Epidemiological evidence suggests that low birth weight is associated with an increased risk of cardiovascular, metabolic and neuroendocrine disorders in adult life. Glucocorticoid administration ...during pregnancy reduces offspring birth weight and alters the maturation of the lung and other organs. We hypothesised that prenatal exposure to excess glucocorticoids or stress might represent a mechanism linking foetal growth with adult pathophysiology. In rats, birth weight is reduced following prenatal exposure to the synthetic steroid dexamethasone, which readily crosses the placenta, or to carbenoxolone, which inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the physiological feto-placental 'barrier' to maternal glucocorticoids. As adults, the offspring exhibit permanent hypertension, hyperglycaemic, increased hypothalamic-pituitary-adrenal (HPA) axis activity and behaviour reminiscent of anxiety. Physiological variations in placental 11beta-HSD2 activity correlate directly with foetal weight. In humans, 11beta-HSD2 gene mutations cause low birth weight. Moreover, low-birth-weight babies have higher plasma cortisol levels throughout adult life, indicating HPA axis programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors, key among which is the glucocorticoid receptor (GR) itself. The differential programming of the GR in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the GR gene. Overall, the data suggest that both pharmacological and physiological exposure prenatally to excess glucocorticoids programmes cardiovascular, metabolic and neuroendocrine disorders in adult life.
Environmental effects on the materno–foetal interaction determine birth outcomes that predict health over the lifespan. Thus, maternal undernutrition or stress associate with low birth weight, ...leading to an increased risk of metabolic and cardiovascular illness in the offspring. We argue that these effects are, in part, mediated by direct and indirect effects on the hypothalamic-pituitary-adrenal (HPA) axis such that (i) the effect of maternal adversity on foetal growth is mediated by adrenal glucocorticoids and (ii) environmental adversity alters maternal physiology and behaviour, which then programs HPA activity in the offspring.
Numerous clinical studies associate an adverse prenatal environment with the development of cardio-metabolic disorders and neuroendocrine dysfunction, as well as an increased risk of psychiatric ...diseases in later life. Experimentally, prenatal exposure to stress or excess glucocorticoids in a variety of animal models can malprogram offspring physiology, resulting in a reduction in birth weight and subsequently increasing the likelihood of disorders of cardiovascular function, glucose homeostasis, hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviours in adulthood. During fetal development, placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) provides a barrier to maternal glucocorticoids. Reduced placental 11beta-HSD2 in human pregnancy correlates with lower birth weight and higher blood pressure in later life. Similarly, in animal models, inhibition or knockout of placental 11beta-HSD2 lowers offspring birth weight, in part by reducing glucose delivery to the developing fetus in late gestation. Molecular mechanisms thought to underlie the programming effects of early life stress and glucocorticoids include epigenetic changes in target chromatin, notably affecting tissue-specific expression of the intracellular glucocorticoid receptor (GR). As such, excess glucocorticoids in early life can permanently alter tissue glucocorticoid signalling, effects which may have short-term adaptive benefits but increase the risk of later disease.
Glucocorticoid Programming SECKL, JONATHAN R.; MEANEY, MICHAEL J.
Annals of the New York Academy of Sciences,
December 2004, Letnik:
1032, Številka:
1
Journal Article
Recenzirano
: Epidemiological evidence suggests that an adverse fetal environment permanently programs physiology, leading to increased risks of cardiovascular, metabolic, and neuroendocrine disorders in ...adulthood. Prenatal glucocorticoid excess or stress might link fetal maturation and adult pathophysiology. In a variety of animal models, prenatal glucocorticoid exposure or inhibition of 11β‐hydroxysteroid dehydrogenase type 2 (11β‐HSD2), the fetoplacental “barrier” to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycemia, and increased hypothalamic‐pituitary‐adrenal axis (HPA) activity and behavior resembling anxiety. In humans, 11β‐HSD2 gene mutations cause low birth weight and reduced placental 11β‐HSD2 activity associated with intrauterine growth retardation. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors; key is the glucocorticoid receptor itself. Differential programming of the glucocorticoid receptor in different tissues reflects effects upon one or more of the multiple tissue‐specific alternate first exons/promoters of the glucocorticoid receptor gene. Overall, the data suggest that either pharmacological or physiological exposure to excess glucocorticoids prenatally programs pathologies in adult life.
An adverse foetal environment is associated with increased risk of cardiovascular, metabolic, neuroendocrine and psychological disorders in adulthood. Exposure to stress and its glucocorticoid ...hormone mediators may underpin this association. In humans and in animal models, prenatal stress, excess exogenous glucocorticoids or inhibition of 11β-hydroxysteroid dehydrogenase type 2 (HSD2; the placental barrier to maternal glucocorticoids) reduces birth weight and causes hyperglycemia, hypertension, increased HPA axis reactivity, and increased anxiety-related behaviour. Molecular mechanisms that underlie the ‘developmental programming’ effects of excess glucocorticoids/prenatal stress include epigenetic changes in target gene promoters. In the case of the intracellular glucocorticoid receptor (GR), this alters tissue-specific GR expression levels, which has persistent and profound effects on glucocorticoid signalling in certain tissues (e.g. brain, liver, and adipose). Crucially, changes in gene expression persist long after the initial challenge, predisposing the individual to disease in later life. Intriguingly, the effects of a challenged pregnancy appear to be transmitted possibly to one or two subsequent generations, suggesting that these epigenetic effects persist.
Post-traumatic stress disorder (PTSD) is characterized by the co-existence of a persistent strong memory of the traumatic experience and amnesia for the peritraumatic context. Most animal models, ...however, fail to account for the contextual amnesia which is considered to play a critical role in the etiology of PTSD intrusive memories. It is also unclear how aging affects PTSD-like memory. Glucocorticoids alter the formation and retention of fear-associated memory. Here, we investigated whether a deficiency of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) (an intracellular glucocorticoid generating enzyme) and aging modulates fear conditioning and PTSD-like memory in mice. We first measured memory in 6 months and 24 months old 11β-HSD1 deficient (HSD1 KO) and wildtype (WT) mice following paired tone-shock fear conditioning. Then, separate groups of mice were exposed to restraint stress immediately after unpaired tone-shock contextual fear conditioning. Compared with young controls, aged WT mice exhibited enhanced auditory cued fear memory, but contextual fear memory was not different. Contextual fear memory retention was attenuated in both young and aged HSD1 KO mice. In contrast, auditory cued fear memory was reduced 24 h after training only in aged HSD1 KO mice. When fear conditioned with stress, WT mice displayed PTSD-like memory (i.e., increased fear to tone not predictive of shock and reduced fear to ‘aversive’ conditioning context); this was unchanged with aging. In contrast, young HSD1 KO mice fear conditioned with stress showed normal fear memory (i.e., increased fear response to conditioning context), as observed in WT mice fear conditioned alone. While aged HSD1 KO mice fear conditioned with stress also displayed normal contextual fear memory, the fear response to the ‘safe’ tone remained. Thus, a deficiency of 11β-HSD1 protects against both amnesia for the conditioning context and hypermnesia for a salient tone in young adult mice but only contextual amnesia is prevented in aged mice. These results suggest that brain 11β-HSD1 generated glucocorticoids make a significant contribution to fear conditioning and PTSD-like memory. 11β-HSD1 inhibition may be useful in prevention and/or treatment of PTSD.
•11β-HSD1 deficiency attenuates fear conditioning in 6 months and 24 months old male mice.•Auditory cued fear memory is enhanced with aging.•Restraint stress immediately after fear conditioning induces PTSD-like memory: both enhanced fear memory for a salient tone (not predictive of shock) and amnesia for the ‘aversive’ conditioning context.•11β-HSD1 deficiency prevents PTSD-like memory in young adult mice, but the abnormal fear response to the ‘safe’ tone persists in aged mice.
It has been long recognised that the glucocorticoid administration to pregnant mammals (including humans) reduces offspring birth weight. Epidemiologically, low weight or thinness at birth is ...associated with an increased risk of cardiovascular and metabolic disorders in adult life. So, does fetal exposure to glucocorticoids produce such ‘programming’ of adult disorders? Here data are reviewed which show, in rodents and other model species, that antenatal exposure to glucocorticoids reduces offspring birth weight and produces permanent hypertension, hyperglycaemia, hyperinsulinaemia, altered behaviour and neuroendocrine responses throughout the lifespan. This occurs with exogenous (dexamethasone) or endogenous glucocorticoids, the latter achieved by inhibiting 11β-hydroxysteroid dehydrogenase type 2, the feto-placental enzymic barrier to maternal glucocorticoids. Processes underlying fetal programming include determination of the ‘set point’ of the hypothalamic–pituitary–adrenal axis and of tissue glucocorticoid receptor expression. Detailed molecular mechanisms are being dissected. Analogous stress axis hyperreactivity occurs in lower birth weight humans and may be an early manifestation and indicate approaches to manipulation or prevention of the phenotype.
The adverse metabolic consequences of obesity are best predicted by the quantity of visceral fat. Excess glucocorticoids produce visceral obesity and diabetes, but circulating glucocorticoid levels ...are normal in typical obesity. Glucocorticoids can be produced locally from inactive 11-keto forms through the enzyme 11β hydroxysteroid dehydrogenase type 1 (11β HSD-1). We created transgenic mice overexpressing 11β HSD-1 selectively in adipose tissue to an extent similar to that found in adipose tissue from obese humans. These mice had increased adipose levels of corticosterone and developed visceral obesity that was exaggerated by a high-fat diet. The mice also exhibited pronounced insulin-resistant diabetes, hyperlipidemia, and, surprisingly, hyperphagia despite hyperleptinemia. Increased adipocyte 11β HSD-1 activity may be a common molecular etiology for visceral obesity and the metabolic syndrome.
Epidemiological evidence suggests that an adverse prenatal environment permanently 'programs' physiology and increases the risk of cardiovascular, metabolic, neuroendocrine and psychiatric disorders ...in adulthood. Prenatal stress or exposure to excess glucocorticoids might provide the link between fetal maturation and adult pathophysiology. In a variety of animal models, prenatal stress, glucocorticoid exposure and inhibition (or knockout of) 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2)--the fetoplacental barrier to maternal glucocorticoids--reduce birth weight and cause increases in adult blood pressure, glucose levels, hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviors. In humans, mutations in the gene that encodes 11beta- hydroxysteroid dehydrogenase type 2 are associated with low birth weight. Babies with low birth weight have higher plasma cortisol levels throughout life, which indicates HPA-axis programming. In human pregnancy, severe maternal stress affects the offspring's HPA axis and is associated with neuropsychiatric disorders; moreover, maternal glucocorticoid therapy alters offspring brain function. The molecular mechanisms that underlie prenatal programming might reflect permanent changes in the expression of specific transcription factors, including the glucocorticoid receptor; tissue specific effects reflect modification of one or more of the multiple alternative first exons or promoters of the glucocorticoid receptor gene. Intriguingly, some of these effects seem to be inherited by subsequent generations that are unexposed to exogenous glucocorticoids at any point in their lifespan from fertilization, which implies that these epigenetic effects persist.
Highlights • HPA activity and obesity are related, but the literature is highly inconsistent. • Much of this inconsistency arises from divergent methodologies across studies. • This systematic review ...finds obesity may be related to HPA hyperresponsivity. • Dysregulation in adipocyte cortisol metabolism may affect HPA activity in obesity.
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