GLUCOCORTICOIDS ENHANCE INTRACELLULAR SIGNALING VIA ADENYLATE-CYCLASEAT 3 DISTINCT LOCI IN THE FETUS - A MECHANISM FOR HETEROLOGOUS TERATOGENIC SENSITIZATION

Although high doses of glucocorticoids are teratogenic, endogenous hor mones are necessary for development. Because of the central role of cA MP to control cell differentiation, we examined the dose dependence, t issue selectivity, and critical periods involved in glucocorticoid reg ulation of fetal intracellular signaling mediated by adenylate cyclase . Pregnant rats were given dexamethasone at doses spanning the thresho ld for therapeutic effects (0.05, 0.2, and 0.8 mg/kg) on either Gestat ional Days 11, 12, and 13 or Days 17, 18, and 19. Development of adeny late cyclase was evaluated in cell membrane preparations using basal a ctivity in the absence or presence of GTP, maximal G-protein activatio n by fluoride, and maximal catalytic subunit stimulation by forskolin- Mn2+. Even at the lowest dose, dexamethasone on gestational days 11 th rough 13 enhanced fetal adenylate cyclase activity by accelerating dev elopment of both the G-protein component and the catalytic subunit. As a result, supersensitivity of the response to beta-adrenergic recepto r stimulation by isoproterenol was also produced, even though developm ent of beta-adrenergic receptors was unaffected. Treatment with dexame thasone later in gestation similarly fostered development of both G-pr otein and catalytic subunit components, with selectivity for liver and heart as opposed to brain. Again, heterologous sensitization to isopr oterenol stimulation was demonstrable; in addition, late gestational t reatment elevated yet a third signal transduction locus, the beta-adre nergic receptor binding site. These effects are likely contributors to glucocorticoid teratogenesis (high doses) or to more subtle disruptio n of cell development (low doses); because adenylate cyclase is at the convergence of multiple neuronal, hormonal, and environmental inputs, glucocorticoids may sensitize the cell to heterologous stimuli, lower ing the threshold for teratogenesis by other agents. (C) 1994 Academic Press, Inc.