Article

Programming hyperglycaemia in the rat through prenatal exposure to glucocorticoids-fetal effect or maternal influence? J Endocrinol

October 2001
Journal of Endocrinology 170(3):653-60

October 2001
170(3):653-60

Source
PubMed

Authors:

Moffat J Nyirenda

University of Malawi

Jonathan Seckl

The University of Edinburgh

In a previous study, we showed that exposure of rats to dexamethasone (Dex) selectively in late pregnancy produces permanent induction of hepatic phosphoenolpyruvate carboxykinase (PEPCK) expression and hyperglycaemia in the adult offspring. The mechanisms by which glucocorticoids cause this programming are unclear but may involve direct actions on the fetus/neonate, or glucocorticoids may act indirectly by affecting maternal postnatal nursing behaviour. Using a cross-fostering paradigm, the present data demonstrate that switching the offspring at birth from Dex-treated dams to control dams does not prevent induction of PEPCK or hyperglycaemia. Similarly, offspring born to control dams but reared by Dex-treated dams from birth maintain normal glycaemic control. During the neonatal period, injection of saline per se was sufficient to cause exaggeration in adult offspring responses to an oral glucose load, with no additional effect from Dex. However, postnatal treatment with either saline or Dex did not alter hepatic PEPCK activity. Prenatal Dex permanently raised basal plasma corticosterone levels, but under stress conditions there were no differences in circulating corticosterone levels. Likewise, Dex-exposed rats had similar plasma catecholamine concentrations to control animals. These findings show that glucocorticoids programme hyperglycaemia through mechanisms that operate on the fetus or directly on the neonate, rather than via effects that alter maternal postnatal behaviour during the suckling period. The hyperglycaemic response does not appear to result from abnormal sympathoadrenal activity or hypothalamic-pituitary-adrenal response during stress.

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Data

Nov 2016

Prenatal Stress Induces Metabolic Impairment in Adolescent Male Wistar Rat

Article

Full-text available

Mar 2013

A large number of studies have reported associations between prenatal stress and offspring lifetime consequences. Chronic gestational stress alters maternal glucocorticids and subsequently disturbs intrauterine environment which may lead to metabolic disorders in the offspring. The aim of this study was to investigate the effects of chronic prenatal stress on the metabolic parameters in adolescent male Wistar rat. We examined the effects of maternal 8 and 20 days foot-shock stress on body weight, plasma corticosterone, insulin, glucose, triglyceride and cholesterol concentrations of dams and offspring. Stress was induced by a foot-shock box twice a day (1 h/session) for 8 consecutive days beginning on E8 in 8-day stressed group and for 20 consecutive days beginning on E1 in 20-day stressed group. The results obtained from this investigation indicate that gestational chronic foot-shock stress arises maternal plasma corticosterone concentration. In addition, maternal plasma triglyceride and cholesterol concentrations significantly elevated following 20-day gestational stress. Prenatal stress induces lower birth weight and body weight gain in offspring. Furthermore, prenatal stressed offspring had significant elevation in plasma glucose concentration without marked alteration in plasma insulin, corticosterone, triglyceride and cholesterol concentrations. These data suggest that prenatal stress could result in impaired glucose metabolism in the adolescent rats which is independent of timing of the stress exposure.

Fetal programming of the hypothalamic-pituitary-adrenal axis : is cortisol production upregulated centrally in low birthweight individuals?

Thesis

Jan 2003

Alexandra Monica Vivienne Ward

p>The first study compared three tests of central HPAA function in a group of low birthweight men aged 60-69 years from Hertfordshire, UK. There were no differences in the free cortisol response to awakening or ACTH and cortisol responses during a 100μg corticotrophin-releasing hormone (CRH) test, but low birthweight men had significantly smaller pituitary-adrenal responses during a dexamethasone-suppressed CRH test. While these findings do not explain the HPAA abnormalities associated with low birthweight in previous studies, they provide further evidence of dysregulation of the HPAA in men who were small at birth. In further analysis of the data, blood pressure, glucose tolerance and plasma lipid concentrations were not related to these measures of central HPAA activity, despite significant positive correlations with morning cortisol concentrations. These data suggest that other mechanisms, for example altered glucocorticoid metabolism, are responsible for elevating circulating cortisol concentrations in men with cardiovascular risk factors. The second study explored cortisol and blood pressure responses to a series of psychological stress tests in a group of young men and women from Adelaide, Australia. Cortisol responses were not related to size at birth in either sex, but in women there was a significant inverse relationship between birthweight and blood pressure reactivity. This study provides the first human evidence that haemodynamic responses to psychological stress may be programmed antenatally, suggesting a potential mechanism linking reduced fetal growth with raised blood pressure and cardiovascular disease in later life. In summary, this research does not support the idea that the HPAA is upregulated centrally in low birthweight individuals, but adds to the evidence that the activity of the axis may be influenced by factors affecting fetal growth. The work presented in this thesis has added complexity to the role of the HPAA in the fetal origins of adult disease, and confirms that this is likely to remain an exciting area of research in years to come.</p

Prenatal Glucocorticoids: Short-Term Benefits and Long-Term Risks

Article

Full-text available

Nov 2012

Antenatal glucocorticoids: Where are we after forty years?

Article

Dec 2014

Since their introduction more than forty years ago, antenatal glucocorticoids have become a cornerstone in the management of preterm birth and have been responsible for substantial reductions in neonatal mortality and morbidity. Clinical trials conducted over the past decade have shown that these benefits may be increased further through administration of repeat doses of antenatal glucocorticoids in women at ongoing risk of preterm and in those undergoing elective cesarean at term. At the same time, a growing body of experimental animal evidence and observational data in humans has linked fetal overexposure to maternal glucocorticoids with increased risk of cardiovascular, metabolic and other disorders in later life. Despite these concerns, and somewhat surprisingly, there has been little evidence to date from randomized trials of longer-term harm from clinical doses of synthetic glucocorticoids. However, with wider clinical application of antenatal glucocorticoid therapy there has been greater need to consider the potential for later adverse effects. This paper reviews current evidence for the short- and long-term health effects of antenatal glucocorticoids and discusses the apparent discrepancy between data from randomized clinical trials and other studies.

Decreased hippocampal MR/GR ratio is associated with low-birth weight in Cynomolgus macaque neonates.

Article

Apr 2013
J MOL ENDOCRINOL

During pregnancy, glucocorticoids transfer environmental signals to the growing brain and its associated neuroendocrine system to modulate their maturation and function during adolescence and adulthood. Increased in utero exposure to glucocorticoids is associated with impaired fetal growth resulting in low birth weight and compromised neural development. The underlying molecular changes affecting brain development however, are largely unknown. Here, we compared the relative mRNA expression of genes directly involved in glucocorticoid signaling in the hippocampus, amygdala and cortex of female non-human primate neonates (Macaca fascicularis) of naturally occurring normal and low birth weights. We focused on the glucocorticoid and mineralocorticoid receptor genes as well as that for 11ß-hydroxysteroid dehydrogenase type 1, and found a significantly decreased mineralocorticoid/glucocorticoid receptor mRNA ratio in the hippocampus and lower expression of 11ß-hydroxysteroid dehydrogenase type 1 in the amygdala associated with low birth weight. The mineralocorticoid/glucocorticoid receptor mRNA ratios in the amygdala and cortex were not associated with birth weight, reflecting tissue-specific effects. Protein quantification in the hippocampus confirmed our finding of a decreased hippocampal mineralocorticoid/glucocorticoid receptor ratio. Our data suggest that the mineralocorticoid/glucocorticoid receptor ratio in the hippocampus and the expression of 11ß-hydroxysteroid dehydrogenase type 1 in the amygdala are associated with intrauterine growth restriction in non-human primates during early perinatal development.

Multigenerational effects of fetal dexamethasone exposure on the hypothalamic-pituitary-adrenal axis of first- and second-generation female offspring

Article

Dec 2012

Objective: Synthetic glucocorticoid (sGC) administration to women threatening preterm delivery increases neonatal survival. Evidence shows that fetal exposure to glucocorticoid levels higher than appropriate for current maturation programs offspring development. We examined fetal sGC multigenerational effects on F1 and F2 female offspring hypothalamo-pituitary-adrenal axis (HPAA) function. Study design: At 0.7 gestation, pregnant F0 ewes received 4 dexamethasone injections (2 mg, approximately 60 μg/kg(-1) per day(-1), 12 hours apart) or saline (control). F1 female offspring were bred to produce F2 female offspring. Postpubertal HPAA function was tested in F1 and F2 ewes. Results: F1 and F2 ewe lambs showed reduced birthweight and morphometrics. Dexamethasone increased baseline but reduced stimulated HPAA activity in F1 and F2 female offspring. Conclusion: This is the first demonstration that sGC doses in the clinical range have multigenerational effects on hypothalamo-pituitary-adrenal activity in a precocial species, indicating the need for the study of long-term effects of fetal sGC exposure.

Maternal effects obscure condition-dependent sex allocation in changing environments

Article

Full-text available

Apr 2019

Climate change increases environmental fluctuations which thereby impact population demography. Species with temperature-dependent sex determination may experience more extreme sex ratio skews, but this has not been considered in species with chromosomally determined sex. However, anticipatory maternal effects cause lifelong physiological changes impacting sex ratios. Here we show, in mice, that more sons were born to mothers in good condition when their breeding environment matched their gestational environment, consistent with theoretical predictions, but mothers in mismatched environments have no condition-sex ratio relationship. Thus, the predicted effect of condition on sex ratio was obscured by maternal effects when the environment changed. This may explain extreme sex ratio skews in reintroduced or translocated populations, and sex ratio skews may become more common and less predictable with accelerating environmental change.

The Impact of Prenatal Glucocorticoid Exposure on the Ovine Kidney

Thesis

Full-text available

Feb 2006

Amanda J. Meyer

Circadian rhythms meet in utero metabolic programming

Article

May 2016
ACTA PHYSIOL

Louise Dalgaard

Faria et al (in this issue) investigated the effects on offspring glucose metabolism from rat dams having day-restricted feeding during gestation and lactation. Day-restricted feeding was maintained throughout gestation and in the lactating period. Feeding at day is in contrast to the normal circadian rhythm of rats and cause decreased food intake of the dams, decreased birth weight of pups, impaired glucose tolerance of male offspring and decreased islet glucose stimulated insulin secretion (GSIS). This article is protected by copyright. All rights reserved.

Intergenerational effects of early life programming: The role of glucocorticoids and maternal obesity

Thesis

Jan 2011

Lincoln Liu

Hypertension and type two diabetes mellitus (Type 2 DM) are serious chronic illnesses that impact on the lives of millions of people around the world. Various epidemiological studies have shown a relationship between early life events such as intrauterine growth retardation (IUGR) resulting in low birth weight and the development of these chronic illnesses in adult life. To explain the link between these two events, it has been suggested that an ‘insult’ at a critical time point of development can ‘program’ alterations in gene expression, organ size, and cell number. This has been termed “the early life origins of disease’. There is also evidence that these programmed effects are not limited to the first generation but can also be passed to subsequent generations. With changes in lifestyle in modern society, the prevalence of obesity is increasing, in association with problems such as type 2 DM, hypertension, fatty liver, atherosclerosis and the metabolic syndrome. Obesity during pregnancy is linked to problems such as gestational diabetes, hypertension and early miscarriage as well as a higher risk of congenital malformations. Maternal obesity has also been recognised as one of the factors capable of ‘programming’ the offspring, increasing the risk of childhood and adult disorders such as obesity and hypertension. In this thesis I have used two animal models to explore the underlying mechanisms of programming and its intergenerational effects: i) a rat model of prenatal glucocorticoid over-exposure (the dexamethasone-programmed rat) and ii) a mouse model of obesity during pregnancy.Using the dexamethasone-programmed rat, I have shown that prenatal glucocorticoid overexposure reduces fetal and placental weight in the first generation (F1) offspring, in association with alterations in gene expression in placenta and liver. In addition, I have shown effects on fetal and placental weights and gene expression in the second generation (F2) offspring. The observed changes in gene expression in the F2 offspring differ from those in the first generation. Thus, although effects on fetal growth are seen in both generations, the underlying mechanisms appear to be different. We also observed marked parent of origin effects on fetal and placental growth and gene expression in the second generation. In the mouse model of maternal obesity, birth weight was decreased in the F1 offspring. At weaning, the offspring of obese mothers were heavier than controls, however this difference in weight was not persistent. At three months of age, F1 female offspring of obese mothers showed altered expression of hepatic genes important in lipid regulation and metabolism. More striking changes were seen in the F2 generation in which there was an effect of paternal exposure to maternal obesity to decrease birth weight. There were also parent of origin effects on organ weights and insulin levels at six months of age. These results provide evidence for the transmission of programming effects to a second generation in two different programming models and suggest that the mechanisms leading to these effects differ between generations.

The Role of Maternal Dietary Proteins in Development of Metabolic Syndrome in Offspring

Article

Full-text available

Nov 2015

The prevalence of metabolic syndrome and obesity has been increasing. Pre-natal environment has been suggested as a factor influencing the risk of metabolic syndrome in adulthood. Both observational and experimental studies showed that maternal diet is a major modifier of the development of regulatory systems in the offspring in utero and post-natally. Both protein content and source in maternal diet influence pre- and early post-natal development. High and low protein dams' diets have detrimental effect on body weight, blood pressure191 and metabolic and intake regulatory systems in the offspring. Moreover, the role of the source of protein in a nutritionally adequate maternal diet in programming of food intake regulatory system, body weight, glucose metabolism and blood pressure in offspring is studied. However, underlying mechanisms are still elusive. The purpose of this review is to examine the current literature related to the role of proteins in maternal diets in development of characteristics of the metabolic syndrome in offspring.

PRE-, PERI-, AND POSTNATAL RISK FACTORS IN BORDERLINE PERSONALITY DISORDER

Thesis

Jan 2011

Cornelia E. Schwarze

In addition to the well-recognised effects of both, genes and adult environment, it is now broadly accepted that adverse conditions during pregnancy contribute to the development of mental and somatic disorders in the offspring, such as cardiovascular disorders, endocrinological disorders, metabolic disorders, schizophrenia, anxious and depressive behaviour and attention deficit hyperactivity disorder (ADHD). Early life events may have long lasting impact on tissue structure and function and these effects appear to underlie the developmental origins of vulnerability to chronic diseases. The assumption that prenatal adversity, such as maternal emotional states during pregnancy, may have adverse effects on the developing infant is not new. Accordant references can be found in an ancient Indian text (ca. 1050 before Christ), in biblical texts and in documents originating during the Middle Ages. Even Hippocrates stated possible effects of maternal emotional states on the developing fetus. Since the mid-1950s, research examining the effects of maternal psychosocial stress during pregnancy appeared in the literature. Extensive research in this field has been conducted since the early 1990s. Thus, the relationship between early life events and long-term health outcomes was already postulated over 20 years ago. David Barker and colleagues demonstrated that children of lower birth weight - which represents a crude marker of an adverse intrauterine environment - were at increased risk of high blood pressure, cardiovascular disorders, and type-2 diabetes later in life. These provocative findings led to a large amount of subsequent research, initially focussing on the role of undernutrition in determining fetal outcomes. The phenomenon of prenatal influences that determine in part the risk of suffering from chronic disease later in life has been named the “fetal origins of health and disease” paradigm. The concept of “prenatal programming” has now been extended to many other domains, such as the effects of prenatal maternal stress, prenatal tobacco exposure, alcohol intake, medication, toxins, as well as maternal infection and diseases. During the process of prenatal programming, environmental agents are transmitted across the placenta and act on specific fetal tissues during sensitive periods of development. Thus, developmental trajectories are changed and the organisation and function of tissue structure and organ system is altered. The biological purpose of those ‘early life programming’ may consist in evolutionary advantages. The offspring adapts its development to the expected extrauterine environment which is forecast by the clues available during fetal life. If the fetus receives signals of a challenging environment, e.g. due to maternal stress hormones or maternal undernutrition, its survival may be promoted due to developmental adaptation processes. However, if the expected environment does not match with the real environment, maladapation and later disease risk may result. For example, a possible indicator of a “response ready” trait, such as hyperactivity/inattention may have been advantageous in an adverse ancient environment. However, it is of disadvantage when the postnatal environment demands oppositional skills, such as attention and concentration – e.g. in the classroom, at school, to achieve academic success. Borderline personality disorder (BPD) is a prevalent psychiatric disorder, characterized by impulsivity, affective instability, dysfunctional interpersonal relationships and identity disturbance. Although many studies report different risk factors, the exact etiologic mechanisms are not yet understood. In addition to the well-recognised effects of genetic components and adverse childhood experiences, BPD may potentially be co-determined by further environmental influences, acting very early in life: during pre- and perinatal period. There are several hints that may suggest possible prenatal programming processes in BPD. For example, patients with BPD are characterized by elevated stress sensitivity and reactivity and dysfunctions of the neuroendocrine stress system, such as the hypothalamic pituitary adrenal (HPA) axis. Furthermore, patients with BPD show a broad range of somatic comorbidities – especially those disorders for which prenatal programming processes have been described. During infancy and childhood, BPD patients already show behavioural and emotional abnormalities as well as pronounced temperamental traits, such as impulsivity, emotional dysregulation and inattention that may potentially be co-determined by prenatal programming processes. Such temperamental traits - similar to those, seen in patients with ADHD - have been described to be associated with low birthweight which indicates a suboptimal intrauterine environment. Moreover, the functional and structural alterations in the central nervous system (CNS) in patients with BPD might also be mediated in part by prenatal agents, such as prenatal tobacco exposure. Prenatal adversity may thus constitute a further, additional component in the multifactorial genesis of BPD. The association between BPD and prenatal risk factors has not yet been studied in such detail. We are not aware of any further study that assessed pre- and perinatal risk factors, such as maternal psychoscocial stress, smoking, alcohol intake, obstetric complications and lack of breastfeeding in patients with BPD.

Prenatal Drug Exposures Sensitize Noradrenergic Circuits to Subsequent Disruption by Chlorpyrifos

Article

Sep 2015

We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg) used in the management of preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar β-adrenergic receptors; the receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels that would serve to augment the functional consequence of receptor deficits. The pretreatments also altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern, reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each case the net effects represented a change in the developmental trajectory of noradrenergic circuits, rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants.

A Low Maternal Protein Diet During Pregnancy and Lactation Induce Liver Offspring Dysfunction, in the Rat

Article

Full-text available

Jan 2015

Effect of protein malnutrition during gestation and lactation on the physiology and liver structure

Conference Paper

Full-text available

Aug 2013

Andrea N. Chisari

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

Article

Full-text available

Jul 2015

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

A low maternal protein diet during pregnancy and lactation induce liver offspring damage, in the rat.

Article

Full-text available

Feb 2015

Pregnancy and fetal development are periods of rapid growth and cell differentiation when mother and offspring are vulnerable to changes. Adverse events during development can be linked to an increased risk in developing metabolic diseases. The aim of this work is to study the effect of protein malnutrition during gestation and lactation on liver morphology and physiology. Pregnant Wistar rats of three months of age who were fed a diet containing 8% of proteins, malnourished group (M) or 20% control group (C). The male offspring of mothers M, or male offspring from mothers C were euthanized. Blood was drawn and liver were dissected. Body weights and liver were lower in the M group. Liver dysfunction was observed by increased serum transaminase, cholesterol and triglycerides in liver. At weaning glucose in M rats was significantly lower relative to controls. Serum proteins, albumin and triglycerides, significantly decreased compared to the control. Both glycogen as proteins liver content decreased in the group M with respect to C. We observed inflammation by increasing TNF-α and IL-6. Histology showed a significant liver injury, cellular swelling was observed, hydropic degeneration, characterized by pale cytoplasm as a result of an increased volume of water stored in the cells. Conclusion: The lack of protein during development compromises the integrity of the structural and functional liver, manifested in adulthood. this issue has not been well studied, and the discussion below does not attempt to differentiate the various maternal manipulations leading to offspring IUGR [2]. The concept of 'developmental programming' proposes that challenges during an organism's development evoke a persistent physiological response in the offspring [3]. Epidemiological investigations such as those conducted on the children conceived during the Dutch famine of 1944–1945 have highlighted the association between poor maternal nutrition, lowered birth weight and subsequent adult disease [4,5]. Several different experimental animal protocols have been used for the evaluation of developmental programming of metabolism: global nutrient restriction [6,7]; or, maternal exposure to an isocaloric low protein diet [8,9]. However there is little research relating to the lack of protein in pregnant women with metabolic disturbances in a vital organ such as the liver of the offspring. Individuals who suffered severe malnutrition during the development stage, have a high predisposition to suffer metabolic

Epigenetic and transgenerational reprogramming of brain development

Article

Apr 2015

Tracy L. Bale

Neurodevelopmental programming - the implementation of the genetic and epigenetic blueprints that guide and coordinate normal brain development - requires tight regulation of transcriptional processes. During prenatal and postnatal time periods, epigenetic processes fine-tune neurodevelopment towards an end product that determines how an organism interacts with and responds to exposures and experiences throughout life. Epigenetic processes also have the ability to reprogramme the epigenome in response to environmental challenges, such as maternal stress, making the organism more or less adaptive depending on the future challenges presented. Epigenetic marks generated within germ cells as a result of environmental influences throughout life can also shape future generations long before conception occurs.

Cardiovascular Risk Factors in Children After Repeat Doses of Antenatal Glucocorticoids: An RCT

Article

Full-text available

Jan 2015

Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity but could have adverse long-term effects on cardiometabolic health in offspring. We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to betamethasone or placebo treatment, ≥7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at <32 weeks' gestation. In this follow-up study, children were assessed at 6 to 8 years' corrected age for body composition, insulin sensitivity, ambulatory blood pressure, and renal function. Of 320 eligible childhood survivors, 258 were studied (81%; 123 repeat betamethasone group; 135 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar total fat mass (geometric mean ratio 0.98, 95% confidence interval [CI] 0.78 to 1.23), minimal model insulin sensitivity (geometric mean ratio 0.89, 95% CI 0.74 to 1.08), 24-hour ambulatory blood pressure (mean difference systolic 0 mm Hg, 95% CI -2 to 2; diastolic 0 mm Hg, 95% CI -1 to 1), and estimated glomerular filtration rate (mean difference 1.2 mL/min/1.73m(2), 95% CI -3.2 to 5.6). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not increase risk factors for cardiometabolic disease at early school age. Copyright © 2015 by the American Academy of Pediatrics.

Gene-Environment Interactions Controlling Energy and Glucose Homeostasis and the Developmental Origins of Obesity

Article

Full-text available

Jan 2015

Obesity and type 2 diabetes mellitus (T2DM) often occur together and affect a growing number of individuals in both the developed and developing worlds. Both are associated with a number of other serious illnesses that lead to increased rates of mortality. There is likely a polygenic mode of inheritance underlying both disorders, but it has become increasingly clear that the pre- and postnatal environments play critical roles in pushing predisposed individuals over the edge into a disease state. This review focuses on the many genetic and environmental variables that interact to cause predisposed individuals to become obese and diabetic. The brain and its interactions with the external and internal environment are a major focus given the prominent role these interactions play in the regulation of energy and glucose homeostasis in health and disease. Copyright © 2015 the American Physiological Society.

Prenatal Nicotine Alters the Developmental Neurotoxicity of Postnatal Chlorpyrifos Directed Toward Cholinergic Systems: Better, Worse, or Just "Different?"

Article

Dec 2014
BRAIN RES BULL

This study examines whether prenatal nicotine exposure sensitizes the developing brain to subsequent developmental neurotoxicity evoked by chlorpyrifos, a commonly-used insecticide. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of nicotine and chlorpyrifos given individually. By itself nicotine elicited overall upregulation of the ACh markers, albeit with selective differences by sex, region and age. Likewise, chlorpyrifos alone had highly sex-selective effects. Importantly, all the effects showed temporal progression between adolescence and adulthood, pointing to ongoing synaptic changes rather than just persistence after an initial injury. Prenatal nicotine administration altered the responses to chlorpyrifos in a consistent pattern for all three markers, lowering values relative to those of the individual treatments or to those expected from simple additive effects of nicotine and chlorpyrifos. The combination produced global interference with emergence of the ACh phenotype, an effect not seen with nicotine or chlorpyrifos alone. Given that human exposures to nicotine and chlorpyrifos are widespread, our results point to the creation of a subpopulation with heightened vulnerability. Copyright © 2014. Published by Elsevier Inc.

Neuroendocrine link between stress, depression and diabetes

Article

Full-text available

Nov 2013

Clinical studies have indicated a frequent coexistence of depression and diabetes. Both of these diseases are associated with similar changes in the structure and function of the central nervous system cells and with similar disturbances of cognitive processes. Some morphological and functional changes occurring in these diseases seem to result from exaggerated glucocorticoid, proinflammatory cytokine or glutamate action. Glucocorticoids induced by stress are known not only to affect synaptic plasticity but also to disturb brain glucose metabolism and decrease insulin sensitivity. Functional neuroimaging studies demonstrated altered glucose metabolism in the brains of depressed patients. Changes in the amount or activity of key metabolic enzymes and a lower sensitivity of insulin receptors have been detected in the brains of animal models of both of these diseases. Hence, excess glucocorticoids can lead to impaired insulin action and glucose metabolism, to limited energy supply for proper neuronal function and, consequently, to disturbed synaptic plasticity.

Feed allowance and maternal backfat levels during gestation influence maternal cortisol levels, milk fat composition and offspring growth

Article

Full-text available

Jan 2013

The fetal and early postnatal environment can have a long-term influence on offspring growth. Using a pig model, we investigated the effects of maternal body condition (thin or fat) and maternal gestation feeding level (restricted, control or high) on maternal stress, milk composition, litter size, piglet birth weight and pre-weaning growth. A total of sixty-eight thin (backfat depth about 8 mm) and seventy-two fat (backfat depth about 12 mm) gilts were selected at about 22 weeks. This backfat difference was then accentuated nutritionally up to service at about 32 weeks. During gestation, individual gilts from within each group were randomly allocated to a gestation diet at the following feed allowances: 1·8 kg/d (restricted); 2·5 kg/d (control) and 3·5 kg/d (high) until day 90 of gestation. During gestation restricted gilts had higher levels of cortisol than high and control fed animals. Piglets born to fat gilts had higher average daily gain during the lactation period and higher weaning weights at day 28 than piglets born to thin gilts. Gilts on a high feed level had heavier piglets than those provided with restricted and control allocations. Fat gilts had less saturated fat in their milk at day 21 of lactation and higher unsaturated fat levels. No differences were found in the n-6:n-3 PUFA ratio in the milk between thin and fat gilts. In conclusion, maternal body condition influenced the daily weight gain of offspring up to weaning (day 28) and milk fat composition. Furthermore, maternal feed level during gestation alters maternal cortisol levels and milk fat composition.

Prenatal Dexamethasone, as Used in Preterm Labor, Worsens the Impact of Postnatal Chlorpyrifos Exposure on Serotonergic Pathways

Article

Nov 2013

This study explores how glucocorticoids sensitize the developing brain to the organophosphate pesticide, chlorpyrifos. Pregnant rats received a standard therapeutic dose (0.2mg/kg) of dexamethasone on gestational days 17-19; pups were given subtoxic doses of chlorpyrifos on postnatal days 1-4, (1mg/kg, <10% cholinesterase inhibition). We evaluated serotonin (5HT) synaptic function from postnatal day 30 to day 150, assessing the expression of 5HT receptors and the 5HT transporter, along with 5HT turnover (index of presynaptic impulse activity) in brain regions encompassing all the 5HT projections and cell bodies. These parameters are known targets for neurodevelopmental effects of dexamethasone and chlorpyrifos individually. In males, chlorpyrifos evoked overall elevations in the expression of 5HT synaptic proteins, with a progressive increase from adolescence to adulthood; this effect was attenuated by prenatal dexamethasone treatment. The chlorpyrifos-induced upregulation was preceded by deficits in 5HT turnover, indicating that the receptor upregulation was an adaptive response to deficient presynaptic activity. Turnover deficiencies were magnified by dexamethasone pretreatment, worsening the functional impairment caused by chlorpyrifos. In females, chlorpyrifos-induced receptor changes reflected relative sparing of adverse effects compared to males. Nevertheless, prenatal dexamethasone still worsened the 5HT turnover deficits and reduced 5HT receptor expression in females, demonstrating the same adverse interaction. Glucocorticoids are used in 10% of U.S. pregnancies, and are also elevated in maternal stress; accordingly, our results indicate that this group represents a large subpopulation that may have heightened vulnerability to developmental neurotoxicants such as the organophosphates.

Prenatal Dexamethasone Augments the Neurobehavioral Teratology of Chlorpyrifos: Significance for Maternal Stress and Preterm Labor

Article

Oct 2013

Glucocorticoids are the consensus treatment given in preterm labor and are also elevated by maternal stress; organophosphate exposures are virtually ubiquitous, so human developmental coexposures to these two agents are common. This study explores how prenatal dexamethasone exposure modifies the neurobehavioral teratology of chlorpyrifos, one of the most widely used organophosphates. We administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg); offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces barely-detectable (<10%) inhibition of brain cholinesterase activity. Dexamethasone did not alter brain chlorpyrifos concentrations, nor did either agent alone or in combination affect brain thyroxine levels. Assessments were carried out from adolescence through adulthood encompassing T-maze alternation, Figure 8 maze (locomotor activity, habituation), novelty-suppressed feeding and novel object recognition tests. For behaviors where chlorpyrifos or dexamethasone individually had small effects, the dual exposure produced larger, significant effects that reflected additivity (locomotor activity, novelty-suppressed feeding, novel object recognition). Where the individual effects were in opposite directions or were restricted to only one agent, we found enhancement of chlorpyrifos' effects by prenatal dexamethasone (habituation). Finally, for behaviors where controls displayed a normal sex difference in performance, the combined treatment either eliminated or reversed the difference (locomotor activity, novel object recognition). Combined exposure to dexamethasone and chlorpyrifos results in a worsened neurobehavioral outcome, providing a proof-of-principle that prenatal glucocorticoids can create a subpopulation with enhanced vulnerability to environmental toxicants.

Elevated Glucocorticoids during Ovine Pregnancy increase Appetite and produce Glucose Dysregulation and Adiposity in Their Granddaughters in response to ad libitum feeding at one year of age

Article

May 2013

Objective: Synthetic glucocorticoids (sGCs) are administered to women threatening preterm labor. We have shown multigenerational endocrine and metabolic effects of fetal sGC exposure. We hypothesized that sGC exposure would alter the second filial generation (F2) offspring neonatal leptin peak that controls development of appetitive behavior with metabolic consequences. Study design: F0 nulliparous ewes were bred to a single ram. Beginning at day 103 of gestation (term 150 days), dexamethasone (DEX) ewes received 4 injections of 2 mg DEX intramuscularly, 12 hours apart. Control ewes received saline. Ewes lambed naturally. At 22 months of age, F1 offspring were mated to produce F2 offspring. At 10 months of age, F2 female offspring were placed on an ad libitum feeding challenge for 12 weeks. Results: DEX F2 female offspring did not show a postnatal leptin peak and their plasma cortisol concentration was elevated in the first days of life. During the feeding challenge, DEX F2 offspring consumed 10% more feed and gained 20% more weight compared with control F2 offspring. At the end of the feeding challenge, DEX F2 offspring had greater adiposity compared with control F2 offspring. F2 sGC offspring showed impaired insulin secretion in response to an intravenous glucose tolerance test. Conclusion: sGC administration to F0 mothers eliminates the neonatal leptin peak in F2 female offspring potentially by inhibition caused by elevated cortisol in the DEX F2 offspring. F2 offspring showed increased appetite, weight gain, and adiposity during an ad libitum feeding challenge accompanied by decreased insulin response to an intravenous glucose tolerance test.

Prenatal Dexamethasone Augments the Sex-Selective Developmental Neurotoxicity of Chlorpyrifos: Implications for Vulnerability after Pharmacotherapy for Preterm Labor

Article

Feb 2013

Glucocorticoids are routinely given in preterm labor and are also elevated by maternal stress; organophosphate exposures are virtually ubiquitous, so coexposures to these two agents are pervasive. We administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg); offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces barely-detectable (<10%) inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of dexamethasone and chlorpyrifos given individually. Dexamethasone did not enhance the systemic toxicity of chlorpyrifos, as evidenced by weight gain and measurements of cholinesterase inhibition during chlorpyrifos treatment. Nevertheless, it enhanced the loss of presynaptic ACh function selectively in females, who ordinarily show sparing of organophosphate developmental neurotoxicity relative to males. Females receiving the combined treatment showed decrements in choline transporter binding and choline acetyltransferase activity that were unique (not found with either treatment alone), as well as additive decrements in nicotinic receptor binding. On the other hand, males given dexamethasone showed no augmentation of the effects of chlorpyrifos. Our findings indicate that prior dexamethasone exposure could create a subpopulation that is especially vulnerable to the adverse effects of organophosphates or other developmental neurotoxicants.

Early Metabolic Defects in Dexamethasone-Exposed and Undernourished Intrauterine Growth Restricted Rats

Article

Full-text available

Nov 2012
PLOS ONE

Poor fetal growth, also known as intrauterine growth restriction (IUGR), is a worldwide health concern. IUGR is commonly associated with both an increased risk in perinatal mortality and a higher prevalence of developing chronic metabolic diseases later in life. Obesity, type 2 diabetes or metabolic syndrome could result from noxious "metabolic programming." In order to better understand early alterations involved in metabolic programming, we modeled IUGR rat pups through either prenatal exposure to synthetic glucocorticoid (dams infused with dexamethasone 100 µg/kg/day, DEX) or prenatal undernutrition (dams feeding restricted to 30% of ad libitum intake, UN). Physiological (glucose and insulin tolerance), morphometric (automated tissue image analysis) and transcriptomic (quantitative PCR) approaches were combined during early life of these IUGR pups with a special focus on their endocrine pancreas and adipose tissue development. In the absence of catch-up growth before weaning, DEX and UN IUGR pups both presented basal hyperglycaemia, decreased glucose tolerance, and pancreatic islet atrophy. Other early metabolic defects were model-specific: DEX pups presented decreased insulin sensitivity whereas UN pups exhibited lowered glucose-induced insulin secretion and more marked alterations in gene expression of pancreatic islet and adipose tissue development regulators. In conclusion, these results show that before any catch-up growth, IUGR rats present early physiologic, morphologic and transcriptomic defects, which can be considered as initial mechanistic basis of metabolic programming.

Prenatal Exposure to Stress and Stress Hormones Influences Child Development

Article

Jul 2006
INFANT YOUNG CHILD

Stress has significant consequences throughout the lifetime. However, when it occurs early in life, the implications may be particularly profound and long lasting. Evidence suggests that high levels of maternal stress during pregnancy are associated with alterations in the normal activity of the maternal hypothlalamic-pituitary-adrenocortical (HPA) and placental axis. Increased activity of this system is related to shortened gestation and impaired fetal growth, factors that place infants at a greater risk for a wide variety of developmental problems. In addition to the implications for birth outcome, our findings suggest that prenatal exposure to stress and stress hormones directly influences development of the fetal central nervous system (CNS). Fetuses who are exposed to disregulated production of stress hormones display impaired learning. Elevated levels of stress or stress hormones during pregnancy are also associated with more difficult infant temperament and disruption of infant HPA axis activity. These data suggest that prenatal experiences can have lasting implications for development.

Prenatal Exposure to Bereavement and Type-2 Diabetes: A Danish Longitudinal Population Based Study

Article

Full-text available

Aug 2012
PLOS ONE

The etiology of type-2 diabetes is only partly known, and a possible role of prenatal stress in programming offspring for insulin resistance has been suggested by animal models. Previously, we found an association between prenatal stress and type-1 diabetes. Here we examine the association between prenatal exposure to maternal bereavement during preconception and pregnancy and development of type-2 diabetes in the off-spring. We utilized data from the Danish Civil Registration System to identify singleton births in Denmark born January 1(st) 1979 through December 31(st) 2008 (N = 1,878,246), and linked them to their parents, grandparents, and siblings. We categorized children as exposed to bereavement during prenatal life if their mothers lost an elder child, husband or parent during the period from one year before conception to the child's birth. We identified 45,302 children exposed to maternal bereavement; the remaining children were included in the unexposed cohort. The outcome of interest was diagnosis of type-2 diabetes. We estimated incidence rate ratios (IRRs) from birth using log-linear poisson regression models and used person-years as the offset variable. All models were adjusted for maternal residence, income, education, marital status, sibling order, calendar year, sex, and parents' history of diabetes at the time of pregnancy. We found children exposed to bereavement during their prenatal life were more likely to have a type-2 diabetes diagnosis later in life (aIRR: 1.31, 1.01-1.69). These findings were most pronounced when bereavement was caused by death of an elder child (aIRR: 1.51, 0.94-2.44). Results also indicated the second trimester of pregnancy to be the most sensitive period of bereavement exposure (aIRR:2.08, 1.15-3.76). Our data suggests that fetal exposure to maternal bereavement during preconception and the prenatal period may increase the risk for developing type-2 diabetes in childhood and young adulthood.

Growth and insulin dynamics in two generations of female offspring of mothers receiving a single course of synthetic glucocorticoids

Article

Sep 2012

Synthetic glucocorticoid administration to women threatening preterm delivery increases neonatal survival. However, mounting evidence shows that fetal exposure to glucocorticoid levels higher than appropriate for current maturation adversely programs offspring development. We examined fetal synthetic glucocorticoid multigenerational metabolic effects on F1 and F2 female offspring. At 0.7 gestation, pregnant F0 ewes received 4 injections of dexamethasone (2 mg, approximately 60 ug.kg(-1) day(-1) 12 hours apart) or saline (control). F1 female offspring were bred to produce F2 female offspring. Postpubertal pancreatic β-cell function was tested in F1 and F2 by intravenous glucose tolerance test. F1 and F2 ewe lambs showed reduced birthweight and morphometrics, and similar increased fasting glucose and decreased intravenous glucose tolerance test β-cell response. This is the first demonstration of multigenerational programming of later life β-cell response by clinically relevant doses of synthetic glucocorticoid indicating the need for study of long-term effects of fetal exposure to synthetic glucocorticoid.

A methyl-deficient diet fed to rats during the pre- and peri-conception periods of development modifies the hepatic proteome in the adult offspring

Article

Full-text available

Aug 2012

A methyl-deficient diet (MD) lacking folic acid and the associated methyl donors choline and methionine, fed to the laboratory rat during the periods of oocyte and embryo development, has been shown to programme glucose metabolism in the offspring. The hepatic proteome of the male offspring of female rats fed MD diets for 3 weeks prior to mating and for the first 5 days of gestation has been examined by 2-dimensional gel electrophoresis. Three groups of differentially abundant proteins associated with energy metabolism, amino acid metabolism and antioxidant defence were identified in the soluble proteins extracted from the liver from the MD offspring at both 6 and 12 months of age. Altered mitochondrial activity in other programming models leads to a similar pattern of differential protein abundance. Two of the differentially abundant proteins were identified as GAPDH and PGK-1 by mass spectrometry. Western blotting showed that there were multiple isoforms of both proteins with similar molecular weights but different isoelectric points. The differentially abundant spots reduced in the MD offspring corresponded to minor isoforms of GAPDH and PGK-1. The levels of PPAR-alpha, SREBP and glucocorticoid receptor mRNAs associated with other models of prenatal programming were unchanged in the MD offspring. The data suggest that a diet deficient in folic acid and associated methyl donors fed during the peri-conception and early preimplantation periods of mammalian development affects mitochondrial function in the offspring and that the posttranslational modification of proteins may be important.

Developmental Programming by Perinatal Glucocorticoids

Article

Full-text available

Sep 2022
MOL CELLS

Jun Young Hong

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.

Prenatal Stress as a Factor of the Development of Addictive States

Article

Nov 2020

Regulators of glucocorticoid receptor function in an animal model of depression and obesity

Article

Mar 2018
J NEUROENDOCRINOL

Obesity is a disease that often co‐occurs with depression, and some evidence indicates that chronic stress in the perinatal period, in association with overactive glucocorticoids, can cause permanent changes that increase the risk of the development of both depression and obesity later in life. However, the mechanism responsible for the overly potent action of glucocorticoids in both depression and obesity is not known. The aim of the present study was to determine the expression of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) and the factors that affect GR function (FKBP51, Bag‐1 and HSP70) in a prenatal stress animal model of depression, a model of obesity and a model of both depression and obesity. Prenatal stress but not high‐fat diet (HFD) was found to decrease the GR concentration in the frontal cortex. The level of the Bag‐1M (46 kDa) isoform was also decreased in this structure but only in prenatal‐stressed animals that did not show depression‐like behaviour in the Porsolt test and were fed the standard diet (STD). In the model of depression employed here, decreases in MR expression and GR co‐chaperone (FKBP51) levels in the hippocampus were also observed, and HFD intensified the prenatal stress‐induced changes in MR expression. The obtained results indicated that prenatal stress affected the expression of GRs, MRs and their co‐chaperones in the brain, but its effects were different in the frontal cortex and hippocampus. The decrease in MR density in the hippocampus and increased plasma insulin level seemed to be the most significant changes observed in the model of the co‐occurrence of depression and obesity, which could limit the neuroprotective effects associated with the activation of MR and be a marker of peripheral insulin resistance, respectively. This article is protected by copyright. All rights reserved.

Prenatal stress accelerates offspring growth to compensate for reduced maternal investment across mammals

Article

Nov 2017

Significance Maternal stress during gestation causes numerous effects on infant physiology that extend well into adulthood. We contribute to the ongoing debate on whether these effects are adaptive outcomes or merely the product of energetic constraints by presenting an integrated hypothesis that predicts the diversity of observed maternal effects on offspring growth, incorporating both theoretical explanations into one coherent framework. Empirical tests of this hypothesis across mammals suggest that the timing of the stressor during gestation and a simultaneous consideration of maternal investment and adaptive growth plasticity effects are crucial for a full comprehension of prenatal stress effects on offspring growth. The results support an adaptive life history perspective on maternal effects that is relevant for evolutionary biology, medicine, and psychology.

Gestational experience alters sex allocation in the subsequent generation

Article

Full-text available

Jul 2016

Empirical tests of adaptive maternal sex allocation hypotheses have presented inconsistent results in mammals. The possibility that mothers are constrained in their ability to adjust sex ratios could explain some of the remaining variation. Maternal effects, the influence of the maternal phenotype or genotype on her developing offspring, may constrain sex allocation through physiological changes in response to the gestational environment. We tested if maternal effects constrain future parental sex allocation through a lowered gestational stress environment in laboratory mice. Females that experienced lowered stress as embryos in utero gave birth to female-biased litters as adults, with no change to litter size. Changes in offspring sex ratio was linked to peri-conceptual glucose, as those females that had increasing blood glucose peri-conceptionally gave birth to litters with a higher male to female sex ratio. There was, however, no effect of the lowered prenatal stress for developing male embryos and their sperm sex ratio when adult. We discuss the implications of maternal effects and maternal stress environment on the lifelong physiology of the offspring, particularly as a constraint on later maternal sex allocation.

Adaptive and Maladaptive Aspects of Developmental Stress

Chapter

Jan 2013

Chronic hyperactivation of the hypothalamus–pituitary axis is associated with the suppression of reproductive, growth, thyroid and immune functions that may lead to various pathological states. Although many individuals experiencing stressful events do not develop pathologies, stress seems to be a provoking factor in those individuals with particular vulnerability, determined by genetic factors or earlier experience. Exposure of the developing brain to severe and/or prolonged stress may result in hyperactivity of the stress system, defective glucocorticoid negative feedback, altered cognition, novelty seeking, increased vulnerability to addictive behaviours and mood-related disorders. Therefore, stress-related events that occur in the perinatal period can permanently change brain and behaviour of the developing individual. Prenatal restraint stress (PRS) in rats is a well-documented model of early stress known to induce long-lasting neurobiological and behavioural alterations including impaired feedback mechanisms of the HPA axis, disruption of circadian rhythms and altered neuroplasticity. Together with the HPA axis the glutamate system is particularly impaired, and such impairment appears to be involved in the anxious profile of PRS rats. Chronic treatments with antidepressants at adulthood have proven high predictive validity of the PRS rat as animal model of depression/anxiety and reinforce the idea of the usefulness of the PRS rat as an interesting animal model for the design and testing of new pharmacologic strategies in the treatment of stress-related disorders.

Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

Article

Feb 2003

S Gupta

In the late-gestation sheep, increased fetal plasma cortisol concentration and placental oestradiol (E(2)) output contribute to fetal organ maturation, in addition to the onset of parturition. Both cortisol and E(2) are believed to regulate the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which interconverts bioactive 11-hydroxy glucocorticoids and their inactive 11-keto metabolites. 11beta-HSD1, abundantly expressed in fetal liver, operates primarily as a reductase enzyme to produce bioactive cortisol and thus regulates local hepatic glucocorticoid concentrations. Cortisol acts through the glucocorticoid receptor (GR) present in the liver. In this study, we examined the effects of cortisol and E(2) on hepatic 11beta-HSD1 and GR in the liver of chronically catheterized sheep fetuses treated with saline (n=5), cortisol (1.35 mg/h; n=5), saline+4-hydroxyandrostendione, a P450 aromatase inhibitor (4-OHA; 1.44 mg/h; n=5), or cortisol+4-OHA (n=5). Cortisol infusion resulted in increased plasma concentrations of fetal cortisol and E(2); concurrent administration of 4-OHA attenuated the increase in plasma E(2) concentrations. Using immunohistochemistry, we showed that fetal hepatocytes expressed both 11beta-HSD1 and GR proteins. Cortisol treatment increased GR in both cytosol and nuclei of hepatocytes; concurrent administration of 4-OHA was associated with distinct nuclear GR staining. Western blot revealed that cortisol, in the absence of increased E(2) concentrations, significantly increased concentrations of 11beta-HSD1 (34 kDa) and GR (95 kDa) proteins. 11beta-HSD1 enzyme activity was measured in the liver microsomal fraction in the presence of [(3)H]cortisone (10(-)(6) M) or [(3)H]cortisol (10(-)(6) M) and NADPH (reductase activity) or NADP(+) (dehydrogenase activity) respectively. 11beta-HSD1 reductase activity was significantly greater in the presence of cortisol. In summary, we found that, in sheep during late gestation, cortisol increased both 11beta-HSD1 and GR in the fetal liver, and these effects were accentuated in the absence of increased E(2).

Prenatal Nicotine Changes the Response to Postnatal Chlorpyrifos: Interactions Targeting Serotonergic Synaptic Function and Cognition

Article

Jan 2015
BRAIN RES BULL

Nicotine and chlorpyrifos are developmental neurotoxicants that target serotonin systems. We examined whether prenatal nicotine exposure alters the subsequent response to chlorpyrifos given postnatally. Pregnant rats received nicotine throughout gestation at 3mg/kg/day, a regimen designed to achieve plasma levels seen in smokers; chlorpyrifos was given to pups on postnatal days (PN) 1-4 at 1mg/kg, just above the detection threshold for brain cholinesterase inhibition. We assessed long-term effects from adolescence (PN30) through full adulthood (PN150), measuring the expression of serotonin receptors and serotonin turnover (index of presynaptic impulse activity) in cerebrocortical brain regions encompassing the projections that are known targets for nicotine and chlorpyrifos. Nicotine or chlorpyrifos individually increased the expression of serotonin receptors, with greater effects on males than on females and with distinct temporal and regional patterns indicative of adaptive synaptic changes rather than simply an extension of initial injury. This interpretation was confirmed by our finding an increase in serotonin turnover, connoting presynaptic serotonergic hyperactivity. Animals receiving the combined treatment showed a reduction in these adaptive effects on receptor binding and turnover relative to the individual agents, or even an effect in the opposite direction; further, normal sex differences in serotonin receptor concentrations were dissipated or reversed, an effect that was confirmed by behavioral evaluations in the Novel Objection Recognition Test. In addition to the known liabilities associated with maternal smoking during pregnancy, our results point to additional costs in the form of heightened vulnerability to neurotoxic chemicals encountered later in life. Copyright © 2015. Published by Elsevier Inc.

Prenatal exposure to glucocorticoids affects body weight, serum leptin levels, and hypothalamic neuropeptide-Y expression in pre-pubertal female rat offspring

Article

Apr 2014
INT J DEV NEUROSCI

Glucocorticoid secretion is a key endocrine response to stress. It has been reported that prenatal stress induces long-lasting alterations in body weight regulation systems, which persist after the stress has ceased. In this study, the long-term effects of prenatal glucocorticoid exposure on body weight changes and the expression of appetite-regulating factors were examined in female rats. Pregnant rats were given normal drinking water (control) or dexamethasone (1μg/mL) dissolved in drinking water (DEX) from day 13 of pregnancy until delivery. Then, the body weight change, serum leptin levels, and hypothalamic NPY mRNA levels of their offspring were examined. The DEX dams gained significantly less body weight during pregnancy than the control dams. The DEX dams' offspring exhibited a significantly lower birth weight than the offspring of the control dams, and the same was true for body weight at postnatal days 20 and 28. The offspring of the DEX dams displayed significantly higher serum leptin levels and significantly lower hypothalamic NPY mRNA levels compared with the offspring of the control dams. Significant inverse correlations were detected between body weight and the serum leptin level, and between the serum leptin level and the hypothalamic NPY mRNA level. On the other hand, a significant positive correlation was detected between body weight and the hypothalamic NPY mRNA level. These results indicate that leptin production is increased in a long-lasting manner in offspring exposed to glucocorticoids during the prenatal period and that this results in attenuated body weight gain and hypothalamic NPY expression during the pre-pubertal period.

Impaired imprinting and social behaviors in chicks exposed to mifepristone, a glucocorticoid receptor antagonist, during the final week of embryogenesis

Article

Dec 2013

Unlabelled: The effects of glucocorticoid receptor dysfunction during embryogenesis on the imprinting abilities and social behaviors of hatchlings were examined using "fertile hen's egg-embryo-chick" system. Methods and results: Of embryos treated with mifepristone (0.4μmol/egg) on day 14, over 75% hatched a day later than the controls (day 22) without external anomalies. The mifepristone-treated hatchlings were assayed for imprinting ability on post-hatching day 2 and for social behaviors on day 3. The findings were as follows: imprinting ability (expressed as preference score) was significantly lower in mifepristone-treated hatchlings than in controls (0.65±0.06 vs. 0.92±0.02, P<0.005). Aggregation tests to evaluate the speed (seconds) required for four chicks, individually isolated with cardboard dividers in a box, to form a group after removal of the barriers showed that aggregation was significantly slower in mifepristone-treated hatchlings than in controls (8.7±1.1 vs. 2.6±0.3, P<0.001). In belongingness tests to evaluate the speed (seconds) for a chick isolated at a corner to join a group of three chicks placed at the opposite corner, mifepristone-treated hatchlings took significantly longer than controls (4.5±0.4/40 cm vs. 2.4±0.08/40 cm, P<0.001). In vocalization tests, using a decibel meter to measure average decibel level/30s (chick vocalization), mifepristone-treated hatchlings had significantly weaker vocalizations than controls (14.2±1.9/30s vs. 26.4±1.3/30s P<0.001). In conclusion, glucocorticoid receptor dysfunction during the last week embryogenesis altered the programming of brain development, resulting in impaired behavioral activities in late life.

Prenatal Caffeine Ingestion Induces Transgenerational Neuroendocrine Metabolic Programming Alteration in Second Generation Rats.

Article

Dec 2013
TOXICOL APPL PHARM

Our previous studies have demonstrated that prenatal caffeine ingestion induces an increased susceptibility to metabolic syndrome with alterations of glucose and lipid metabolic phenotypes in adult first generation (F1) of intrauterine growth retardation (IUGR) rats, and the underlying mechanism is originated from a hypothalamic-pituitary-adrenal (HPA) axis-associated neuroendocrine metabolic programming alteration in utero. This study aims to investigate the transgenerational effects of this programming alteration in adult second generation (F2). Pregnant Wistar rats were administered with caffeine (120mg/kg.d) from gestational day 11 until delivery. Four groups in F2 were set according to the cross-mating between control and caffeine-induced IUGR rats. F2 were subjected to a fortnight ice water swimming stimulus on postnatal month 4, blood samples were collected before and after stress. Results showed that the majority of the activities of HPA axis and phenotypes of glucose and lipid metabolism were altered in F2. Particularly, comparing with the control group, caffeine groups had an enhanced corticosterone levels after chronic stress. Compared with before stress, the serum glucose levels were increased in some groups whereas the triglycerides levels were decreased. Furthermore, total cholesterol gain rates were enhanced but the high-density lipoprotein-cholesterol gain rates were decreased in most caffeine groups after stress. These transgenerational effects were characterized partially with gender and parental differences. Taken together, these results indicate that the reproductive and developmental toxicities and the neuroendocrine metabolic programming mechanism by prenatal caffeine ingestion have transgenerational effects in rats, which may help to explain the susceptibility to metabolic syndrome and associated diseases in F2.

Regulation of fetal lung development in response to maternal overnutrition

Article

Sep 2013
CLIN EXP PHARMACOL P

With the worldwide obesity epidemic, the proportion of women entering pregnancy overweight or obese has increased significantly in recent years. Babies born to obese women are at an increased risk of respiratory complications at birth and in childhood. In addition to maternal diabetes, there are a number of metabolic changes that the fetus of an overnourished mother experiences in utero that may modulate lung development and represent the mechanisms underlying the increased risk of respiratory complications. Herein we highlight a series of factors associated with the intrauterine environment of an overnourished mother that may impact on fetal lung development and lead to an increased risk of complications at birth or in postnatal life.

Long-term circulatory and renal consequences of intrauterine growth restriction: Circulatory and renal consequences of IUGR

Article

Jul 2007

Intrauterine growth restriction (IUGR) and probably also early postnatal altered nutrition in very‐low‐birthweight babies may, in the long term, be followed by the various disorders that are included in the metabolic syndrome. This discovery has raised a new paradigm about the background to cardiovascular disease, arterial hypertension, obesity, type 2 diabetes and dyslipidaemic disorders that play a prominent role in shortening human life. In this review article, present knowledge about the background to renal dysfunction as seen in IUGR is summarized. The way in which arterial hypertension and cardiovascular dysfunction may be programmed in IUGR is also speculated. Conclusion: During the last decade, knowledge of the long‐term consequences of IUGR has increased at a very rapid rate. At present, it is most important not only to develop efficient methods of preventing and diagnosing IUGR, but to work out follow‐up and treatment programmes for the control of the disorders which may follow this condition. Proper postnatal feeding and infant growth may be essential for long‐term outcome.

Mechanical-tactile stimulation (MTS) intervention in a neonatal stress model alters adult adipose tissue deposition and prevents hyperinsulinemia in male rats

Article

Jan 2013

Preterm infants are exposed to numerous stressors during hospitalization and by term corrected gestational age they have lower body weight but a greater proportion of total body as well as abdominal visceral adipose tissue (VAT) accumulation. Greater abdominal VAT stores have a known association with metabolic syndrome. Mechanical-tactile stimulation (MTS) improves modulation of stress response in both humans and rodents. We hypothesize that MTS, administered during an established model of neonatal stress, would decrease stress-driven adiposity and prevent associated metabolic imbalances in adult rats. Neonatal stress, administered to rat pups from postnatal days 5 to P9, consisted of needle puncture and hypoxic/hyperoxic challenge during 60min of maternal separation (STRESS; n=20). Mechanical-tactile stimulation (MTS; n=20) was administered to rat pups for 10min during maternal separation in the stress protocol. Control animals received standard care (CTL; n=20). MRI measured adult (P120) abdominal total fat mass, subcutaneous (SAT) and visceral adipose tissue (VAT). Body weight and fasting serum adiponectin, leptin, glucose, insulin, and corticosterone were also measured. STRESS results in elevated VAT/SAT ratio compared to CTL but lower abdominal total fat mass and abdominal SAT. STRESS males experience hyperinsulinemia. Both STRESS and MTS had elevated leptin with lower adiponectin and corticosterone compared to CTL. In summary, neonatal stress promotes greater abdominal VAT accumulation and, in males, caused hyperinsulinemia and hypoadiponectinemia. Importantly, MTS normalized the VAT/SAT ratio and prevented hyperinsulinemia. We speculate that MTS ameliorates some of the negative metabolic consequences of early life perturbations due to neonatal stress exposure.

Prenatal glucocorticoid exposure and physiological programming of adult disease

Article

May 2006

Moffat J Nyirenda

Compelling epidemiological evidence suggests that the early environment is an important determinant of later risk of disease. In particular, low birth weight has been associated with an increased risk of cardiovascular and metabolic disorders, including hypertension, Type 2 diabetes mellitus and ischemic heart disease, independent of classical adult lifestyle risk factors such as smoking, adult weight, social class, excess alcohol intake and sedentary lifestyle. These observations have led to a revolutionary concept of early life physiological programming. The molecular mechanisms that underlie this relationship remain unclear, but one major hypothesis implicates fetal overexposure to glucocorticoid stress hormones. This article will review evidence for this hypothesis.

Outcome of Prenatal Dexamethasone Treatment of Congenital Adrenal Hyperplasia

Article

May 2003
ENDOCRINOLOGIST

An abstract is unavailable. This article is available as HTML full text and PDF.

Developmental Programming of Obesity and Type 2 Diabetes

Article

Feb 2007
Fetal Matern Med Rev

c1 MH Vickers, Liggins Institute, University of Auckland, Auckland, New Zealand.

Fetal and infant growth and impaired glucose tolerance: Authors' reply

Article

Full-text available

Dec 1991

The effects of sympathetic nervous system activation and psychological stress on glucose metabolism and blood pressure in subjects with Type 2 (non-insulin-dependent) diabetes mellitus

Article

Full-text available

Oct 1992

The sympathetic nervous system may contribute to excessive hepatic glucose output in Type 2 (non-insulin dependent) diabetes mellitus and could be implicated in the interrelated problem of hypertension. The aim of these studies was to determine whether subjects with Type 2 diabetes had normal sensitivity (compared with age- and weight-matched non-diabetic subjects) to noradrenaline infusion (60 ng.kg-1.min-1 for 60 min) and to compare the responses with oral tyramine administration (800 mg), and psychological stress (using competitive computer games). Noradrenaline infusion caused significantly greater plasma glucose (mean increment 2.1 +/- 0.4 vs 0.6 +/- 0.1 mmol/l, p less than 0.005) and pressor responses (mean systolic increment 21 +/- 3 vs 11 +/- 1 mmHg, p less than 0.02) in the diabetic subjects. The excessive glycaemia was due to increased hepatic glucose output rather than reduced glucose disposal. Tyramine administration caused significantly increased hepatic glucose output and plasma glucose levels, but with similar responses in the diabetic and non-diabetic subjects; the pulse and pressor responses were also similar between the groups. The psychological stressor induced significant increases in pulse, blood pressure and non-esterified fatty acid levels in the combined group of subjects (p less than 0.01) but did not influence plasma glucose levels in either diabetic or non-diabetic subjects. We conclude that pharmacologically-induced sympathetic nervous stimulation can induce hyperglycaemia. Subjects with uncomplicated Type 2 diabetes have increased sensitivity to exogenous noradrenaline but may not hyperrespond to endogenous sympathetic activation.

Glucocorticoids regulate the induction of P-enolpyruvate carboxykinase (GTP) gene transcription during diabetes

Article

Full-text available

Jul 1993

The hormonal regulation of transcription of the phosphoenolpyruvate carboxykinase (GTP) (4.1.1.32) (PEPCK) gene during diabetes was studied using transgenic mice containing a chimeric gene consisting of segments of the PEPCK promoter (-2000/+73, -460/+73, -355/+73) linked to bovine growth hormone (bGH) reporter gene. The effect of diabetes and insulin on transgenic mice containing a mutation in cAMP regulatory sequences at -90/-82 and -250/-234 was also studied. In addition, we analyzed the transcriptional response of the PEPCK gene to adrenalectomy, the administration of glucocorticoids, and alterations in dietary protein and carbohydrate. Our results indicate that deletion of the insulin regulatory sequence of the PEPCK promoter did not affect dietary control of PEPCK gene expression. However, glucocorticoids and the glucocorticoid regulatory unit appear to be essential for induction of PEPCK gene transcription by diabetes. By contrast, mutation of cAMP regulatory elements of the PEPCK promoter did not limit induction of PEPCK transcription by diabetes, nor did it affect negative regulation of transcription by insulin. These results provide evidence for the interaction of insulin and glucocorticoid regulatory elements in the control of PEPCK gene transcription and suggest an important role of glucocorticoids as a gluconeogenic activator during diabetes.

Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring

Article

Full-text available

Jun 1998

Low birth weight in humans is predictive of insulin resistance and diabetes in adult life. The molecular mechanisms underlying this link are unknown but fetal exposure to excess glucocorticoids has been implicated. The fetus is normally protected from the higher maternal levels of glucocorticoids by feto-placental 11β-hydroxysteroid dehydrogenase type-2 (11β-HSD2) which inactivates glucocorticoids. We have shown previously that inhibiting 11β-HSD2 throughout pregnancy in rats reduces birth weight and causes hyperglycemia in the adult offspring. We now show that dexamethasone (a poor substrate for 11β-HSD2) administered to pregnant rats selectively in the last week of pregnancy reduces birth weight by 10% (P < 0.05), and produces adult fasting hyperglycemia (treated 5.3±0.3; control 4.3±0.2 mmol/liter, P = 0.04), reactive hyperglycemia (treated 8.7±0.4; control 7.5±0.2 mmol/liter, P = 0.03), and hyperinsulinemia (treated 6.1±0.4; control 3.8±0.5 ng/ml, P = 0.01) on oral glucose loading. In the adult offspring of rats exposed to dexamethasone in late pregnancy, hepatic expression of glucocorticoid receptor (GR) mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA (and activity) are increased by 25% (P = 0.01) and 60% (P < 0.01), respectively, while other liver enzymes (glucose-6- phosphatase, glucokinase, and 11β-hydroxysteroid dehydrogenase type-1) are unaltered. In contrast dexamethasone, when given in the first or second week of gestation, has no effect on offspring insulin/glucose responses or hepatic PEPCK and GR expression. The increased hepatic GR expression may be crucial, since rats exposed to dexamethasone in utero showed potentiated glucose responses to exogenous corticosterone. These observations suggest that excessive glucocorticoid exposure late in pregnancy predisposes the offspring to glucose intolerance in adulthood. Programmed hepatic PEPCK overexpression, perhaps mediated by increased GR, may promote this process by increasing gluconeogenesis.

Impaired Glucose Tolerance and Elevated Blood Pressure in Low Birth Weight, Nonobese, Young South African Adults: Early Programming of Cortisol Axis 1

Article

Full-text available

Dec 2000

Low birth weight is associated with increased cardiovascular and metabolic disorders in adult life, although the mechanisms of this effect remain uncertain. There is one report of increased morning plasma cortisol levels in an elderly low birth weight cohort, but whether this is primary or secondary to other aspects of the phenotype is unclear. We investigated the association between low birth weight and glucose intolerance, blood pressure, and dyslipidemia in young, nonobese adults from a community undergoing the health transition with a high prevalence of both noncommunicable diseases and low birth weight. Additionally, we investigated whether altered basal and stimulated cortisol levels as a marker of hypothalamic-pituitary-adrenal responsiveness or cortisol metabolism were associated with low birth weight in these young adults. Twenty-year-old, historically disadvantaged, urbanized South Africans (n = 137) with birth weights either below the 10th percentile [underweight for age (UFA)] or between the 25th and 75th percentiles [appropriate for gestational age (AFA)] had anthropometry, blood pressure, lipid levels, and glucose tolerance measured. In a subset (n = 62), 0900 h plasma cortisol concentrations, cortisol responses to 1 microg ACTH, and urinary glucocorticoid metabolites were measured. The mothers of UFA infants were themselves lighter and had a lower body mass index (P: = 0. 0016). At age 20 yr, although the UFA group was still smaller and lighter, with a lower body mass index, they had higher fasting plasma glucose levels (P: = 0.047), and a greater proportion demonstrated glucose intolerance (11.9% vs. 0%; P: < 0.01). The UFA group also had higher systolic [UFA, 126.0 +/- 13.3 (+/-SD); AFA, 122.0 +/- 11.7 mm Hg; P: = 0.007] and diastolic (72.3 +/- 8.4 vs. 69. 5 +/- 8.7 mm Hg; P: = 0.02) blood pressures, after covarying for current weight and gender. Plasma cortisol levels determined at 0900 h were higher in the UFA group (484.9 +/- 166.3 vs. 418.6 +/- 160.6 nmol/L) and showed a greater plasma cortisol response to low dose ACTH stimulation (area under the curve for cortisol: UFA, 77,238 +/- 19,511; AFA, 66,597 +/- 16,064 nmol/L.min; P: = 0.04). In conclusion, the link between low birth weight and adult glucose intolerance and blood pressure elevation occurs in young adults in a high risk, disadvantaged population despite a lack of full catch-up growth. Moreover, cortisol axis activation is an early feature in the process linking low birth weight with adult cardiovascular and metabolic disease and is not dependent upon adult obesity or full catch-up growth, at least in this population undergoing the health transition.

A simplification of the protein assay method of Lowry which is more generally applicable

Article

Dec 1977
ANAL BIOCHEM

G.L. Peterson

Prenatal Treatment in Congenital Adrenal Hyperplasia Due to 21Hydroxylase Deficiency: UpDate 88 of the French Multicentric Study

Article

Jan 1989

A multicentric study of prenatal treatment of congenital adrenal hyperplasia (CAH) resulting from 21-hydroxylase deficiency in 43 pregnancies at risk for CAH is presented. The mothers were given dexamethasone per os, 0.5 mg either 12-hourly or 8-hourly. From the analysis of the results obtained in the present study and review of the literature, it would appear that the first condition for successful prevention of female virilization in utero (a total of 6 cases) is to start treatment as early as possible, no later than the 7th week. The dose of dexamethasone should be related to maternal size: 20 μg/kg/day (in 2 or 3 fractioned) doses would seem to be both efficient and safe. Adrenal suppression of both maternal and fetal adrenal function should be controlled by appropriate hormonal determinations. Finally, the advantages of early prenatal diagnosis or no prenatal diagnosis are discussed.

Association between low birthweight and high resting pulse in adult life: Is the sympathetic nervous system involved in programming the insulin resistance syndrome?

Article

Aug 1997

To test the hypothesis that elevated sympathetic nervous system (SNS) activity could be determined in utero and be one of the processes mediating the link between size at birth and insulin resistance and raised blood pressure in adult life, we have studied the resting pulse rate of 449 men and women aged 46 to 54 (mean 50) years born in Preston, Lancashire, England whose birth size was recorded in detail. The subjects were visited at home by trained fieldworkers who measured resting pulse rate and blood pressure using an automated recorder. The resting pulse rate ranged from 44 to 108 (mean 73) beats min−1 . It rose with increasing body mass index (r = 0.14, p = 0.003) and waist to hip ratio (adjusted for sex r = 0.10, p = 0.003) and correlated significantly with systolic and diastolic blood pressures (p = 0.001), fasting glucose (p = 0.02), split proinsulin (p = 0.001), and triglyceride concentrations (p = 0.02). The pulse rate fell progressively from 76 beats min−1 among subjects who weighed 5.5 lb (2.5 kg) or less at birth to 71 beats min−1 among those who weighed 7.5 lb (3.3 kg) or more (decline in pulse rate per kg increase in birthweight = 2.7, 95 % CI 0.6 to 4.8 beats min−1 ). The association was independent of current body mass index, waist to hip ratio and of potential confounding variables including smoking, alcohol consumption, and social class. Although the resting pulse rate is an imperfect index of SNS activity, these findings are consistent with the hypothesis that elevated SNS activity established in utero is one mechanism linking small size at birth with the insulin resistance syndrome in adult life. © 1997 by John Wiley & Sons, Ltd.

Chronic Corticosterone Impairs Memory Performance in the Barnes Maze

Article

Apr 1998
PHYSIOL BEHAV

Chronic stress has been reported to impair spatial memory and cause hippocampal impairment in rodents. Glucocorticoids are believed to be the active agent in this impairment. Studies have demonstrated that chronic glucocorticoid administration results in animals being impaired in the Morris water maze (MWM) or eight-arm radial maze. Although both of these methods are well established means of testing spatial memory, neither might be considered optimal for studying the behavioral effects of stress. The Morris maze is itself highly stressful to the animals. The eight-arm maze relies on a food reward to motivate the animals, and glucocorticoids have profound effects on hunger and satiety. We therefore investigated behavioral deficits of corticosterone-treated animals in the two previously used mazes and the Barnes circular platform maze (BCM), a test similar in design to the Morris maze, but one that does not require the animal to perform a highly stressful swim. Consistent with results in other tests, we found that animals that had been treated for 3 months with stress-equivalent concentrations of glucocorticoids showed significantly impaired behavior in the Barnes maze.

An Early Prenatal Exposure to Excess Glucocorticoid Leads to Hypertensive Offspring in Sheep

Article

Feb 1998

1. Recent studies in animals have linked fetal exposure to excess maternal glucocorticoids with the later occurrence of cardiovascular disorders, particularly hypertension. 2. To test the hypothesis that prenatal treatment could impact on adult blood pressure two groups of pregnant ewes were transported from the farm to the Institute at either 22–29 days of pregnancy (pretreatment group 1) or 59–66 days of pregnancy (pretreatment group 2), subjected to 48 h treatment with dexamethasone (0.28 mg day−1 kg−1 for 2 days) and then returned to the farm. The control group remained at the farm for the entire pregnancy. Lambs were then studied at approximately 4, 10 and 19 months after birth. 3. The basal mean arterial pressure in pretreatment group 1 (80 ± 1 mmHg at 124 days; 83 ± 1 mmHg at 309 days and 89 ± 1 mmHg at 558 days; n = 6) was significantly different (P < 0.05 in all groups) from that in the control group of lambs (74 ± 2 mmHg at 110 days; 76 ± 1 mmHg at 323 days and 81 ± 1 mmHg at 568 days; n = 7). However, prenatal glucocorticoid exposure did not alter vascular sensitivity to noradrenaline, angiotensin II and adrenocorticotropic hormone in these sheep at any of the ages studied, nor did it affect basal or adrenocorticotropic hormone-induced concentrations of Cortisol or basal plasma renin concentrations in the lambs at any age. 4. These data support the hypothesis that excess glucocorticoid exposure in early pregnancy, during a critical developmental stage or ‘window’, programmes higher blood pressure that persists in later life.

Possibility of the amplification of hormone receptors by a single treatment in newborn age

Article

Feb 1979
Acta Physiol Acad Sci Hungar

Administration of insulin to newborn rats was shown to amplify the hormone receptors. Blood sugar values in animals thus treated were lower in the adult age, which could be explained by increased sensitivity to endogenous insulin; the decrease of blood sugar in response to exogenous insulin was similar in magnitude, however, it occurred at a lower level compared to the controls. These changes were more marked in female than in male rats.

Determination of phosphoenolpyruvate carboxykinase activity with deoxyguanosine 5′-diphosphate as nucleotide substrate

Article

Aug 1979

Glucocorticoid Therapy for Rheumatic Diseases: Maternal, Fetal, and Breast-Feeding Considerations

Article

Oct 1992

William F. Rayburn

Glucocorticoids form the mainstay of therapy for many rheumatic diseases, especially systemic lupus erythematosus (SLE). Prednisone is the drug of choice, because it has been well described during the pregnancy and is the primary drug for maintenance therapy or to induce a remission. Principles for prescribing glucocorticoids would apply during pregnancy, recognizing that many effects of rheumatic disease and long-term therapy are similar to physiologic changes of pregnancy. Particular attention should be placed on screening for pregnancy-induced glucose intolerance, hypertension, and delayed fetal growth. Although animal studies suggest an increased risk of oral clefts associated with glucocorticoids, several human studies have failed to demonstrate teratogenic or toxic effects. Nevertheless, rare cases of transient fetal adrenal suppression have been reported, so all infants should be monitored in the nursery. Breast-feeding is safe, with clinically insignificant amounts of the drug being concentrated in breast milk.

Islet transplantation in diabetic pregnant rats normalizes glucose homeostasis in their offspring

Article

Jul 1992
J Dev Physiol

Diabetes of the mother during pregnancy induces alterations in the fetus, resulting in impaired glucose homeostasis in the offspring. In youngsters of severely diabetic mothers, during glucose infusion, hyperinsulinemia is associated with hyperresponsiveness of the beta-cells and insulin resistance. In order to normalize maternal metabolism, isolated islets from neonatal rats were transplanted into the vena porta of severely hyperglycemic (Streptozotocin) rats at day 15 of gestation. Strict glycemic control of the mothers was achieved throughout further gestation and lactation. In the adult offspring of these transplanted rats insulin levels during glucose infusion were significantly lower than in the offspring of sham-transplanted diabetic mothers and were not different from controls. The work confirms that the diabetic state of the mother during late gestation (the period of development of the endocrine pancreas and of the insulin-receptor system) is the inducing factor for the abnormal glucose homeostasis in the offspring, and normalisation of the hyperglycemia eliminates these long-term consequences.

Molecular Physiology of the Regulation of Hepatic Gluconeogenesis and Glycolysis

Article

Feb 1992

Understanding the regulation of hepatic glucose metabolism had its foundation in the elucidation of several pathways, but recent advances have come from the application of molecular genetics. Five years ago little was known about the primary structure of the key regulatory enzymes. Since then, the primary sequence of liver GK, 6-PF-1-K, Fru-1,6-P2ase, PK, PEPCK, and 6-PF-2-K/Fru-2,6-P2ase have been derived from cDNA sequences and/or determined by direct protein sequencing. This has provided new insights into the molecular mechanisms of catalysis and the regulation of these enzymes by covalent modification. Isolation of the cDNAs for these enzymes also has allowed for the quantitation of specific mRNAs and permitted analysis of hormonal control of specific gene expression. The genes for these enzymes have been isolated and sequenced, and their promoter regions are being identified and characterized. Hormone response elements have been delineated in several of the promoters. The promoter regions for 6-PF-2-K/Fru-2,6-P2ase and Fru-1,6-P2ase have also been identified, and future research will focus on the elucidation of the mechanisms whereby hormones regulate the expression of these genes. A number of generalizations can be made about the regulation of gene expression of glycolytic/gluconeogenic enzymes. First, there is coordinate hormonal regulation of gene expression and these effects are consonant with their physiologic actions. Insulin induces the mRNAs that encode glycolytic enzymes and represses the mRNAs that encode gluconeogenic enzymes; cAMP has opposite effects. Both can increase or decrease transcription. Whereas insulin and cAMP affect all of these mRNAs, glucocorticoids appear to have a more restricted action. Second, transcriptional and posttranscriptional regulatory mechanisms are involved. The synthesis of all of the mRNAs discussed is regulated by hormones. Relatively little is known about how mRNA stability is regulated in general, but it is clear that PEPCK mRNA is stabilized by agents that increase the rate of transcription of the gene. Under appropriate metabolic signals this dual control of mRNA synthesis and stability provides for a long-term increase in PEPCK mRNA and protein. Studies with PK mRNA are less direct, but suggest a similar dual mechanism. It will be interesting to see whether multilevel regulation is restricted to these two mRNAs, both of which are involved in the same substrate cycle, or whether the stability of other mRNAs involved in hepatic glucose metabolism is also affected. Third, glucose appears to be important in the regulation of these hepatic genes.(ABSTRACT TRUNCATED AT 400 WORDS)

Glucocorticoids regulate the ontogenic transition of adrenergic receptor subtypes in rat liver

Article

Feb 1991
LIFE SCI

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.

The effects of corticosteroid administration before preterm delivery: An overview of the evidence from controlled trials

Article

Feb 1990
Br J Obstet Gynaecol

Continuing differences of opinion among obstetricians and neonatologists about the place of corticosteroid administration before preterm delivery have prompted us to carry out a systematic review of the relevant controlled trials, using methods designed to minimize systematic and random error. Data from 12 controlled trials, involving over 3000 participants, show that corticosteroids reduce the occurrence of respiratory distress syndrome overall and in all the subgroups of trial participants that we examined. This reduction in respiratory morbidity was associated with reductions in the risk of intraventricular haemorrhage, necrotizing enterocolitis and neonatal death. There is no strong evidence suggesting adverse effects of corticosteroids. The risks of fetal and neonatal infection may be raised if they are administered after prolonged rupture of the membranes, but this possibility is not substantiated by the results of the available trials. The available data on long-term follow-up suggest that the short-term beneficial effects of corticosteroids may be reflected in reduced neurological morbidity in the longer term.

Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 1989; 298: 564-567

Article

Apr 1989

In national samples of 9921 10 year olds and 3259 adults in Britain systolic blood pressure was inversely related to birth weight. The association was independent of gestational age and may therefore be attributed to reduced fetal growth. This suggests that the intrauterine environment influences blood pressure during adult life. It is further evidence that the geographical differences in average blood pressure and mortality from cardiovascular disease in Britain partly reflect past differences in the intrauterine environment. Within England and Wales 10 year olds living in areas with high cardiovascular mortality were shorter and had higher resting pulse rates than those living in other areas. Their mothers were also shorter and had higher diastolic blood pressures. This suggests that there are persisting geographical differences in the childhood environment that predispose to differences in cardiovascular mortality.

Maturation of the adrenocortical stress response: Neuroendocrine control mechanisms and the stress hyporesponsive period

Article

Apr 1986
BRAIN RES

During the first two weeks of life rat pups show a markedly reduced adrenocortical response to stress, and this period of adrenocortical quiescence has been termed the 'stress non-responsive period' (SNRP). The adaptive value of the SNRP can be understood in terms of the effects of glucocorticoids on CNS development: excessively high or low corticoid levels are associated with abnormal neural and behavioral development. We have attempted to explain adrenocortical activity during this period in terms of the unique pattern of glucocorticoid-receptor concentrations that exist in the brain and pituitary of the neonatal rat. This pattern of receptor concentrations results in a negative-feedback condition at the level of the brain and pituitary that ensures the low, stable corticoid levels that appear to be optimal for neuronal development in glucocorticoid-sensitive brain regions.

Critical Exposure Time for Androgenization of the Developing Hypothalamus in the Female Rat

Article

Jun 1968

P-enolpyruvate carboxykinase and pyruvate carboxylase in the developing liver

Article

Oct 1967

1. Phosphoenolpyruvate carboxykinase and pyruvate carboxylase were measured in foetal, newborn and adult rat liver extracts by a radiochemical assay involving the fixation of [(14)C]bicarbonate. 2. Pyruvate-carboxylase activity in both foetal and adult liver occurs mainly in mitochondrial and nuclear fractions, with about 10% of the activity in the cytoplasm. 3. Similar studies of the intracellular distribution of phosphoenolpyruvate carboxykinase show that more than 90% of the activity is in the cytoplasm. However, in the 17-day foetal liver about 90% of the activity is in mitochondria and nuclei. 4. Pyruvate-carboxylase activity in both particulate and soluble fractions is very low in the 17-day foetal liver and increases to near adult levels before birth. 5. Phosphoenolpyruvate-carboxykinase activity in the soluble cell fraction increases 25-fold in the first 2 days after birth. This same enzyme in the mitochondria has considerable activity in the foetal and adult liver and is lower in the newborn. 6. Kinetic and other studies on the properties of phosphoenolpyruvate carboxykinase have shown no differences between the soluble and mitochondrial enzymes. 7. It is suggested that the appearance of the soluble phosphoenolpyruvate carboxykinase at birth initiates the rapid increase in overall gluconeogenesis at this stage.

Cortisol hypersection and cognitive impairment in depression

Article

Apr 1984
ARCH GEN PSYCHIAT

We attempted to investigate the relationship between hypothalamic-pituitary-adrenal axis activity and cognitive function by measuring mean urinary free cortisol (MUFC) excretion and performance on the Halstead Category Test in depressed patients and normal controls. We observed a significant relationship between category test errors and MUFC in the depressed patients, but not in the controls. While an even more robust correlation was observed between age and category test errors in the patients, it appeared that age and depression interacted to produce severe cognitive impairment. Depression-related cortisol hypersecretion or its underlying determinants may contribute to depression-related cognitive dysfunction.

Cortisol Synthesis Inhibition: A New Treatment Strategy for the Clinical and Endocrine Manifestations of Depression

Article

Mar 1995
BIOL PSYCHIAT

Evidence exists that oversecretion of cortisol may be responsible for the clinical manifestations and serotonergic abnormality in depressive illness. Using the cortisol synthesis inhibitor ketoconazole, we investigated the effects of directly lowering cortisol on the symptoms and the response of prolactin (PRL) to d-fenfluramine in eight patients suffering from major depression. Prolactin responses to d-fenfluramine were measured, and patients were treated with 400-600 mg of ketoconazole for 4 weeks, after which they were retested. Five patients treated with ketoconazole recovered from their depression, while the other three had decreases in their Hamilton Depression Rating Scale (HAMD) scores of < or = 50% and were deemed partial responders. Posttreatment prolactin responses to d-fenfluramine were higher than pretreatment values. Ketoconazole normalizes the blunted prolactin responses to d-fenfluramine and may be an effective method by which to treat depression. This implies that hypercortisolemia may be responsible for the clinical features and serotonergic subsensitivity observed in depression.

Fetal Nutrition and Cardiovascular Disease in Adult Life

Article

May 1993

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.

Inhibition of 11 -Hydroxysteroid Dehydrogenase in Pregnant Rats and the Programming of Blood Pressure in the Offspring

Article

Jul 1996

Recent epidemiological studies have linked low birth weight with the later occurrence of cardiovascular and metabolic disorders, particularly hypertension. We have proposed that fetal exposure to excess maternal glucocorticoids may underpin this association. Normally, the fetus is protected from maternal glucocorticoids by placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD). We have previously shown that treatment of pregnant rats with dexamethasone, a synthetic glucocorticoid that is poorly metabolized by the enzyme, reduces birth weight and produces elevated blood pressure in the adult offspring. Moreover, low activity of placental 11beta-HSD correlates with low birth weight in rats. Here, we show that maternal administration of carbenoxolone, a potent inhibitor of 11 beta-HSD, throughout pregnancy leads to reduced birth weight (mean 20 percent decrease) and elevated blood pressures (increase in mean arterial pressure, 9 mm Hg in males, 7 mm Hg in females) in the adult offspring of carbenoxolone-treated rats. This effect requires the presence of maternal adrenal products, as carbenoxolone given to adrenalectomized pregnant rats had no effect on birth weight or blood pressure. These data support the hypothesis that excess exposure of the fetoplacental unit to maternal glucocorticoids reduces birth weight and programs subsequent hypertension and indicate a key role for placental 11beta-HSD in controlling such exposure.

Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat

Article

Mar 1996
PLACENTA

Hypertension is strongly predicted by a low birthweight:placental weight ratio. Two independent models have been described to explain this association; less than optimal maternal protein nutrition leading to fetal undernutrition, or glucocorticoid excess. Pregnant rats were fed diets containing 18 per cent casein (control) or 9 per cent casein, balanced for energy. On day 20 of gestation the pregnancies were terminated and placentae collected for determination of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) activity. Placental 11 beta HSD normally protects the fetus from the effects of maternal glucocorticoids. Activity was specifically attenuated by mild protein restriction (33 per cent in activity), whilst activities of glucocorticoid-insensitive control enzymes were unchanged and glucocorticoid-inducible glutamine synthetase activity was increased (27 per cent), relative to activity in placentae from control animals. The nutritional manipulation during pregnancy significantly increased systolic blood pressure (17 mmHg) in the resulting offspring in early adulthood. A possible common pathway whereby maternal environmental factors may influence fetal and placental growth and programme disease is inferred.

Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 ??-hydroxysteroid dehydrogenase inhibitor carbenoxolone

Article

Nov 1996

Summary Recent human epidemiological studies have linked low birth weight with a substantially increased risk of non-insulin-dependent diabetes mellitus in later life. These data suggest that the intrauterine environment plays a crucial role in determining later glucose homeostasis, but the mechanism is unknown. We have proposed that exposure of the fetus to excess maternal glucocorticoids may underpin the epidemiological findings. Normally placental 11 β -hydroxysteroid dehydrogenase type 2 (11 β -HSD-2) protects the fetus from the normally higher maternal levels of glucocorticoids by inactivating corticosterone and cortisol to inert 11-keto products. Here we show that administration of carbenoxolone, an inhibitor of placental 11 β -HSD 2, to pregnant rats, leads to a significant reduction in average birth weight (20 % fall). At 6 months of age, the male offspring of carbenoxolone-treated pregnancies had similar weights to controls, but showed significantly higher fasting plasma glucose (6.0 ± 0.3 vs 4.8 ± 0.2 mmol/l; p < 0.01) and exhibited significantly greater plasma glucose (10 % higher) and insulin (38 % higher) responses to an oral glucose load. These effects of carbenoxolone require intact maternal adrenal glands suggesting that inhibition of feto-placental 11 β -HSD 2 is key. These data support the notion that defiency of placental 11 β -HSD, by exposing the fetus to excess maternal glucocorticoids, reduces growth and predisposes to hyperglycaemia in later life. [Diabetologia (1996) 39: 1299–1305]

Birth Weight and Adult Hypertension, Diabetes Mellitus, and Obesity in US Men

Article

Dec 1996

Low birth weight has been associated with several chronic diseases in adults, including hypertension, diabetes mellitus, and obesity. Further study of these diseases in a large cohort with information on a wide variety of risk factors is essential to determine more precisely the risks associated with birth weight. We examined the relation between birth weight and cumulative incidence of adult hypertension, incidence of non-insulin-dependent diabetes mellitus, and prevalence of obesity in a cohort of 22,846 US men (Health Professionals Follow-up Study). Birth weights, medical histories, family histories, and other factors were collected by biennial mailed questionnaires. Logistic regression was used to examine the association between birth weight and these chronic adult diseases. Low birth weight was associated with an increased risk of hypertension and diabetes; high birth weight was associated with an increased risk of obesity. Compared with men in the referent birth weight category (7.0 to 8.4 lb), men who weighed < 5.5 lb had an age-adjusted odds ratio for hypertension of 1.26 (95% confidence interval [CI], 1.11 to 1.44) and for diabetes mellitus of 1.75 (95% CI, 1.21 to 2.54). There was no material change after controlling for adult body mass index and parental histories of hypertension and diabetes mellitus. Compared with men in the referent group, the age-adjusted odds ratio of being in the highest versus the lowest quintile of adult body mass index for men with birth weight > or = 10.0 lb was 2.08 (95% CI, 1.73 to 2.50). These findings support the hypothesis that early life exposures, for which birth weight is a marker, are associated with several chronic diseases in adulthood.

Dexamethasone in the Last Week of Pregnancy Attenuates Hippocampal Glucocorticoid Receptor Gene Expression and Elevates Blood Pressure in the Adult Offspring in the Rat

Article

Dec 1996

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

Congenital adrenal hyperplasia: Update on prenatal diagnosis and treatment

Article

Apr 1999
J STEROID BIOCHEM

The diagnostic term congenital adrenal hyperplasia (CAH) applies to a family of inherited disorders of steroidogenesis caused by an abnormality in one of the five enzymatic steps necessary in the conversion of cholesterol to cortisol. The enzyme defects are translated as autosomal recessive traits, with the enzyme deficient in more than 90% of CAH cases being 21-hydroxylase. In the classical forms of CAH (simple virilizing and salt wasting), owing to 21-hydroxylase deficiency (21-OHD), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Non-classical 21-OHD (NC21OHD) refers to the condition in which partial deficiencies of 21-hydroxylation produce less extreme hyperandrogenemia and milder symptoms. Females do not demonstrate genital ambiguity at birth.

Heightened norepinephrine-mediated vasoconstriction in type 2 diabetes

Article

Jan 2000
METABOLISM

Adrenergic responsiveness (AR) appears to be increased in subjects with diabetes, but measurement of arterial AR in normotensive people with type 2 diabetes mellitus has not been previously reported. We sought to determine whether, compared with control subjects, there is increased arterial AR in type 2 diabetes mellitus and its relationship to the level of systemic sympathetic nervous system activity (SNSa). We studied 15 type 2 diabetic subjects aged 57 +/- 3 years without hypertension or clinical signs of autonomic neuropathy and 13 age-matched control subjects aged 55 +/- 2 years. We assessed vascular alpha-AR by measuring forearm blood flow (FABF) by venous occlusion plethysmography during intrabrachial artery norepinephrine (NE) and phentolamine infusions, as well as arterial plasma NE levels and the extravascular NE release rate (NE2) derived from 3H-NE kinetics, as estimates of systemic SNSa. The vasoconstricting effect of NE during intrabrachial artery NE infusion was greater in type 2 diabetes compared with control subjects (P = .02). The vasodilating effect of phentolamine was greater in type 2 diabetics compared with control subjects (P = .05), suggesting increased endogenous arterial alpha-adrenergic tone. Arterial plasma NE levels (control v type 2, 1.8 +/- 0.10 v 1.84 +/- 0.14 nmol/L, P = .86) and NE2 (control vtype 2, 11.8 +/- 1.54 v 13.3 +/- 0.89 nmol/min/m2, P = .39) were similar in the two groups. In summary, in type 2 diabetes compared with control subjects, (1) the vasoconstriction response to intraarterial NE is greater, (2) plasma NE and NE2 are similar, suggesting similar levels of systemic SNSa, and (3) arterial alpha-adrenergic tone is greater. We conclude that subjects with type 2 diabetes demonstrate inappropriately increased alpha-AR for their level of systemic SNSa.

Doyle LW, Ford GW, Davis NM, Callanan C. Antenatal corticosteroid therapy and blood pressure at 14 years of age in preterm children. Clin Sci 98: 137-142

Article

Feb 2000

Antenatal corticosteroid therapy substantially improves the survival rate of preterm infants, with few side effects. Higher blood pressure in adulthood has been described in several animal species after exposure to antenatal corticosteroids, but there are no similar reports in humans. The objective of the present study was to determine the relationship between exposure to antenatal corticosteroid therapy and blood pressure at 14 years of age. This was a cohort study of 210 preterm survivors with birthweights of <1501 g born in the Royal Women's Hospital, Melbourne, between 1 January 1977 and 31 March 1982. Blood pressure was measured in 177 subjects (84.3%) at 14 years of age with a standard mercury sphygmomanometer. Children exposed to antenatal corticosteroids (n=89) had higher systolic and diastolic blood pressures than those not exposed to corticosteroids (n=88) [mean difference (95% confidence interval) (mmHg): systolic, 4.1 (0.1-8.0); diastolic, 2.8 (0.05-5.6)]. However, few had blood pressure in the hypertensive range. It is concluded that antenatal corticosteroid therapy is associated with higher systolic and diastolic blood pressures in adolescence, and might lead to clinical hypertension in survivors well beyond birth.

Low Birth Weight Predicts Elevated Plasma Cortisol Concentrations in Adults From 3 Populations

Article

Jun 2000

Low birth weight is linked with raised blood pressure in adult life. Recent evidence has suggested that a neuroendocrine disturbance involving the hypothalamic-pituitary-adrenal axis could mediate this link. We therefore investigated the relation between birth weight and fasting plasma cortisol concentrations and the association of cortisol with current blood pressure in population samples of 165 men and women born in Adelaide, South Australia, from 1975 to 1976, 199 men and women born in Preston, UK, from 1935 to 1943, and 306 women born in East Hertfordshire, UK, from 1923 to 1930. Fasting plasma cortisol was measured in plasma samples obtained between 8 and 10 AM. Blood pressure was measured with an automated sphygmomanometer. Low birth weight was associated with raised fasting plasma cortisol concentrations in all 3 populations. A combined analysis that allowed for differences in the gender composition, age, and body mass index between the studies showed that cortisol concentrations fell by 23.9 nmol/L per kilogram increase in birth weight (95% CI 9.6 to 38.2, P<0.001). Fasting plasma cortisol concentrations also correlated positively with the subjects' current blood pressure. However, the association between cortisol and blood pressure was most marked in subjects who were obese (P=0.038 for interaction between body mass index and cortisol, P=0.01 for interaction between waist-to-hip ratio and cortisol). These results show that low birth weight is associated with raised fasting plasma cortisol concentrations. Increased activity of the hypothalamic-pituitary-adrenal axis may link low birth weight with raised blood pressure in adult life.

Irreversible androgenic programming at birth of microsomal and soluble rat liver enzymes active on 4-androstene-3,17-dione and 5-alpha, androstene-3-alpha, 17-beta-diol

711-718

Gustafsson
A Sternberg

Gustafsson JA & Sternberg A 1974 Irreversible androgenic programming at birth of microsomal and soluble rat liver enzymes active on 4-androstene-3,17-dione and 5-alpha, androstene-3-alpha, 17-beta-diol. Journal of Biological Chemistry 249 711–718

Stress and glucocorticoids impair retrieval of long-term spatial memory

Jan 1998
NATURE
787-790

D De Quervain
B Roozendaal
J Mcgaugh

de Quervain D, Roozendaal B & McGaugh J 1998 Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature 394 787-790.

Jan 1998
LANCET
173-177

Ac Ravelli
Jh Van Der Meulen
Rp Michels
Osmond C Barker
Dj Hales
Cn Bleker

Ravelli AC, van der Meulen JH, Michels RP, Osmond C, Barker DJ, Hales CN & Bleker OP 1998 Glucose tolerance in adults after prenatal exposure to famine. Lancet 351 173-177.

Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease

Jan 1989
Br Med J
564-567

Djp Barker
C Osmond
J Goldings
D Kuh
Mej Wadsworth

Barker DJP, Osmond C, Goldings J, Kuh D & Wadsworth MEJ 1989 Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. British Medical Journal 298 564-567.

Jan 1995
351-363

Al Fowden

Fowden AL 1995 Endocrine regulation of fetal growth. Reproduction, Fertility and Development 7 351-363.

Programming hyperglycaemia in the rat through prenatal exposure to glucocorticoids-fetal effect or maternal influence? J Endocrinol

Abstract

No full-text available

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