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Glucocorticoids play important roles in organ development and 'fetal programming'. Fetal exposure to excess glucocorticoids reduces birth weight and causes later hypertension. To investigate these processes further we have determined the detailed ontogeny in the mouse of the glucocorticoid receptor (GR) and 11beta-hydroxysteroid dehydrogenase type-1 (11beta-HSD1), which amplifies glucocorticoid levels locally; the ontogeny was determined using in situ hybridisation from embryonic day 9.5 (E9.5, term=E19) until after birth. At E9.5 fetal GR mRNA levels are very low, except in fetal placenta. GR gene expression rises during gestation with striking tissue-specific differences in timing and extent. Before E13.5, an increase is clear in gastrointestinal (GI) and upper respiratory tracts, discrete central nervous system (CNS) regions, precartilage and especially in the liver (E10.5-E12). Later, further increases occur in lung, GI and upper respiratory tracts, muscle, pituitary and thymus. In a few tissues such increases are temporary, e.g. ureteric ducts (E13.5-E16.5) and pancreas (E14.5-E16.5, expression later falling sharply). Fetal 11beta-HSD1 mRNA expression is first clearly observed at E14.5-E15, initially in the fetal placenta then in the umbilical cord. Later, 11beta-HSD1 expression is seen as follows: (i) from E15 in lung and liver, rising strongly; (ii) thymus, from E15 (lower level); (iii) at low levels in a few brain regions, including the hippocampus (E16.5+); and (iv) in muscle group fascial planes and tendon insertions. This is the first detailed study of the ontogeny of these two genes and, in combination with previous work on the ontogeny of 11beta-HSD2 and the mineralocorticoid receptor, suggests potential critical periods of glucocorticoid sensitivity during development for several organ systems.
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SUMMARY
Using reliable radioimmunoassay methods, the concentrations of prednisolone, prednisolone-hemisuccinate, betamethasone and betamethasone-17-benzoate were determined after administration by various routes. Serum prednisolone and betamethasone concentrations increased to peak levels 2 h after oral administration and then decreased gradually. The half-times of disappearance of prednisolone and betamethasone from blood, after a single oral dose, were both approximately 180–220 min. Five to fifteen minutes after intramuscular injections of 20 mg prednisolone-hemisuccinate the peak serum concentration was 63·7 ± 7·4 μg/ 100 ml and 30 min later plasma unesterified prednisolone reached its highest level (28·8 ± 2·6 μg/100 ml). The administration of steroids through the rectum induced gradual increases in the levels of serum steroids, reaching a maximum of 25% of the peak serum concentrations observed after oral administration. Plasma betamethasone-17-benzoate levels of 300 ng/ 100 ml were observed after topical application of betamethasone-17-benzoate gel to the skin.
In patients with liver disease, the clearance of betamethasone was very slow compared with that in normal control subjects and significant amounts were retained in the blood 24 h after oral administration, showing that the liver is the most important organ for the metabolism of synthetic glucocorticoid. The concentrations of prednisolone and prednisolone-hemisuccinate in the cerebrospinal fluid were very low after the intramuscular injection of prednisolone-hemisuccinate, confirming the relative impermeability of the blood–brain barrier to polar steroids.
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SUMMARY
Dexamethasone caused premature delivery when infused into foetal lambs at rates of 0·06–4·0 mg./24 hr. but it had no effect when administered to pregnant ewes at the rate of 4·0 mg./24 hr. Infusions into the foetus of deoxycorticosterone or corticosterone were ineffective; mixtures of dexamethasone and deoxycorticosterone did not cause parturition more rapidly than dexamethasone alone. Thus, the ability of corticosteroids to cause premature parturition appears to depend on glucocorticoid rather than mineralocorticoid activity.
Parturition induced by dexamethasone was not delayed by administration of 100 mg. progesterone/24 hr. to the ewe or to the foetus. This suggests either that withdrawal of inhibitory effects of progesterone on the myometrium can occur independently of the progesterone concentration in peripheral plasma, or that the mechanism of parturition provoked by corticosteroids in the foetus can override any regulatory influence of progesterone on myometrial contractility.
Partial aeration of the lungs was observed in lambs born vaginally at 117–123 days of gestation after receiving dexamethasone. It is suggested that this may be the result of accelerated appearance of surfactant activity.
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Using an exchange assay to measure occupied and unoccupied binding sites the interaction between [3H]triamcinolone acetonide and rat skin cytosol proteins was studied. A binding site with a high affinity (dissociation constant = 7 × 10−10 mol/l) and a low capacity (400–600 fmol/mg protein) for triamcinolone acetonide was detected. The binding was specific to corticosteroids; fluorinated steroids showed a higher affinity than natural steroids. Non-corticosteroids, with the exception of progesterone, had little or no affinity for the binding site. At 0 °C the second-order rate constant of association was 2·23 × 106 mol/l per min and the first-order rate constant of dissociation was 1·6 × 10−4 per min. In the absence of dithiothreitol and molybdate the specific binding was rapidly abolished. The binding was also labile to heating and proteolytic enzymes. One day after adrenalectomy there was a significant increase in the number of assayable binding sites in the cytosol. The results are consistent with the binding protein being the physiological glucocorticoid receptor in rat skin.
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Cytosols prepared from the liver and various tissues of goldfish (intact or hypophysectomized) and trout (intact) were incubated at 2 °C in the presence of tritiated cortisol or dexamethasone (3 × 10−9 to 3 × 10−6 mol/l) with or without a 1000-fold excess of unlabelled steroid. In contrast to mammals, the specifically bound component represented a very low fraction of the total bound steroid retained on DEAE cellulose filters and did not show saturation over a large range of concentrations.
The subcellular distribution of [3H]dexamethasone was studied in trout liver after intravascular injection of the labelled steroid with and without an excess of unlabelled steroid.
The amount of protein-bound steroid in the cytosol again corresponded to a small (4%) proportion of the free steroid. The large reduction in the uptake of tritiated dexamethasone, which was induced in both the cytosol and nuclei by competing unlabelled dexamethasone, was interpreted as evidence for mediated entry across cellular and nuclear membranes.
These results indicate that high-affinity binding sites are absent, or present only in very small numbers in cytosol from teleost tissues. The entry of glucocorticoids into the nucleus may not require the hormone to be bound to high-affinity cytosolic receptors unless the binding, though quantitatively small, displays a high rate of turnover.
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More than a decade ago our view of gene regulation by glucocorticoids (GC) and other steroid hormones underwent a dramatic change with the discovery of negative crosstalk (transcriptional interference) between the GC receptor (GCR) and transcription factor AP-1 (Jun:Fos). It was initially observed that induction of the collagenase type 1 gene, which is mediated through activation of AP-1 by growth factors and inflammatory cytokines, is repressed by GC. This repression was attributed to mutual negative interactions between AP-1 and GCR. Although the exact molecular mechanism underlying this particular case of transcriptional interference is yet to be determined, it has become clear that this and analogous interactions with other transcription factors (e.g. nuclear factor-kappaB) underlie the anti-inflammatory and immunosuppressive activity of GC. Recent studies conducted at the whole animal level indicate that the interactions between the AP-1 and GC signaling pathways are much more extensive. AP-1-related signaling via the Jun N-terminal kinases can lead to increased levels of circulating GC, which eventually down-modulate AP-1 activity via transcriptional interference. This negative feedback loop is likely to be of great importance for maintenance of homeostasis and regulation of stress responses, including acute and chronic inflammation.
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Abstract
The C6 rat glioma cell line is responsive to glucocorticoid hormones. C6 variants that are hyper-responsive (ST1) and resistant (P7) to hormone treatment have been derived previously. Glucocorticoid treatment of ST1 cells leads to complete reversion of the transformed phenotype and loss of tumorigenic potential. Production of C type retrovirus particles is also induced by glucocorticoids in ST1 cells. Cloning of the genes regulated by glucocorticoids in this cell system was used here as a strategy to uncover the gene products involved in the transformed-to-normal phenotypic change. Construction of a cDNA library from glucocorticoid-treated ST1 cells and screening by differential hybridization resulted in the isolation of three cellular sequences that code for rat metallothioneins (C27 and C41) and α1-acid glycoprotein (C36). Northern blot analysis revealed that expression of these genes was dramatically induced by hydrocortisone in ST1 but not in P7 cells. Viral genomic RNA was used to isolate and characterize retrovirus-related sequences that could also be responsible for the phenotypic reversion phenomenon.
Journal of Endocrinology (1996) 148, 11–17
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Introduction The amount of cortisol available to glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) is largely dependent upon the pre-receptor enzyme 11β-hydroxy-steroid dehydrogenase (11β-HSD; Seckl 1993 , Draper
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ABSTRACT
An investigation spanning two breeding seasons was carried out to examine endocrine changes associated with reproduction in a wild population of the marsupial sugar glider Petaurus breviceps, a small arboreal gliding possum.
Using techniques of equilibrium dialysis and polyacrylamide gel electrophoresis at steady-state conditions, a high-affinity, low-capacity glucocorticoid-binding protein was demonstrated in the plasma of Petaurus breviceps.
Equilibrium dialysis at 36 °C using cortisol gave a high-affinity binding constant of 95 ± 5·2 litres/μmol for a presumed corticosteroid-binding globulin (CBG) while the binding constant for the cortisol-albumin interaction was 3·5 ± 0·4 litres/mmol.
There was no difference between the sexes in the affinity of binding of cortisol to CBG; however, the cortisol-binding capacity underwent seasonal variation in both sexes. Progesterone was bound strongly to the presumed CBG while neither oestradiol nor aldosterone appeared to be bound with high affinity to P. breviceps plasma.
In the males, peaks in the plasma concentration of testosterone coincided with the July–September breeding season in both years. A significant inverse relationship was shown to exist between the plasma testosterone concentration and the CBG-binding capacity.
In both sexes an increase occurred in the plasma concentration of free cortisol during the first breeding season, a pattern which was not repeated in the subsequent breeding season, possibly due to a lower population density in that year.
Journal of Endocrinology (1992) 132, 21–31
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ABSTRACT
Using an exchange assay to measure occupied and unoccupied binding sites, the glucocorticoid receptor in rat skin cytosol has been measured after adrenalectomy and parenteral steroid administration. Adrenalectomy increased the number of receptor sites with maximal effect after 5 days, after which numbers decreased to those of intact animals. Injection of adrenalectomized animals with the unlabelled agonist corticosterone resulted in a rapid dose-related decrease in the number of cytosolic receptor sites at 30 min whereas the antagonist progesterone had no effect. It is concluded that changes in glucocorticoid concentration lead to rapid inverse changes in cytosolic receptor.
J. Endocr. (1984) 102, 161–165
