Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

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.

Mechanisms of disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology.

The relative contribution of genetic and environmental influences to the US black-white disparity in cardiovascular disease (CVD) is hotly debated within the public health, anthropology, and medical communities. In this article, we review evidence for developmental and epigenetic pathways linking early life environments with CVD, and critically evaluate their possible role in the origins of these racial health disparities. African Americans not only suffer from a disproportionate burden of CVD relative to whites, but also have higher rates of the perinatal health disparities now known to be the antecedents of these conditions. There is extensive evidence for a social origin to prematurity and low birth weight in African Americans, reflecting pathways such as the effects of discrimination on maternal stress physiology. In light of the inverse relationship between birth weight and adult CVD, there is now a strong rationale to consider developmental and epigenetic mechanisms as links between early life environmental factors like maternal stress during pregnancy and adult race-based health disparities in diseases like hypertension, diabetes, stroke, and coronary heart disease. The model outlined here builds upon social constructivist perspectives to highlight an important set of mechanisms by which social influences can become embodied, having durable and even transgenerational influences on the most pressing US health disparities. We conclude that environmentally responsive phenotypic plasticity, in combination with the better-studied acute and chronic effects of social-environmental exposures, provides a more parsimonious explanation than genetics for the persistence of CVD disparities between members of socially imposed racial categories.

https://groups.anthropology.northwestern.edu/lhbr/kuzawa_web_files/pdfs/Kuzawa%20and%20Sweet%20AJHB%20early%20view.pdf

Epigenetics and the embodiment of race: developmental origins of US racial disparities in cardiovascular health.

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 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) provides a barrier to maternal glucocorticoids. Reduced placental 11β-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 11β-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.

/pdf/prenatal-stress-glucocorticoids-and-the-programming-of-adult-1sauuc0adb.pdf

Prenatal stress, glucocorticoids and the programming of adult disease

Stress-related variation in the intrauterine milieu may impact brain development and emergent function, with long-term implications in terms of susceptibility for affective disorders. Studies in animals suggest limbic regions in the developing brain are particularly sensitive to exposure to the stress hormone cortisol. However, the nature, magnitude, and time course of these effects have not yet been adequately characterized in humans. A prospective, longitudinal study was conducted in 65 normal, healthy mother–child dyads to examine the association of maternal cortisol in early, mid-, and late gestation with subsequent measures at approximately 7 y age of child amygdala and hippocampus volume and affective problems. After accounting for the effects of potential confounding pre- and postnatal factors, higher maternal cortisol levels in earlier but not later gestation was associated with a larger right amygdala volume in girls (a 1 SD increase in cortisol was associated with a 6.4% increase in right amygdala volume), but not in boys. Moreover, higher maternal cortisol levels in early gestation was associated with more affective problems in girls, and this association was mediated, in part, by amygdala volume. No association between maternal cortisol in pregnancy and child hippocampus volume was observed in either sex. The current findings represent, to the best of our knowledge, the first report linking maternal stress hormone levels in human pregnancy with subsequent child amygdala volume and affect. The results underscore the importance of the intrauterine environment and suggest the origins of neuropsychiatric disorders may have their foundations early in life.

/pdf/maternal-cortisol-over-the-course-of-pregnancy-and-4xj1ud7z0b.pdf

Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems

John R. G. Challis, Frank H. Bloomfield, Alan D. Bocking, Valentina Casciani, Hiroshi Chisaka, Kristin Connor, Xuesen Dong, Peter Gluckman, Jane E. Harding, Jim Johnstone, Wei Li, Stephen Lye, Kunihiro Okamura and Marina Premyslova Departments of Physiology, Medicine and Obstetrics and Gynecology, University of Toronto, CIHR Group in Fetal Development and Health Toronto, Canada; Liggins Institute, University of Auckland, New Zealand; Department of Obstetrics and Gynecology, Tohoku University, Sendai, Japan; and Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada

Fetal signals and parturition.

Objective: Preterm birth is one of the major problems faced in perinatal medicine and is often associated with underlying clinical infection. Treatment with maternal betamethasone has helped to imp...

The Effects of Chorioamnionitis and Betamethasone on 11β, Hydroxysteroid Dehydrogenase Types 1 and 2 and the Glucocorticoid Receptor in Preterm Human Placenta:

Objective: 1 β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) is thought to act as a placental barrier protecting the fetus from high levels of maternal cortisol. On the other hand, intrauterine infection is one of the main causes of preterm birth and adverse fetal outcome, and pro-inflammatory cytokines may contribute to these adverse effects. However, the effect of pro-inflammatory cytokines on 11β-HSD2 is still not clear. Therefore, we have evaluated the effect of tumor necrosisfactor-α (TNF-α) and interleukin-1β (IL-1β) on 11β-HSD2 in cultured human placental trophoblast and in human choriocarcinoma JEG-3 cells.Methods: Placental trophoblast cells were isolatedfrom human term placenta. Placental trophoblast cells and JEG-3 cells were treated with TNF-α (0.1-10 ng/mL) or IL-1β (0.1-10 ng/mL). Real-time reverse transcription polymerase chain reaction and Western blot were used to study the regulation of 1 11β-HSD2 expression. 11β-HSD2 activity was determined by measuring the rate of cortisol to cortison...

Effect of Pro-inflammatory Cytokines on Expression and Activity of 11β-Hydroxysteroid Dehydrogenase Type 2 in Cultured Human Term Placental Trophoblast and Human Choriocarcinoma JEG-3 Cells:

Pre-pregnant maternal dieting status and its relation to gestation length and placental COX-2 protein levels

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Fetal signals and parturition.

The Effects of Chorioamnionitis and Betamethasone on 11β, Hydroxysteroid Dehydrogenase Types 1 and 2 and the Glucocorticoid Receptor in Preterm Human Placenta:

Effect of Pro-inflammatory Cytokines on Expression and Activity of 11β-Hydroxysteroid Dehydrogenase Type 2 in Cultured Human Term Placental Trophoblast and Human Choriocarcinoma JEG-3 Cells:

Pre-pregnant maternal dieting status and its relation to gestation length and placental COX-2 protein levels