GLUCOCORTICOIDS REGULATE THE DEVELOPMENT OF INTRACELLULAR SIGNALING -ENHANCED FOREBRAIN ADENYLATE-CYCLASE CATALYTIC SUBUNIT ACTIVITY AFTERFETAL DEXAMETHASONE EXPOSURE

Although glucocorticoids cause growth retardation and interfere with c ell development. selective promotion of some aspects of cell function also has been reported. The current study examines whether glucocortic oids enhance intracellular transduction mechanisms mediated by adenyla te cyclase in the developing forebrain, a region in which steroids hav e been shown to interfere with cell replication, maturation. and growt h. Pregnant rats were given dexamethasone at doses spanning the thresh old for growth impairment (0.05, 0.2, and 0.8 mg/kg) on gestational da ys 17, 18, and 19, and development of adenylate cyclase was evaluated in membrane preparations, using four different activity measures: basa l adenylate cyclase in the absence or presence of GTP, maximal G-prote in activation by fluoride in the presence of GTP, and stimulation medi ated by forskolin-Mn2+. which bypasses the G-proteins. Prenatal exposu re to dexamethasone produced a dose-dependent impairment of body growt h, with smaller deficits in forebrain weights (brain sparing) indicati ve of systemic toxicity. Basal adenylate cyclase activity was unaffect ed by dexamethasone treatment, regardless of whether GTP was present i n the assay. Similarly, fluoride stimulation developed normally in all dexamethasone groups. However, forskolin-Mn2+-stimulated activity was significantly enhanced in a dose-dependent fashion. These results sug gest that glucocorticoids serve as positive factors for the developmen t of adenylate cyclase catalytic subunit activity, independently of th eir adverse effects on general growth and development: thus, these hor mones may be a primary regulator of cell signaling during early develo pment.