Properties and ontogeny of the glucocorticoid receptor in the placenta and fetal lung of the sheep

Abstract

The cytosolic glucocorticoid receptor of ovine placental zona intima has been characterized and measured between day 51 of pregnancy and term, and levels compared with those in fetal lung. By ion-exchange and gel-filtration chromatography the molybdate-stabilized receptor was found to be an acidic molecule with Stokes radius approximately 8 nm; these physicochemical characteristics of the ovine placental receptor are comparable to those of receptors in glucocorticoid target tissues from nonruminants. Concentrations of cytosolic receptor in placenta (mean, 139 fmol/mg protein) were lower than those in fetal lung (627 fmol/mg) at all stages of gestation investigated. To some extent this difference was accounted for by a twofold higher concentration of protein in placental cytosols compared with those from fetal lung. In both tissues, cytosolic receptor concentrations were maximal between days 91 and 130, when fetal adrenal steroid secretion is low; receptor concentrations decreased before term. Fetal hypophysectomy, which resulted in prolonged gestation, raised receptor concentrations in placenta, but not in fetal lung. In both tissues, apparent dissociation constants for [3H]dexamethasone binding to glucocorticoid receptors were in the range 0.5-7.1 nmol/l; these dissociation constants did not change consistently between day 100 and term. In whole-cell preparations of placenta and fetal lung incubated in vitro there was time-dependent specific binding of [3H]dexamethasone by nuclei, and binding of labelled cytosolic receptor to isolated nuclei occurred at all stages of gestation investigated. Binding of [3H]dexamethasone by cytosolic receptor from placenta and fetal lung was inhibited by progesterone and 17 alpha-hydroxyprogesterone, as well as by cortisol, cortisone, 11-deoxycorticosterone and 11 beta-hydroxyprogesterone; 20 alpha-hydroxyprogesterone and 17 alpha,20 alpha-dihydroxypregn-4-en-3-one were less effective. In experiments to evaluate the possible antagonistic action of progesterone in whole-cell preparations, uptake of [3H]dexamethasone by nuclei was increased up to twofold in placental minces incubated with aminoglutethimide or epostane, when progesterone synthesis was reduced by 98 and 92 per cent respectively. Nuclear uptake in minces of fetal lung was blocked by concentrations of progesterone found in placenta. The existence of a placental glucocorticoid receptor confirms that fetal cortisol may act directly on the placenta to induce the enzymatic changes controlling the onset of labour.(ABSTRACT TRUNCATED AT 400 WORDS)