasis of pregnancy and should be carefully monitored in clinical settings.
... Placental CRF plays a crucial role in regulating the fetal HPA axis [124,126]. In rodent studies, the reduced HPA axis sensitivity and anxiety-like behaviors in offspring of dams with overactive HPA axis during pregnancy was in part explained by an attenuated hippocampal GR expression [127,128]. Also immune activity and psychosocial stress causes elevated glucocorticoid levels [129]. Maternal psychosocial stress is known to long-term modify the offspring HPA axis activity epigenetically towards increased stress sensitivity [130] and suicide risk [131,132]. ...
Obesity and diabetes is a worldwide public health problem among women of reproductive age. This narrative review highlights recent epidemiological studies regarding associations of maternal obesity and diabetes with neurodevelopmental and psychiatric disorders in offspring, and provides an overview of plausible underlying mechanisms and challenges for future human studies. A comprehensive search strategy selected terms that corresponded to the domains of interest (maternal obesity, different types of diabetes, offspring cognitive functions and neuropsychiatric disorders). The databases searched for articles published between January 2010 and April 2019 were PubMed, Web of Science and CINAHL. Evidence from epidemiological studies strongly suggests that maternal pre-pregnancy obesity is associated with increased risks for autism spectrum disorder, attention-deficit hyperactivity disorder and cognitive dysfunction with modest effect sizes, and that maternal diabetes is associated with the risk of the former two disorders. The influence of maternal obesity on other psychiatric disorders is less well studied, but there are reports of associations with increased risks for offspring depression, anxiety, schizophrenia and eating disorders, at modest effect sizes. It remains unclear whether these associations are due to intrauterine mechanisms or explained by confounding family-based sociodemographic, lifestyle and genetic factors. The plausible underlying mechanisms have been explored primarily in animal models, and are yet to be further investigated in human studies.
... Analysis of the offspring 3 months after birth under either normoglycemic or hypoglycemic conditions showed that ACTH and cortisol plasma concentrations were significantly increased both at baseline and under hypoglycemic conditions, indicating elevated offspring HPA-axis activity [57]. Similar effects were also reported under hypoxemic conditions in high-dose dexamethasone-treated sheep during late gestation [58] and in prenatally dexamethasone-treated rats [59]. Studies of prenatal synthetic glucocorticoids exposure and postnatal HPA-axis function in human fetuses born at term show increased cortisol responses and HPAaxis function after a postnatal stressor during the first 2 days of life, with the infants that received betamethasone earlier in pregnancy (mid-gestation) having significantly higher cortisol responses than infants with later gestational exposure [39] ( Figure 2B). ...
A number of prenatal experiences are associated with adverse outcomes after birth, ranging from cardiovascular problems to psychiatric disease. Prenatal stress is associated with neurodevelopmental alterations that persist after birth and manifest at the behavioral level, for example, increased fearfulness, and at the physiological one, that is, brain structural and functional changes. Understanding the mechanisms that drive these lasting effects may help in preventing long-term negative outcomes of prenatal stress. Elevated glucocorticoid signaling in utero may be one of the key mediators of prenatal stress effects on the offspring. In this review, we summarize how prenatal glucocorticoids may impact the activity of the fetal hypothalamic–pituitary–adrenal (HPA) axis, disrupt neurodevelopmental processes and alter the epigenetic landscape of the fetus. We also discuss the need to take into consideration the interaction of these processes with the offspring’s genetic landscape.
... Thus, A large number of studies have confirmed elevated levels of glucocorticoids in the prenatally stressed offspring (Nicolaides et al., 2015;van Bodegom et al., 2017).We also have detected high glucocorticoids in offspring in previous (Liao et al., 2019). Meanwhile, Exposure of the fetus to stress or high levels of glucocorticoids-whether from exogenous or endogenous origins can permanently affect GR expression (Levitt et al., 1996). The GR expression in female offspring hippocampus may involve in the prenatal stress outcome. ...
Accumulating evidence from preclinical and clinical studies indicates prenatal exposure to stress or excess glucocorticoids can affect offspring brain. Glucocorticoid receptor (GR) is an important target of glucocorticoid. Therefore the aim of the present study was to investigate the expression of GR in prenatally stressed adult offspring and the relationship between GR expression and behavior in offspring. Pregnant rats received restraint stress during the last week of pregnancy. Hippocampal glucocorticoid receptor expression levels in the offspring were detected on postnatal 60 (P60).Cognition function was also detected. It shows significantly lower hippocampal GR expression was observed in female prenatally stressed offspring compared with their controls at P60. Corresponding to the expression of GR, female prenatally stressed offspring exhibited poorer spatial learning and memory abilities in the Barnes maze than control, This suggests that cognitive impairment in prenatally stressed rat offspring attribute lower hippocampal GR expression.
... Interestingly, the negative impact of the inhibition of this enzyme was prevented by maternal adrenalectomy. These outcomes, as well as central HPA regulatory changes, were similarly observed in rodent (rat and mouse) models of both synthetic and endogenous glucocorticoids in late pregnancy295,549,598 .Furthermore, investigations of the outcomes following excess glucocorticoid exposure have demonstrated that children of mothers who experienced stress or were treated with glucocorticoids at the end of pregnancy had altered basal glucocorticoid concentrations, HPA response to stressors such as heel prick blood draw, public speaking and mental arithmetic tasks (Trier Social Stress Test for children)[260][261][262][266][267][268][269] and impaired behaviour, including, including ADHD symptoms[270][271][272] , elevated anxiety 272 and cognitive development273 . This was similarly observed in animal studies. ...
The consumption of alcohol during pregnancy is frequent despite clear guidelines that indicate that abstinence is the safest option to prevent adverse offspring outcomes. These outcomes range from overt craniofacial abnormalities through to outcomes such as mental illness, hyperactivity and social difficulties. Human and animal studies have demonstrated that these neurological outcomes may be due to impaired function of the hypothalamic-pituitary-adrenal axis (HPA) in offspring, resulting in altered basal glucocorticoid tone and disrupted responsiveness to stress. However, little is known of the impact of alcohol consumption around the time of conception, known as the periconceptional period, on offspring HPA function. Therefore, this study aimed to use a well-established rat model of ethanol consumption during the periconceptional period (PC:EtOH) to investigate offspring HPA activity, including behaviours, stress responsiveness and underlying molecular pathways. As alcohol consumption directly alters HPA function, this study also aimed to examine if PC:EtOH exposure impairs maternal HPA activity and related physiological pathways, including renal and metabolic function.
Female Sprague-Dawley rats were treated with PC:EtOH (12.5% v/v EtOH liquid diet) or a control diet from 4 days before conception, until embryonic day (E) 4. Behavioural tests were performed on offspring at three months of age to assess mental illness-like phenotypes (utilising the Forced Swim Test [FST] and Social Interaction [SI] paradigm), and at five months of age, HPA reactivity tests (combined dexamethasone suppression test [DST] and corticotropin-releasing hormone stimulation test [CST] and restraint stress) were performed. In a separate study, basal corticosterone concentrations were measured at 6 months, and adrenal glands were collected for analysis of steroidogenic gene expression. Aged cohorts (12-14 months) were utilised to measure basal plasma corticosterone, followed by the collection of adrenal glands, pituitary glands, hypothalamus and hippocampal tissue for analysis of various steroidogenesis and glucocorticoid signalling genes and pathology. In a separate cohort of aged rats, telemetry was used to asses blood pressure, heart rate and plasma corticosterone concentrations during 30-minute restraint stress.
Maternal hormones (corticosterone, aldosterone), renal function and plasma glucose and lipids were assessed at various stages in gestation. Adrenal glands were collected from dams at E5, E15 and E20 for analysis of steroidogenic gene expression. Placental samples were collected at E20 and genes expression of the glucocorticoid (Nr3c1) and corticotrophin hormone receptor (Crh-r1) measured.
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This study revealed that PC:EtOH exposure resulted in altered offspring behavioural outcomes, including increased depressive-like behaviour in the forced swim test and altered social interaction with a novel rat. Adult offspring also demonstrated HPA hyperactivity, with elevated responses to the DST/CST challenge. Although there was no difference observed in adult offspring, aged PC:EtOH female offspring demonstrated an altered response to restraint, with reduced stress-induced plasma corticosterone and pressor response. Interestingly, PC:EtOH exposure also resulted in reduced basal plasma corticosterone concentrations in adult and aged female but not male offspring. Furthermore, female offspring showed pituitary gland abnormalities and increased mRNA for Nr3c1 and heat shock protein 90 (Hsp901a) in the hippocampus, suggesting altered HPA signalling and regulatory pathways. Adrenal and hypothalamic mRNA expression of genes regulating glucocorticoid production were not overtly altered by PC:EtOH in aged offspring.
PC:EtOH significantly increased plasma corticosterone in the dam prior to mating (E-2). During pregnancy, PC:EtOH resulted in lower concentrations at E5, no differences at E15, and an increase at E20. Only minor changes in the expression of genes which regulate adrenal steroidogenesis were observed in PC:EtOH dams at E5 and E15, with the latter likely to have contributed to the observed increase in plasma corticosterone at E20. PC:EtOH had no impact on metabolic parameters (high and low-density lipoproteins and triglycerides) or renal function (food, water, urinary flow and renal electrolytes) in late gestation. However, placental markers of glucocorticoid exposure were elevated in response to exposure.
This study supports the hypothesis that periconceptional ethanol exposure alters the HPA of the mother and programs sex-specific alterations in offspring in a rat model. Maternal HPA and related physiological changes as a consequence of PC:EtOH is likely to contribute to the HPA hyperresponsiveness, and underlie behavioural outcomes observed in this study. Furthermore, these changes to the HPA may be independent of the adrenal gland, with central regulatory pathways involving the hippocampus altered by PC:EtOH.
This thesis has provided novel and important evidence that alcohol exposure around the time of conception impairs offspring mental-health like outcomes and induces HPA dysregulation. This work reinforces the concept that the maternal stress axis is highly sensitive to perturbations during early pregnancy. As this system is critical in many major physiological pathways, this can have significant long-term disease implications for both the mother and the child, supporting the critical need for education of appropriate health and wellbeing in preparation for pregnancy.
... During development, there is a relatively high expression of GR from midgestation onwards (Diaz et al., 1998), which are essential for normal brain development and offspring survival (Kapoor et al., 2008). In the rat, antenatal stress or maternal administration of glucocorticoids during this time window results in offspring with decreased expression of GR mRNA in specific brain areas involved in glucocorticoid feedback such as the hippocampus, hypothalamus, and pituitary (Levitt et al., 1996;Liu et al., 2001). This reduction could promote pups grow up with altered negative feedback response, manifested as a chronic elevation of corticosterone (Maccari and Morley-Fletcher, 2007). ...
The perinatal window is a critical developmental time when abnormal gestational stimuli may alter the development of the stress system that, in turn, influences behavioral and physiological responses in the newborns. Individual differences in stress reactivity are also determined by variations in maternal care, resulting from environmental manipulations. Despite glucocorticoids are the primary programming factor for the offspring’s stress response, therapeutic corticosteroids are commonly used during late gestation to prevent preterm negative outcomes, exposing the offspring to potentially aberrant stress reactivity later in life. Thus, in this study, we investigated the consequences of one daily s.c. injection of corticosterone (25 mg/kg), from gestational day (GD) 14–16, and its interaction with offspring early handling, consisting in a brief 15-min maternal separation until weaning, on: (i) maternal behavior; and (ii) behavioral reactivity, emotional state and depressive-like behavior in the adolescent offspring. Corticosterone plasma levels, under non-shock- and shock-induced conditions, were also assessed. Our results show that gestational exposure to corticosterone was associated with diminished maternal care, impaired behavioral reactivity, increased emotional state and depressive-like behavior in the offspring, associated with an aberrant corticosterone response. The early handling procedure, which resulted in increased maternal care, was able to counteract the detrimental effects induced by gestational corticosterone exposure both in the behavioral- and neurochemical parameters examined. These findings highlight the potentially detrimental consequences of targeting the stress system during pregnancy as a vulnerability factor for the occurrence of emotional and affective distress in the adolescent offspring. Maternal extra-care proves to be a protective strategy that confers resiliency and restores homeostasis.
... These changes are accompanied by adaptations in the limbic and cortical system, such as increases in the expression of CRHR1 in regions like the PVN (Bravo et al., 2011;Fan et al., 2013;Wang et al., 2013), the amygdala (Bravo et al., 2011;Brunton et al., 2011), the hippocampus (O'Malley et al., 2011, and the prefrontal cortex (Vázquez et al., 2003;O'Malley et al., 2011), which is thought to be crucial for initiation of the stress response (Bale and Vale, 2004;Henckens et al., 2016). In addition, decreased expression of the glucocorticoid receptor in the hippocampus (Henry et al., 1994;Levitt et al., 1996;Green et al., 2011;Bingham et al., 2013) and prefrontal cortex (Green et al., 2011;Bingham et al., 2013) is thought to disrupt the ability of the system to respond appropriately to feedback loops and control stress responses (Jacobson and Sapolsky, 1991;de Kloet et al., 1993;Herman and Cullinan, 1997;Mizoguchi et al., 2003;Herman et al., 2012). ELS results in exaggerated responses to psychological stressors as seen in adult animals exposed to pre-and post-natal stress (Engelmann et al., 1996;Vallée et al., 1997;Tazumi et al., 2005;Brunton and Russell, 2010). ...
Psychoactive substance use is a nearly universal human behavior, but a significant minority of people who use addictive substances will go on to develop an addictive disorder. Similarly, though ~90% of people experience traumatic events in their lifetime, only ~10% ever develop post-traumatic stress disorder (PTSD). Substance use disorders (SUD) and PTSD are highly comorbid, occurring in the same individual far more often than would be predicted by chance given the respective prevalence of each disorder. Some possible reasons that have been proposed for the relationship between PTSD and SUD are self-medication of anxiety with drugs or alcohol, increased exposure to traumatic events due to activities involved in acquiring illegal substances, or addictive substances altering the brain’s stress response systems to make users more vulnerable to PTSD. Yet another possibility is that some people have an intrinsic vulnerability that predisposes them to both PTSD and SUD. In this review, we integrate clinical and animal data to explore these possible etiological links between SUD and PTSD, with an emphasis on interactions between dopaminergic, adrenocorticotropic, GABAergic, and glutamatergic neurobehavioral mechanisms that underlie different emotional learning styles.
... cortisone, 11-dehydrocorticosterone), 11HSD1 converts the inactive glucocorticoids into cortisol/corticosterone (Waddell et al., 1998). Converging basic and clinical evidence suggests that disruptions of these placental enzymes in response to challenge result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral changes later in life (Levitt et al., 1996;Räikkönen et al., 2015;Seckl and Meaney, 2004;Trautman et al., 1995). ...
Adverse experiences during pregnancy induce placental programming, affecting the fetus and its developmental trajectory. However, the influence of 'positive' maternal experiences on the placenta and fetus remain unclear. In animal models of early life stress, environmental enrichment (EE) has ameliorated and even prevented associated impairments in brain and behavior. Here, using a maternal immune activation (MIA) model in rats, we test whether EE attenuates maternal, placental and/or fetal responses to an inflammatory challenge, thereby offering a mechanism by which fetal programming may be prevented. Moreover, we evaluate life-long EE exposure on offspring development and examine a constellation of genes and epigenetic writers that may protect against MIA challenges. In our model, maternal plasma corticosterone and interleukin-1β were elevated 3 h after MIA, validating the maternal inflammatory response. Evidence for developmental programming was demonstrated by a simultaneous decrease in the placental enzymes Hsd11b2 and Hsd11b2/Hsd11b1, suggesting disturbances in glucocorticoid metabolism. Reductions of Hsd11b2 in response to challenge is thought to result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral impairments later in life. The placental, but not maternal, glucocorticoid implications of MIA were attenuated by EE. There were also sustained changes in epigenetic writers in both placenta and fetal brain as a consequence of environmental experience and sex. Following MIA, both male and female juvenile animals were impaired in social discrimination ability. Life-long EE mitigated these impairments, in addition to the sex specific MIA associated disruptions in central Fkbp5 and Oprm1. These data provide the first evidence that EE protects placental functioning during stressor exposure, underscoring the importance of addressing maternal health and well-being throughout pregnancy. Future work must evaluate critical periods of EE use to determine if postnatal EE experience is necessary, or if prenatal exposure alone is sufficient to confer protection.
... Indeed, these models have clearly implicated maternal immune activation (MIA) to several neurobiological disruptions that mimic clinical psychiatric pathology (Gumusoglu & Stevens, 2018). For example, MIA is associated with the manifestation of a heterogeneous set of symptoms, including social and cognitive impairments in the offspring later in life, many of which reportedly occur in a sex-dependent manner (CDC, 2014;Kim et al., increasing susceptibility to behavioral changes later in life (Levitt et al., 1996;Räikkönen et al., 2015;Seckl & Meaney., 2004;Trautman et al., 1995). ...
Adverse experiences during pregnancy induce placental programming, affecting the fetus and its developmental trajectory. However, the influence of positive maternal experiences on the placenta and fetus remain unclear. In animal models of early-life stress, environmental enrichment (EE) has ameliorated and even prevented associated impairments in brain and behavior. Here, using a maternal immune activation (MIA) model in rats, we test whether EE attenuates maternal, placental and/or fetal responses to an inflammatory challenge, thereby offering a mechanism by which fetal programming may be prevented. Moreover, we evaluate life-long EE exposure on offspring development and examine a constellation of genes and epigenetic markers that may protect against MIA challenges. In our model, maternal plasma corticosterone and interleukin-1β were elevated 3 h after MIA, validating the maternal inflammatory response. Evidence for developmental programming was demonstrated by a simultaneous decrease in the placental enzymes Hsd11b2 and Hsd11b2/Hsd11b1, suggesting disturbances in glucocorticoid metabolism. Reductions of Hsd11b2 in response to challenge is thought to result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral impairments later in life. The placental, but not maternal, glucocorticoid implications of MIA were attenuated by EE. There were also sustained changes in epigenetic markers in both placenta and fetal brain as a consequence of environmental experience and sex. Following MIA, both male and female juvenile animals were impaired in social discrimination ability. Life-long EE mitigated these impairments, in addition to the sex specific MIA associated disruptions in central Fkbp5 and Oprm1. These data provide the first evidence that EE protects placental functioning during stressor exposure, underscoring the importance of addressing maternal health and well-being throughout pregnancy. Future work must evaluate critical periods of EE use to determine if postnatal EE experience is necessary, or if prenatal exposure alone is sufficient to confer protection.
... gestation have life-long hypertension (Dodic 1998), as do rats exposed to dexamethasone in late gestation 425 (Levitt 1996). 426 ...
... Indeed, extensive animal studies have simultaneously revealed the impact of ACS on the programming of many fetal tissues and organs [9][10][11]. Across species, ACS administration results in alterations of the hypothalamic-pituitary-adrenal axis [12][13][14][15][16][17], in abnormal metabolism [16,18,19], in hypertension [16,20], and in delayed myelination within the central nervous system [21][22][23]. In humans, because most clinical trials were performed in the 70's, 80's and early 90's, before early childhood assessment of perinatal interventions became standard of good research practices, long term consequences of a single course of ACS have been poorly investigated. ...
Background
Although antenatal betamethasone is recommended worldwide for women at risk of preterm delivery, concerns persist regarding the long-term effects associated with this treatment. Indeed, adverse events, mainly dose-related, have been reported. The current recommended dose of antenatal betamethasone directly derives from sheep experiments performed in the late 60’s and has not been challenged in 45 years. Therefore, randomized trials evaluating novel dose regimens are urgently needed.
Methods
A randomised, double blind, placebo-controlled, non-inferiority trial will be performed in 37 French level 3 maternity units. Women with a singleton pregnancy at risk of preterm delivery before 32 weeks of gestation having already received a first 11.4 mg injection of betamethasone will be randomised to receive either a second injection of 11.4 mg betamethasone (full dose arm) or placebo (half dose arm) administered intramuscularly 24 h after the first injection. The primary binary outcome will be the occurrence of severe respiratory distress syndrome (RDS), defined as the need for exogenous intra-tracheal surfactant in the first 48 h of life. Considering that 20% of the pregnant women receiving the full dose regimen would have a neonate with severe RDS, 1571 patients in each treatment group are required to show that the half dose regimen is not inferior to the full dose, that is the difference in severe RDS rate do not exceed 4% (corresponding to a Relative Risk of 20%), with a 1-sided 2.5% type-1 error and a 80% power. Interim analyses will be done after every 300 neonates who reach the primary outcome on the basis of intention-to-treat, using a group-sequential non-inferiority design.
Discussion
If the 50% reduced antenatal betamethasone dose is shown to be non-inferior to the full dose to prevent severe RDS associated with preterm birth, then it should be used consistently in women at risk of preterm delivery and would be of great importance to their children.
Trial registration
ClinicalTrials.gov identifier: NCT 02897076 (registration date 09/13/2016).
Electronic supplementary material
The online version of this article (10.1186/s12884-019-2206-x) contains supplementary material, which is available to authorized users.
According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, exposure to certain environmental influences during early life may be a key determinant of fetal development and short- and long-term offspring health. Indeed, adverse conditions encountered during the fetal, perinatal, and early childhood stages can alter normal development and growth, as well as put the offspring at elevated risk of developing long-term health conditions in adulthood, including chronic kidney disease (CKD) and cardiovascular diseases. Of relevance in understanding the mechanistic basis of these long-term health conditions, are previous findings showing low glomerular number in human intrauterine growth restriction and low birth weight - indicators of a sub-optimal intrauterine environment. In different animal models, the main sub-optimal intrauterine conditions studied relate to maternal dietary manipulations, poor micronutrient intake, prenatal ethanol exposure, maternal diabetes, glucocorticoid and chemical exposure, hypoxia, and placental insufficiency. These studies have demonstrated changes in kidney structure, glomerular endowment, and expression of key genes and signalling pathways controlling endocrine, excretion and filtration function of the offspring. This review aims to summarize those studies to uncover the effects and mechanisms by which adverse gestational environments impact offspring renal and vascular health in adulthood. This is important for identifying agents and interventions that can prevent and mitigate the long-term consequences of an adverse intrauterine environment on the subsequent generation.
Prenatal stress programmes long-lasting neuroendocrine and behavioural changes in the offspring. Often this programming is maladaptive and sex specific. For example, using a rat model of maternal social stress in late pregnancy, we have demonstrated that adult prenatally stressed male, but not prenatally stressed female offspring display heightened anxiety-like behaviour, whereas both sexes show hyperactive hypothalamo–pituitary–adrenal (HPA) axis responses to stress. Here, we review the current knowledge of the mechanisms underpinning dysregulated HPA axis responses, including evidence supporting a role for reduced neurosteroid-mediated GABAergic inhibitory signalling in the brains of prenatally stressed offspring. How maternal psychosocial stress is signalled from the mother to the fetuses is unclear. Direct transfer of maternal glucocorticoids to the fetuses is often considered to mediate the programming effects of maternal stress on the offspring. However, protective mechanisms including attenuated maternal stress responses and placental 11β-hydroxysteroid dehydrogenase-2 (which inactivates glucocorticoids) should limit materno-fetal glucocorticoid transfer during pregnancy. Moreover, a lack of correlation between maternal stress, circulating maternal glucocorticoid levels and circulating fetal glucocorticoid levels is reported in several studies and across different species. Therefore, here we interrogate the evidence for a role for maternal glucocorticoids in mediating the effects of maternal stress on the offspring and consider the evidence for alternative mechanisms, including an indirect role for glucocorticoids and the contribution of changes in the placenta in signalling the stress status of the mother to the fetus.
Development of the brain and the emergence of the mind constitute some of the most important concerns of contemporary biology. Disturbances during fetal life may have profound implications for a child's future neurological and psychological development, which can in turn impact society. The new edition of this highly respected work presents a comprehensive review of the basic mechanisms of brain development and the pathophysiology of disorders of the infant brain, written by a team of distinguished neuroscientists, neonatologists, and neuropediatricians. The book follows the main milestones of brain development, from formation of the neural tube and wiring of the neurons in the brain. Neurotrophic factors, neurotransmitters, glial cell biology, cerebral circulation development of sensory functions are all described in detail. Furthermore, there are more philosophical chapters on the evolution of the brain and the emergence of consciousness. Clinical considerations are highlighted where relevant.
Development of the brain and the emergence of the mind constitute some of the most important concerns of contemporary biology. Disturbances during fetal life may have profound implications for a child's future neurological and psychological development, which can in turn impact society. The new edition of this highly respected work presents a comprehensive review of the basic mechanisms of brain development and the pathophysiology of disorders of the infant brain, written by a team of distinguished neuroscientists, neonatologists, and neuropediatricians. The book follows the main milestones of brain development, from formation of the neural tube and wiring of the neurons in the brain. Neurotrophic factors, neurotransmitters, glial cell biology, cerebral circulation development of sensory functions are all described in detail. Furthermore, there are more philosophical chapters on the evolution of the brain and the emergence of consciousness. Clinical considerations are highlighted where relevant.
Development of the brain and the emergence of the mind constitute some of the most important concerns of contemporary biology. Disturbances during fetal life may have profound implications for a child's future neurological and psychological development, which can in turn impact society. The new edition of this highly respected work presents a comprehensive review of the basic mechanisms of brain development and the pathophysiology of disorders of the infant brain, written by a team of distinguished neuroscientists, neonatologists, and neuropediatricians. The book follows the main milestones of brain development, from formation of the neural tube and wiring of the neurons in the brain. Neurotrophic factors, neurotransmitters, glial cell biology, cerebral circulation development of sensory functions are all described in detail. Furthermore, there are more philosophical chapters on the evolution of the brain and the emergence of consciousness. Clinical considerations are highlighted where relevant.
Early-life environmental factors can have persistent effects on physiological functions by altering developmental procedures in various organisms. Recent experimental and epidemiological studies now further support the idea that developmental programming is also present in mammals, including humans, influencing long-term health. Although the mechanism of programming is still largely under investigation, the role of endocrine glucocorticoids in developmental programming is gaining interest. Studies found that perinatal glucocorticoids have a persistent effect on multiple functions of the body, including metabolic, behavioral, and immune functions, in adulthood. Several mechanisms have been proposed to play a role in long-term programming. In this review, recent findings on this topic are summarized and the potential biological rationale behind this phenomenon is discussed.
p>The thesis presented examines the role of glucocorticoids in a model of hypertension programmed by maternal nutrition.
A low protein, isoenergetic diet (MLP) in the rat reduced maternal weight gain in late gestation and impaired the activity of placental 11β-hydroxysteroid dehydrogenase Type 2 at day 20 gestation, which changes in maternal hormonal status could not explain. MLP fetuses may therefore be exposed to a greater level of maternal glucocorticoid in late gestation. MLP pups at term were of low to normal birthweight yet exhibited degrees of disproportionate intrauterine growth that appeared to favour maintenance of substrate supply to the brain. Brain growth was maintained in proportion to growth of the body whereas growth of the liver, lungs and trunk was not.
MLP pups from term, into adulthood, demonstrated increased activities of glucocorticoid-inducible enzymes despite normal plasma corticosterone concentrations indicating a degree of hypersensitivity to glucocorticoid action. MLP pups were hypertensive relative to control rats from weaning age. Maternal adrenalectomy successfully ablated the hypertensive state of MLP-male rats which corticosterone, but not aldosterone, replacement to pregnant adrenalectomized rats restored. Hypertension in MLP-males is therefore likely to be glucocorticoid-dependent. Hypertension in MLP-female rats was either delayed or unaffected by maternal adrenalectomy, however, corticosterone replacement to MLP dams elevated the systolic blood pressure of MLP-female offspring.
The data suggest that maternal undernutrition through maternal glucocortoid influence, programmes hypertension in the resultant offspring in the rat. Increased sensitivity to glucocorticoid and angiotensin II action may partially maintain the hypertensive state. Undernutrition-induced fetal over-exposure to predominantly maternal glucocorticoids may contribute to mechanisms underpinning the incidence of adult hypertension associated with low birthweight.</p
Dexamethasone has been widely used in clinical practice to promote fetal lung maturity and reduce neonatal respiratory distress syndrome and perinatal mortality. Nevertheless, its administration is a double-edged sword, as a large number of studies have shown that there are obvious disadvantages in pregnant women and fetal development. In this review, we comprehensively retrospect the latest literature on the toxicological effects and mechanisms of dexamethasone on fetal development, in an attempt to provide a valuable basis for further studies and clinical trials in the future. Overall, prenatal dexamethasone exposure could lead to some adverse consequences on fetal organ systems through intrauterine programming based on the results of current animal and human researches. Potential sequelae include osteoarthritis, hypertension, fatty liver, glomerulosclerosis, depression, diabetes and infertility, some of which can pass on to the next generation. It must be noted that the evidence in humans is preliminary and limited by the small sample size. More studies in large-scale populations are needed to confirm if it raises the risk of sequelae in humans. In addition, we strongly support the application of dexamethasone as a pharmaceutical therapy in pregnant women with coronavirus disease 2019 before a better therapy is developed. However, the adverse side effects that may arise also cannot be ignored.
Resume
Objectif : En cas de retard de croissance intra-utérin, des études antérieures ont démontré une amélioration de l’implémentation des pratiques cliniques et une amélioration du pronostic néonatal précoce en cas de suivi au sein d’un parcours standardisé de soins par rapport à un parcours de soins classique. L’objectif de cette étude était d’évaluer la prévalence des interventions obstétricales chez les fœtus petits pour l’âge gestationnel (PAG) suivi au sein d’un parcours standardisé de soins par rapport au parcours traditionnel de soins classiques.
Méthodes : Nous avons mené une étude rétrospective entre 2015 et 2017, dans une maternité de type III à Lyon, au sein d’une population de fœtus PAG, considérés constitutionnellement petits en cas de diagnostic anténatal de poids foetal < 10ème percentile mais > 3ème percentile sans anomalie au Doppler ombilical au cours de la surveillance anténatale et sans argument échographique faisant suspecter un retard de croissance intra utérin (RCIU). Nous avons recueilli les interventions obstétricales effectuées au cours de la grossesse, ainsi que les modalités de naissance des PAG et leur issue néonatale immédiate dans le parcours classique et dans le parcours standardisé. Après le diagnostic de PAG, le choix du parcours a été laissé au praticien en fonction de ses habitudes, de sa capacité à gérer le suivi et de ses contraintes organisationnelles.
Résultats : Sur la période de l’étude, et après exclusion des fœtus en RCIU, 96 PAG ont été suivi dans le parcours traditionnel et 106 PAG au sein du parcours standardisé. Le parcours classique proposait en analyse multivariée une plus forte prévalence de la corticothérapie prénatale (16,6%) en cas de PAG entre 2015 et 2017 avec OR 7,3 IC 95% [1,41-38,43] par rapport au parcours standardisé (3,7%). De même, le parcours classique proposait une prévalence de déclenchement (54,1%) supérieure au parcours standardisé (33,9%) chez les PAG entre 2015 et 2017 avec OR 3,19 IC 95 % [1,70-7,80]. La puissance post-hoc « a posteriori » de l’étude était de 82,9%.
Conclusion : Cette étude confirme l’absence d’intervention obstétricale excessive dans la population des PAG dans un parcours de soins standardisé. Ce dernier permettrait de réduire les événements obstétricaux inutiles dans le respect du pronostic néonatal intrinsèque aux fœtus petits pour l’âge gestationnel.
The prenatal stress during pregnancy has a wide variety of negative effects on the offspring behaviors. As such, in the present study the effect of prenatal immobilization stress was investigated on the brain BDNF level, spatial memory, anxiety and depression-like behavior in the F1 generation female NMRI mice. Twenty female pregnant mice were randomly allocated to stress and control groups (n = 10/group). The stress group was placed in PVC cylinders (2.5 cm in diameter and 20 cm in length) for one hour/day until the 15th day of pregnancy. The female F1 offspring was nursed by their mothers until reaching 25–30 g (9–10 weeks) which was tested for spatial memory, anxiety and depressive-like behavior using Barnes Maze, elevated plus-maze and forced swimming test, respectively. Also, the brain BDNF level was assessed by the ELISA method. Mice that underwent prenatal restraint stress exhibited impaired spatial memory in the Barnes Maze, which the time and distance to achieve the target hole and the number of errors in the female adult offspring increased than the control group. In the elevated plus-maze, the animals that underwent prenatal restraint stress spent less time in the open arms of the maze and reduced entering the open arms, compared to the control group. In addition, stress caused a significant decrease in swim time and a significant increase in float time for the female adult offspring compared to the control group. The brain BDNF concentration also decreased significantly in the stress group compared to the control group. This data suggests that prenatal stress may impair spatial memory and induce anxiety and depressive-like behavior in the adult offspring female mice via reducing brain BDNF.
Extensive evidence now shows that adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature. These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalizing behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalizing behaviours such as anxiety. Regardless of the causative event or the sex of the offspring, these disorders may begin in childhood or adolescence but extend into adulthood. A mechanism by which adverse events in the perinatal period impact later in life behaviour has been shown to be the changing epigenetic landscape. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA synthesizing enzyme Glutamate Decarboxylase 1, resulting in increased levels of glutamate is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD. Exposure of the fetus or the neonate to high levels of cortisol may be the mediator between perinatal compromise and poor behavioural outcomes as evidence suggests that increased glucocorticoid exposure triggers widespread changes in the epigenetic landscape. This review summarises the current evidence and recent literature about the impact of various perinatal insults on the epigenome and the common mechanisms that may explain the similarity of behavioural outcomes that occur following diverse perinatal compromise.
Prenatal stress programs offspring cognitive and mental health outcome. We reviewed whether prenatal stress also programs cardiovascular dysfunction which potentially modulates cerebrovascular, cognitive and mental health disorders. We focused on maternal stress and prenatal glucocorticoid (GC) exposure which have different programming effects. While maternal stress induced cortisol is mostly inactivated by the placenta, synthetic GCs freely cross the placenta and have different receptor-binding characteristics. Maternal stress, particularly anxiety, but not GC exposure, has adverse effects on maternal-fetal circulation throughout pregnancy, probably by co-activation of the maternal sympathetic nervous system, and by raising fetal catecholamines. Both effects may impair neurodevelopment. Experimental data also suggest that severe maternal stress and GC exposure during early and mid-gestation may increase the risk for cardiovascular disorders. Human data are scarce and especially lacking for older age. Programming mechanisms include aberrations in cardiac and kidney development, and functional changes in the renin-angiotensin-aldosterone-system, stress axis and peripheral and coronary vasculature. Adequate experimental or human studies examining the consequences for cerebrovascular, cognitive and mental disorders are unavailable.
Early life stress (ELS) is a risk factor in the development of psychiatric disorders. The underlying biological mechanisms governing this phenomenon are not fully understood, but dysregulation of stress responses is likely to play a key role. Males and females differ in their propensity to develop psychiatric disorders, with far higher rates of anxiety, major depressive disorder, affective disorders and post-traumatic stress disorder found in women. We hypothesized that sex differences in response to ELS may play a crucial role in differential vulnerability between the sexes. To test this, we evaluated the consequences of pre-pubertal stress (PPS) on the HPA axis in adult female and male Lister Hooded rats. PPS animals were exposed to swim, restraint and elevated platform stress on postnatal days 25–27, controls remained in their home cage. Once adult, animals were either a) sacrificed directly and brains collected or b) sacrificed 20 minutes or 1 week after a social test and trunk blood collected. In the female hippocampal formation, PPS increased expression of FKBP5 and AVPR1a. In the female prefrontal cortex, PPS resulted in increased glucocorticoid receptor expression, increased glucocorticoid:mineralocorticoid (GR:MR) receptor expression ratio and decreased AVPR1a expression. Females exposed to PPS did not show the normal rise in blood corticosterone levels following a social interaction test. In contrast, PPS did not alter the expression of oxytocin or oxytocin receptors, and no effects of PPS were seen in males. However, striking sex differences were found. Females had higher oxytocin receptor expression in the prefrontal cortex and AVPR1a and oxytocin expression in the hypothalamus, whereas males demonstrated higher expression of GR, MR, GR:MR, FKBP5 and oxytocin receptor in the hypothalamus. These results demonstrate heightened reactivity of the female HPA axis to PPS and may help explain why in humans females display an increased susceptibility to certain stress-related psychopathologies.
• LAY SUMMARY
• Women are at greater risk of developing several psychiatric illnesses. Using a rodent model, we show that the female stress system is more reactive to the lasting effects of early life stress. This heightened reactivity of the female stress response may help explain why women are at a greater risk of developing psychiatric disorders.
Epidemiologische, klinische und experimentelle Daten legen nahe, dass der Ursprung somatischer und psychiatrischer Erkrankungen teilweise im Mutterleib zu finden ist. Ungünstige intrauterine Ein-flüsse, wie Stressbelastung, Mangelernährung und Exposition gegenüber Noxen stellen pränatale Stressfaktoren für das ungeborene Kind dar. Nach Hypothese der fetalen Programmierung können diese langandauernde Effekte auf Organogenese, Geburtsausgang und Stoffwechsellage haben und konsekutiv die physische sowie seelische Gesundheit nachhaltig und anhaltend beeinflussen. Die vorliegende Arbeit untersuchte, innerhalb der prospektiven Längsschnitt-Studie POSEIDON (Pre-, Peri- and POstnatal Stress: Epigenetic Impact on DepressiON), die Auswirkungen maternaler psycho-sozialer Stressbelastung während der Spätschwangerschaft auf den Ausgang der Geburt. Die psy-chosoziale Stressbelastung des untersuchten Studienkollektivs von N = 405 Probandinnen im letzten Trimenon der Schwangerschaft (36,77 ± 1,89 SSW p.m.) wurde über sechs schwangerschaftsspezifi-sche Stressvariablen erhoben und lieferten die Grundlage zur Stressgruppeneinteilung. Der Einfluss pränataler psychosozialer Stressbelastung auf die kindliche Entwicklung im Mutterleib wurde anhand der Geburtsparameter: Gestationsalter, Gewicht, Größe und Kopfumfang als Marker einer ungünsti-gen intrauterinen Umgebung der N = 405 Nachkommen untersucht. Zur Analyse der neuroendokrinen Stressachse respektive Aktivität der Hypothalamus-Hypophysen-Nebennierenrinden-Achsen (HHNA), als vermeidlich vermittelnde Instanz pränataler psychosozialer Stressoren, wurde die Stresshormon-konzentration (Cortisol) aus Speichelproben der Mütter und aus in utero angelegten Fingernagel-Abschnitten der Neugeborenen bestimmt. Eine hohe psychosoziale Stressbelastung in der Spätschwangerschaft konnte in der vorliegenden Arbeit mit einer Dysregulation des maternalen Cortisoltagesprofils und einem negativen Geburtsaus-gang assoziiert werden. In diesem Zusammenhang ging ein hohes Maß an milde einzustufenden psy-chosozialen Stressoren mit einer signifikanten Reduktion des Geburtsgewichtes um 217 g (-6,7 %, p = .003), der Größe um 1,2 cm (-2,3 %; p = .003) und des Kopfumfangs um 0,8 cm (-2,3 %; p < .001), auch nach Kontrolle für Störfaktoren, einher. Eine hohe psychosoziale Stressbelastung konnte zudem mit einer Abflachung des Cortisoltagesprofils im Sinne eines verminderten Abfalls der Cortisolkonzentration über den Tag (↓ Cortisol decline, p = .023) assoziiert werden, welche wiederum in Zusammenhang mit signifikant verkürzten Gestationszeiten (p = .003) stand. Darüber hinaus wurden in der vorliegenden Arbeit die Interaktion beider Steroidkonzentrationen untereinander, deren Auswirkungen auf den Geburtsausgang und der Einfluss psychosozialer Stressbelastung auf die Höhe der kindlichen Stresshormonkonzentrationen untersucht. Insgesamt unterstützen die Studienergebnisse zusammen mit Evidenzen aktueller wissenschaftlicher Literatur einen ungünstigen Einfluss pränataler psychosozialer Stressoren auf das ungeborene Kind. Ein wichtiger zugrundeliegender Pathomechanismus der pränatalen Stressübertragung scheint, zu-mindest teilweise, durch eine stressinduzierte Dysregulation der maternalen HHNA-Aktivität mit kon-sekutiver fetaler Glucocorticoid-Überexposition vermittelt zu sein. Diese können den Feten im Mutter-leib für kürzere Gestationszeiten, geringere Geburtsgewichte und deren assoziierte Erkrankungen prädispositionieren. Langanhaltende Konsequenzen der pränatalen psychosozialen Stressbelastung für die kindliche Ent-wicklung und die somatische sowie seelische Gesundheit der POSEIDON-Kinder sollen im Rahmen von Follow-up-Studien untersucht werden. Die frühzeitige Identifizierung von Nachkommen mit be-sonders hohem Risiko für pränatal programmierte Erkrankungen durch psychosoziale Stressfaktoren könnte neue Dimensionen präventiver Ansätze liefern.
В биомедицинской науке последствия стресса в раннем онтогенезе в большинстве случаев рассматриваются как негативные для организма, вызывающие нарушения развития репродуктивных функций, иммунной, нейроэндокринной систем, мозга и поведения, включая когнитивные способности
и устойчивые расстройства психики. На этом фоне набирают силу исследования, обсуждающие последствия ранних стрессов с позиции их возможной адаптивности, оцениваемой как увеличение приспособленности (fitness) в текущем и последующих поколениях. В обзоре дано краткое описание основных механизмов обусловленного материнским стрессом онтогенетического программирования организма потомка на основе обобщающих работ по млекопитающим. Основное же
внимание уделено экспериментам в природе, либо экспериментам, моделирующим природную ситуацию, в которых на некоторых видах позвоночных животных были исследованы последствия материнских стрессов для потомков на фоне контролируемых изменений среды обитания, включая и среду социальную. Фенотипически проявляющиеся у потомков последствия ранних стрессов оказываются полезными для них (адаптивными) в тех случаях, когда условия среды (в т. ч. социальной), в которой существовал организм матери в период формирования яйца или беременности и сразу после рождения выводка, соответствуют условиям среды их будущей жизни. Для матери стрессовые состояния, транслируемые потомкам, могут быть выгодны, поскольку оптимизируют затраты на текущее размножение и в конечном счете могут повышать ее совокупную приспособлен ность независимо от того, повышают они или понижают приспособленность потомков в ближайшей перспективе. Эволюционно-экологический подход в изучении последствий ранних стрессов может быть полезным для понимания процессов формирования здоровья человека. Накопленные на сегодня данные вселяют надежду на то, что будет наконец достигнуто понимание необходимости
сокращения несоответствия между пренатальной и будущей средой жизни человека, несоответствия, существенно повышающего риски заболеваний в зрелом возрасте.
В биомедицинской науке последствия стресса в раннем онтогенезе в большинстве случаев рассматриваются как негативные для организма, вызывающие нарушения развития репродуктивных функций, иммунной, нейроэндокринной систем, мозга и поведения, включая когнитивные способности
и устойчивые расстройства психики. На этом фоне набирают силу исследования, обсуждающие последствия ранних стрессов с позиции их возможной адаптивности, оцениваемой как увеличение приспособленности (fitness) в текущем и последующих поколениях. В обзоре дано краткое описание основных механизмов обусловленного материнским стрессом онтогенетического программирования организма потомка на основе обобщающих работ по млекопитающим. Основное же вни
мание уделено экспериментам в природе, либо экспериментам, моделирующим природную ситуацию, в которых на некоторых видах позвоночных животных были исследованы последствия
материнских стрессов для потомков на фоне контролируемых изменений среды обитания, включая и среду социальную. Фенотипически проявляющиеся у потомков последствия ранних стрессов оказываются полезными для них (адаптивными) в тех случаях, когда условия среды (в т. ч. социальной), в которой существовал организм матери в период формирования яйца или беременности и сразу после рождения выводка, соответствуют условиям среды их будущей жизни. Для матери стрессовые состояния, транслируемые потомкам, могут быть выгодны, поскольку оптимизируют затраты на текущее размножение и в конечном счете могут повышать ее совокупную приспособлен-
ность независимо от того, повышают они или понижают приспособленность потомков в ближайшей перспективе. Эволюционно-экологический подход в изучении последствий ранних стрессов может быть полезным для понимания процессов формирования здоровья человека. Накопленные
на сегодня данные вселяют надежду на то, что будет наконец достигнуто понимание необходимости сокращения несоответствия между пренатальной и будущей средой жизни человека, несоответствия, существенно повышающего риски заболеваний в зрелом возрасте.
Maternal adversity and fetal glucocorticoid exposure has long-term effects on cardiovascular, metabolic and behavioral systems in offspring that can persist throughout the lifespan. These data, along with other environmental exposure data, implicate epigenetic modifications as potential mechanisms for long-term effects of maternal exposures on adverse health outcomes in offspring. Advances in microarray, sequencing and bioinformatic approaches have enabled recent studies to examine the genome-wide epigenetic response to maternal adversity. Studies of maternal exposures to xenobiotics such as arsenic and smoking have been performed at birth to examine fetal epigenomic signatures in cord blood relating to adult health outcomes. However, there have been no epigenomic studies examining these effects in animal models. On the other hand, to date, only a few studies of the effects of maternal psychosocial stress have been performed in human infants, and the majority of animal studies have examined epigenomic outcomes in adulthood. In terms of maternal exposure to excess glucocorticoids by synthetic glucocorticoid treatment, there has been no epigenetic study performed in humans and only a few studies undertaken in animal models. This review emphasizes the importance of examining biomarkers of exposure to adversity throughout development to identify individuals at risk and to target interventions. Thus, research performed at birth will be reviewed. In addition, potential subject characteristics associated with epigenetic modifications, technical considerations, the selection of target tissues and combining human studies with animal models will be discussed in relation to the design of experiments in this field of study.
Corticosteroids exert effects on the hippocampus by binding to intracellular glucocorticoid and/or mineralocorticoid receptors, but the relative importance of each receptor type in mediating corticosteroid effects is poorly understood. There is an extensive serotoninergic (5-HT) innervation of the hippocampus which interacts with corticosteroid-sensitive cells. We have investigated the effect of intracerebroventricular 5,7-dihydroxytryptamine lesions of 5-HT neurons on glucocorticoid and mineralocorticoid receptor messenger ribonucleic acid (mRNA) expression in the rat hippocampus using in situ hybridization histochemistry. In controls, glucocorticoid receptor mRNA was highly expressed in dentate gyrus granule cell neurons, and in pyramidal cells of CA1 and CA2, but levels in CAS and CA4 were significantly lower. 5,7-dihydroxytryptamine-lesioned animals showed significantly less glucocorticoid receptor mRNA in the dentate gyrus (76% decrease), CA1 (42% decrease) and CA2 (52% decrease; all P<0.05 compared with controls). Mineralocorticoid receptor mRNA was expressed at a similar level in all hippocampal subregions in control rats. 5,7-dihydroxytryptamine lesioning led to a significant decrease in mineralocorticoid receptor mRNA expression in CA3 (56% fall) and CA4 (45% fall; both P<0.05), but not in the other subregions. Thus the 5-HT innervation regulates hippocampal corticosteroid receptor mRNA expression.
Glucocorticoid receptors are members of a highly conserved family of steroid receptor proteins, which are ligand-dependent transcription factors. Previous studies have shown that the presence of functional glucocorticoid receptors is a prerequisite for manifestation of cellular responses to hormone. Glucocorticoid receptors undergo down-regulation following treatment with glucocorticoids. To define the molecular mechanisms that are involved in this process we have analyzed the down-regulation of glucocorticoid receptors both in HeLa cells, which contain endogenous receptors, and in cells containing receptors that have been introduced by DNA transfection. Our results show that cells that contain glucocorticoid receptors—either endogenous or transfected—undergo down-regulation of steroid-binding capabilities, as well as reductions in receptor protein and mRNA levels, in a remarkably similar fashion. DNA sequences in the coding region of the human glucocorticoid receptor cDNA appear to be sufficient to account for down-regulation of receptor. This novel finding suggests that unique mechanisms are involved in controlling glucocorticoid receptor homeostasis.
Rats were subjected to restraint stress for nine hours daily, on three consecutive days, at various stages of pregnancy from days 9–20, and the postnatal development and behaviour of the offspring assessed on a wide-ranging battery of tests. Stress at any of the stages of pregnancy investigated caused a significant decrease in offspring body weight persisting up to 6 weeks of age, and delayed the appearance of certain developmental landmarks such as ear opening, auditory startle and cliff avoidance responses. Postnatal mortality and impairment of ability to orient to the home cage were also significantly increased in the offspring from rats stressed on days 18–20 of pregnancy. In a second experiment, the effects of restraint stress on days 18–20 were investigated in more detail. At birth, stressed and control offspring were fostered onto mothers from the same treatment group or cross-fostered onto mothers from the opposite treatment group and assessed as before, to determine whether the adverse effects observed in the first experiment were prenatally or postnatally mediated. The effects were most marked in prenatally stressed pups reared by stressed mothers and least marked in controls reared by controls, with the other two cross-fostered groups being intermediate; this indicates that the effects were induced partly prenatally at the time of treatment and partly postnatally by the rearing mothers that had been stressed.
Purpose:
To review evidence that essential hypertension is a growth-related disorder with origins in childhood and manifestations in adult life.
Principal evidence:
Blood pressure rises with age in children and adults. In children, the rise closely relates to growth and to skeletal and sexual maturation. Adolescents with highest pressure are heavier and had as children grown fastest; as adults, they show the greatest increase of pressure with age and are more likely to develop hypertension and coronary heart disease. In adults, the rate of increase of pressure relates to earlier pressure. One interpretation of this is that a self-perpetuating mechanism is at work. Genetic and environmental factors influence these events.
Hypothetical mechanisms:
Most forms of secondary hypertension have two pressor mechanisms; a primary cause, e.g. renal clip, and a second process, which is slow to develop, capable of maintaining hypertension after removal of the primary cause, and probably self-perpetuating in nature. We suggest that essential hypertension also has two mechanisms, both based upon cardiovascular hypertrophy: (1) a growth-promoting process in children (equivalent to the primary cause in secondary hypertension); and (2) a self-perpetuating mechanism in adults.
A study was made of the effects of prenatal stress on the reactivity of the hypothalamic-pituitary adrenal (HPA) axis in male and female offspring. Rat dams were subjected to noise and light stress on an unpredictable basis throughout pregnancy. At 28 days of age mRNA for POMC, proenkephalin and prodynorphin were measured in the hypothalamus of the offspring. A marked reduction was found in POMC mRNA in PS females (PSF) but not in males (PSM), but the other mRNA's did not differ from controls (C). At 60 days of age, PSF has 3 times higher resting levels of serum corticosterone (COR) and significantly lower dexamethasone (DEX)3H hippocampal binding sites than CF. Overnight adrenalectomy abolished the difference in DEX binding. After 10 min exposure to open field PS males and females voided more fecal pellets and made fewer center entries than C offspring, testifying to increased emotionality. Open field stress caused a 3-5-fold rise in circulating COR in all groups within 15 min, which returned to baseline by 90 min in all rats except PSF. These data show that prenatal stress can cause permanent alterations in the behavior of both sexes in stressful situations but appears to cause a selective effect on the HPA axis in the female rat.
During neonatal development, adrenergic control of hepatic glucose metabolism undergoes a transition from beta-receptor to alpha 1-receptor-mediated dominance coincident with the onset of function of the hypothalamus-pituitary-adrenocortical axis at the conclusion of the third to fourth week postpartum. To determine whether glucocorticoids contribute to this switch, neonatal rats were given 1 mg/kg of dexamethasone on postnatal days 13, 14 and 15 and the adrenergic receptor population examined by radioligand binding techniques. Dexamethasone accelerated the maturational replacement of beta-receptors with the alpha 1-subtype; the loss of beta-receptors was not reversible upon discontinuing treatment. When the glucocorticoid was given earlier, on days 7, 8 and 9, similar effects were obtained, but the suppression of the beta-subtype was only temporary; treatment before parturition (gestational days 17, 18 and 19) failed to suppress beta-receptor binding. These results suggest that, during a critical period, adrenocorticosteroids provide an important signal for the transition of adrenergic control of hepatic function.
Neurotoxic effects of prenatal administration of dexamethasone were examined in the fetal rhesus monkey brain at 135 and 162 days of gestation (term is 165 days). In an experimental design mimicking human clinical trials, dexamethasone was given intramuscularly to pregnant monkeys on day 132 (single injection with doses of 0.5, 5, or 10 mg/kg maternal body weight) or on days 132 and 133 (multiple injections at 12-h intervals with 0.125 x 4, 1.25 x 4, or 2.5 mg/kg x 4). The fetuses were delivered by caesarean section on day 135 or day 162 and hippocampal slices were prepared for evaluation. Light and electron microscopic observation revealed decreased numbers of pyramidal neurons in the hippocampal CA regions and of granular neurons in the dentate gyrus associated with degeneration of neuronal perikarya and dendrites. Axodendritic synaptic terminals of the mossy fibers in the CA3 hippocampal region showed pronounced degeneration. Degeneration was dose-dependent and multiple injections induced more severe damage than single injections of the same total dose. Even the lowest dose (0.5 mg/kg, which is similar to the dose used in human clinical trials) produced these changes. Degenerative changes induced by dexamethasone treatment (5 mg/kg) on days 132 and 133 were also clearly evident in fetuses studied at 162 days. Therefore, caution is recommended in the use of prenatal corticosteroids in premature deliveries.
Adult rats handled (H) daily for the first 3 weeks of life show a dramatically altered adrenocortical response to stress. We found that H animals secreted less ACTH and corticosterone (B) during and following the termination of stress than did nonhandled (NH) controls. In contrast, H and NH animals did not differ in basal B secretion at any point in the diurnal cycle, nor in adrenocortical responses to exogenously administered oCRF or ACTH. Moreover, the clearance rate for B was similar in H and NH animals. H animals were more sensitive than NH animals to the inhibitory effects of either B or dexamethasone on stress-induced adrenocortical activity. In a dose-response study, both glucocorticoids administered 3 h prior to testing suppressed the adrenocortical response to a 20-min restraint stress to a greater extent in the H animals. Handling increased type II, glucocorticoid receptor binding capacity in the hippocampus of adult animals (approximately 50% increase in capacity, with no change in affinity). There were no handling-induced changes in type II receptor binding capacity in the hypothalamus or pituitary, nor in type I receptor binding capacity in the hippocampus. Following chronic (5 mg/kg/day) treatment with B, hippocampal type II receptor binding capacity was significantly reduced in the B-treated H animals, compared with saline-treated H animals, and indistinguishable from saline-treated NH animals. Down-regulated H animals, like NH animals, hypersecreted B following the termination of stress in comparison to the saline-treated H animals.(ABSTRACT TRUNCATED AT 250 WORDS)
To examine whether prenatal exposure to glucocorticoids could adversely affect subsequent cellular development of the lung, we administered 0.2 mg/kg of dexamethasone to pregnant rats on gestational days 17, 18, and 19. Lungs of the offspring were then examined for patterns of cell acquisition (DNA) and growth (protein). DNA concentration (a marker of cell packing density) and DNA content (a measure of total cell numbers) were reduced during gestation, and the shortfalls in concentration persisted past weaning. Disruption of development was also apparent in the protein/DNA ratio, which was consistently elevated, a finding consistent with cellular hypertrophy. In addition, lung ODC became coupled to beta-adrenergic receptors prematurely in the dexamethasone group, suggesting that neural control of tissue differentiation is altered. These data indicate that prenatal glucocorticoids may compromise lung development through effects on cell replication and differentiation, which derive, in part, from alterations in the reception of trophic neural signals.
Although the presence of mineralocorticoid binding sites have been demonstrated in brain, little is known about their physiological role. The purpose of this study was to evaluate possible interactions between a relatively short 2-day central infusion of aldosterone (5 ng/h) and a diverse group of centrally acting pressor agents. The intracerebroventricular infusion of aldosterone selectively attenuated the pressor response produced by the injection of arginine vasopressin (AVP, 10-400 ng) into the lateral ventricle without altering the responses to ventricular administration of 50-200 ng angiotensin II (ANG II), 150 ng carbachol, and 0.5 and 1 M hypertonic sodium chloride. No aldosterone-vasopressin interaction occurred in rats receiving a simultaneous central infusion of aldosterone and RU 28318 [7 beta-hydroxy-3-oxo-7 alpha-propyl(17 alpha)-pregn-4-ene-21-potassium carboxylate], a specific mineralocorticoid receptor antagonist. Baroreflex reactivity and the pressor response to intravenous AVP were not modified by the aldosterone treatment, indicating that overall cardiovascular reactivity was not depressed. Because the vascular reactivity of the mesenteric artery to AVP and norepinephrine remained unchanged after 2 days of central aldosterone infusion, and because plasma levels of aldosterone were not altered, the selective inhibition by this mineralocorticoid of the central AVP response appears to be purely central in origin. This specific central effect of aldosterone is mediated through interaction with mineralocorticoid receptors.
The cloning of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) cDNAs provides a basis for understanding the actions of glucocorticoids in the central nervous system. Structural evidence is presented for the identity of the type I corticosteroid binding site as the MR expressed in the brain. This identification is supported by the anatomical distribution of MR mRNA, determined by in situ hybridization histochemistry, which parallels the steroid autoradiographic localization of the type I sites. An in vitro assay for MR and GR function demonstrates that these receptors respond to different levels of glucocorticoid, suggesting that together they confer a larger dynamic range of sensitivity to this hormone. These studies lead to a new hypothesis for glucocorticoid action in the central nervous system.
The experimental literature on the behavioral sequelae of prenatal stress in rodents is reviewed, from which few conclusions can be drawn except that some change in activity-reactivity may be induced. Were more careful consideration given to certain methodologic dimensions, greater clarity of empirical relations could be achieved. These dimensions are: (1) the sex, species, and strain of animal observed; (2) the specification of the prenatal manipulation; and (3) the precision and completeness of the behavioral description which is the dependent variable studied. Multiple descriptions, as in a test-battery approach, appear to be inefficient and generally unwarranted.
Recently, both glucocorticoid receptor immunoreactivity and glucocorticoid receptor messenger RNA levels were found in multiple brain areas, especially in the neuroepithelium during the late prenatal development of the rat brain. To better understand the potential influence of stress on fetal brain development by release of maternal adrenocortical steroids, we have investigated the effects of corticosterone administration to pregnant rats on the locomotor activity of their prepubertal offspring. On day 16 of pregnancy female rats were implanted with either placebo or corticosterone pellets (release of 2.4 mg/day for seven days). After birth their offspring were nursed by foster mothers to avoid any postnatal effects of the corticosterone pellets. At three weeks of age, the offspring were tested for spontaneous motor behaviours. Both male and female offspring from corticosterone treated mothers showed significantly increased spontaneous ambulation, motility and rearing compared to placebo treated groups. No significant sex differences were found in locomotor activity between male and female offspring from placebo groups. Following d-amphetamine (1.5 mg/kg) treatment, a preferential dopamine releasing agent, we observed a significant increase in ambulation, motility and rearing activity in the male offspring treated with corticosterone. In the female offspring, only the rearing activity was significantly higher after d-amphetamine treatment in the prenatal corticosterone group compared with the placebo treated group. Basal dopamine metabolism (dihydroxyphenylacetic acid/dopamine ratio) was increased in the dorsal striatum and ventral striatum of male and female offspring from corticosterone-treated dams. In the male offspring, corticosterone treatment was associated with a disappearance of the right side dominance of dopamine metabolism in the dorsal striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
Neonatal handling permanently alters hypothalamic-pituitary-adrenal responses to stress. This effect is, in part, mediated by a handling-induced increase in forebrain glucocorticoid receptor gene expression. The effect of postnatal handling on glucocorticoid receptor expression appears to be mediated by an increase in serotonin (5-HT) activity, acting via a 5-HT2 receptor with a high affinity for 5-HT (i.e. the 5-HT2H receptor). In the present study we examined the nature of the effects of handling on the relevant 5-HT systems. We found that: (1) handling increases 5-HT turnover in regions of the neonatal rat brain where glucocorticoid receptor expression is altered (i.e. the hippocampus and frontal cortex), but not in regions where glucocorticoid receptor expression in unaffected (e.g. hypothalamus and amygdala); (2) handling has no long-term effects on hippocampal or frontal cortex 5-HT turnover, and is actually associated with a decrease in 5-HT concentrations; and (3) handling does not alter 5-HT2 receptor density in the hippocampus or frontal cortex in neonates (although there are surprising effects on 5-HT2 receptor density in the frontal cortex of adult animals). Taken together these data provide further evidence for the importance of 5-HT in mediating the effects of handling on the development of glucocorticoid receptor expression, but suggest that the role of 5-HT is unique to early development; differences in glucocorticoid receptor expression in adult handled and non-handled animals are not associated with long-term differences in either 5-HT levels or 5-HT2 receptors.
Environmental enrichment increases glucocorticoid receptor expression in hippocampal pyramidal neurons, but the molecular mechanisms are unknown. Several transcription factors are expressed in hippocampal neurons where they respond to environmental stimuli. In this study 12 adult male rats (n = 6 in each group) were exposed to enriched or isolated environment for 30 days. The expression of AP-2 mRNA, studied by in situ hybridization, was attenuated by environmental enrichment in the CA2 and CA3 subfields of the hippocampus. AP-2 may be involved in the environmental effect of glucocorticoid receptor gene expression in these neurons.
Severe and prolonged physical and psychological stress is known to cause brain damage; long-term torture victims in prison have later developed psychiatric disorders and cerebral cortical atrophy observed in CT scans (Jensen, Genefke, Hyldebrandt, Pedersen, Petersen, and Weile, 1982). In nonhuman primates, we observed degeneration and depletion of the hippocampal neurons in African green monkeys that had been severely abused by cagemates and died with complications of multiple gastric ulcers and adrenal cortical hyperplasia (Uno, Tarara, Else, Suleman and Sapolsky, 1989). In our previous studies the administration of dexamethasone (DEX) (5 mg/kg) to pregnant rhesus monkeys at 132 to 133 days of gestation induced degeneration and depletion of the hippocampal pyramidal and dentate granular neurons in the brains of 135-gestation-day fetuses, and these changes were retained in the brains of fetuses at near term, 165 days of gestation (Uno, Lohmiller, Thieme, Kemnitz, Engle, Roecker, and Farrell, 1990). We also found that implantation of a cortisol pellet in the vicinity of the hippocampus in adult vervet monkeys induced degeneration of the CA3 pyramidal neurons and their dendritic branches (Sapolsky, Uno, Rebert, and Finch, 1990). Thus, hippocampal pyramidal neurons containing a high concentration of glucocorticoid receptors appear to be highly vulnerable to either hypercortisolemia caused by severe stress or to exposure to exogenous glucocorticoids. To study the long-term postnatal sequelae of prenatal brain damage, eight rhesus monkeys were treated with either DEX (5 mg/kg), 5 animals, or vehicle, 3 animals, at 132 to 133 days of gestation. After natural birth, all animals lived with their mothers for 1 year. At 9 months of age, we found that DEX-treated animals had significantly high plasma cortisol at both base and post-stress (isolation) levels compared to age-matched vehicle-treated animals. Magnetic resonance images (MRI) of the brain at 20 months of age showed an approximately 30% reduction in size and segmental volumes of the hippocampus in DEX-treated compared to vehicle-treated animals. Measurements of whole brain volume by MRI showed no significant differences between DEX and vehicle groups. Prenatal administration of a potent glucocorticoid (DEX) induced an irreversible deficiency of the hippocampal neurons and high plasma cortisol at the circadian baseline and post-stress levels in juvenile rhesus monkeys. These results suggest that the hippocampus mediates negative feedback of cortisol release; a lack or deficiency of the hippocampal neurons attenuates this feedback resulting in hypercortisolemia.(ABSTRACT TRUNCATED AT 400 WORDS)
Postnatal handling alters hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Handling also increases hippocampal glucocorticoid receptor density, and this effect appears to form, in part at least, the basis for the effect of handling on HPA responsiveness to stress. In the present study we have used in situ hybridization techniques to examine the effect of postnatal handling on the expression of glucocorticoid and mineralocorticoid receptor mRNAs in various cell fields of the dorsal hippocampus in adult rats. Grain counting analysis over individual cells showed that postnatal handling significantly increased (40-50%) glucocorticoid receptor mRNA in all hippocampal cell fields. In contrast, handling had no effect on mineralocorticoid receptor mRNA expression. These findings are consistent with the results of receptor binding studies showing that handling increases hippocampal glucocorticoid receptor, but not mineralocorticoid receptor density. Thus, the increase in glucocorticoid receptor binding in handled animals is likely associated with altered rates of receptor biosynthesis. Moreover, the handling effect is quite specific, altering glucocorticoid receptor, but not mineralocorticoid receptor mRNA expression. The mechanism(s) whereby glucocorticoid receptor gene expression is permanently increased by postnatal handling remains to be determined.
The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) is thought to protect the non-selective mineralocorticoid receptor from occupation by glucocorticoids, and to modulate access of glucocorticoids to glucocorticoid receptors resulting in protection of the fetus and gonads. A ubiquitous low affinity NADP+ dependent enzyme (11 beta HSD1) and a tissue specific, high affinity NAD+ dependent form (11 beta HSD2) of 11 beta HSD exist. We now report the isolation of a cDNA coding for human 11 beta HSD2. The new isoform is NAD+ dependent, exclusively dehydrogenase in directionality, inhibited by glycyrrhetinic acid and metabolizes the synthetic glucocorticoid dexamethasone; it displays Km values for corticosterone and cortisol of 5.1 nM and 47 nM, respectively. Sequence alignment shows that 11 beta HSD2 shares 35% identity with 17 beta HSD2, but is only 14% identical with 11 beta HSD1. The 11 beta HSD2 gene is highly expressed in kidney, colon, pancreas and placenta and the message is also present in the ovary, prostate and testis. These data suggest that 11 beta HSD2 plays an important role in modulating mineralocorticoid and glucocorticoid receptor occupancy by glucocorticoids.
Prenatal stress is considered as an early epigenetic factor able to induce long-lasting alterations in brain structures and functions. It is still unclear whether prenatal stress can induce long-lasting modifications in the hypothalamo-pituitary-adrenal axis. To test this possibility the effects of restraint stress in pregnant rats during the third week of gestation were investigated in the functional properties of the hypothalamo-pituitary-adrenal axis and hippocampal type I and type II corticosteroid receptors in the male offspring at 3, 21 and 90 days of age. Plasma corticosterone was significantly elevated in prenatally-stressed rats at 3 and 21 days after exposure to novelty. At 90 days of age, prenatally-stressed rats showed a longer duration of corticosterone secretion after exposure to novelty. No change was observed for type I and type II receptor densities 3 days after birth, but both receptor subtypes were decreased in the hippocampus of prenatally-stressed offspring at 21 and 90 days of life. These findings suggest that prenatal stress produces long term changes in the hypothalamo-pituitary-adrenal axis in the offspring.
Intraoperative observations, necropsy, and angiographic studies support the presumption that neurovascular compression of the left ventrolateral medulla may cause neurogenic hypertension. Pulsatile irritation of the ventrolateral medulla at the root-entry zone of cranial nerves IX and X increases blood pressure in animals. To identify and assess the distribution of neurovascular compression at the ventrolateral medulla in human beings, we did a prospective single-blind study in 24 patients with essential hypertension, in 14 patients with renal hypertension, and in 14 normal subjects. To detect neurovascular compression, we used axial and coronal double-echo and magnetic-resonance angiography sequences. Blood pressure control and duration of hypertension were not different in the two groups of patients. 20 patients with essential hypertension had magnetic tomographic evidence of left-sided neurovascular compression at the ventrolateral medulla; 2 patients with renal hypertension and 1 of the normal subjects had a positive finding on the left. On the right side, we found signs of neurovascular compression in 4 patients with essential hypertension, in 4 with renal hypertension, and in 2 of the normal subjects. With magnetic resonance tomography, it is possible to evaluate the neurovascular relations in the posterior fossa and detect neurovascular compression at the ventrolateral medulla. These data in living subjects give further evidence of an association between neurovascular compression at the left ventrolateral medulla and essential hypertension.
Environmental manipulation alters hippocampal glucocorticoid receptor (GR) expression in neonatal rats, but effects in adults have not been documented. Chronic environmental enrichment (EE) increases nerve-growth factor (NGF) concentrations in the adult rat hippocampus. Here we demonstrate that EE induces GR, but not mineralocorticoid receptor (MR) gene expression in specific hippocampal subfields (CA1 and CA2). This is accompanied by increased expression of mRNA encoding the (NGF-induced) immediate early gene NGFI-A in CA2, whereas expression of NGFI-B mRNA decreased in CA1 and CA2. The nature of any relationship between NGF, the transcription factors and GR remains to be determined, but the results demonstrate that chronic environmental manipulations alter hippocampal GR gene expression in adult rats.
Low birthweight is associated with the subsequent development of common disorders of adult life, especially hypertension; maternal malnutrition has been suggested as the cause. We suggest an alternative aetiology—increased fetal exposure to maternal glucocorticoids. This hypothesis is supported by our findings that in rats decreased activity of the enzyme that acts as a placental barrier to maternal glucocorticoids (11 β-hydroxysteroid dehydrogenase) is associated with low birthweight. Furthermore, increased exposure of the fetus to exogenous glucocorticoids leads to low birthweight and subsequent hypertension in the offspring. Glucocorticoids acting during critical periods of prenatal development may, like other steroid hormones, exert organisational effects or imprint patterns of response that persist throughout life. Thus, the lifetime risk of common disorders may be partly determined by the intrauterine environment.
Hypertension is strongly predicted by the combination of low birthweight and a large placenta. This association could be due to increased fetal exposure to maternal glucocorticoids. Fetal protection is normally effected by placental 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which converts physiological glucocorticoids to inactive products. We found that rat placental 11 beta-OHSD activity correlated positively with term fetal weight and negatively with placental weight. Offspring of rats treated during pregnancy with dexamethasone (which is not metabolised by 11 beta-OHSD) had lower birthweights and higher blood pressure when adult than did offspring of control rats. Increased fetal glucocorticoid exposure secondary to attenuated placental 11 beta-OHSD activity may link low birthweight and high placental weight with hypertension.
Babies who are small at birth or during infancy have increased rates of cardiovascular disease and non-insulin-dependent diabetes as adults. Some of these babies have low birthweights, some are small in relation to the size of their placentas, some are thin at birth, and some are short at birth and fail to gain weight in infancy. This paper shows how fetal undernutrition at different stages of gestation can be linked to these patterns of early growth. The fetuses' adaptations to undernutrition are associated with changes in the concentrations of fetal and placental hormones. Persisting changes in the levels of hormone secretion, and in the sensitivity of tissues to them, may link fetal undernutrition with abnormal structure, function, and disease in adult life.
In order to test the hypothesis that maternal corticosterone influences hypothalamus-pituitary-adrenal (HPA) system activity in the adult rat and behaviors related to it, we induced a moderate increase in maternal plasma level of corticosterone by adding the hormone to the drinking water of the dams (200 micrograms/ml) from the day after delivery to weaning. Our previous experiments have shown that this procedure produces plasma levels of the hormone in the range of those following a mild psychic stress (from 4.3 +/- 0.5 to 9.5 +/- 1.8 micrograms/100 ml in the dams, and from 0.7 +/- 0.1 to 1.2 +/- 0.2 micrograms/100 ml in the pups at 10 days of lactation). Adrenal weights were slightly and temporarily decreased by treatment in both mothers and offspring. Only the male progeny was investigated in this study. Corticosterone-nursed rats had significantly less corticosterone and ACTH in basal conditions and after a 2 min restraint stress at 3 months of age, and showed better performances at weaning and at 1, 2 and 3 months of life in the Morris water maze. Our results demonstrate that a moderate increase in maternal corticosterone during lactation influences the activity of HPA axis and improves spatial learning ability of the adult offspring.