GLUCOCORTICOID-INDUCED INCREASE IN PLASMA CORTICOSTEROID-BINDING GLOBULIN LEVELS IN FETAL SHEEP IS ASSOCIATED WITH INCREASED BIOSYNTHESIS AND ALTERATIONS IN GLYCOSYLATION

In fetal sheep, there is a concomitant prepartum rise in cortisol and corticosteroid-binding globulin (CBG) that maintains a low free plasma cortisol level and allows for a low negative feedback effect of corti sol on the secretion of ACTH from the fetal pituitary. However, the st imulus for the prepartum increase in CBG and the mechanism(s) of this effect are not known. It has been proposed that glucocorticoids increa se CBG concentrations, and therefore, we infused fetal sheep with the synthetic glucocorticoid dexamethasone (DEX; 2 mug/min over 15 min eve ry 2 h for 96 h, n = 5) or saline (n = 5). The plasma corticosteroid-b inding capacity increased from 30.0 +/- 2.4 to 55.6 +/- 7.7 and 92.6 /- 11.1 ng/ml at 48 and 96 h, respectively, of DEX infusion. To examin e possible mechanisms of increasing fetal plasma CBG, we first cloned and sequenced a sheep CBG cDNA and purified the protein. This allowed us to deduce the primary structure of ovine CBG and to demonstrate tha t hepatic CBG mRNA abundance (single transcript of 1.8 kilobases) rose from 0.9 +/- 0.2 to 3.6 +/- 1.6 arbitrary units after 96 h of DEX tre atment. Fetal DEX treatment produced a significant increase (7.1 +/- 1 .2% to 13.1 +/- 1.4%) in the Concanavalin-A-binding forms of CBG that predominate in adult sheep plasma. There was negligible transfer of pu rified [I-125] CBG from the ewe to fetal plasma, urine, or amniotic fl uid. We also injected adult sheep with DEX (10 mg/day for 4 days) and demonstrated a significant decrease in plasma corticosteroid-binding c apacity by 24 h, which remained suppressed for the duration of the stu dy. After 96 h of DEX treatment, there was also a significant decrease in adult hepatic CBG mRNA abundance. We conclude that glucocorticoids increase fetal plasma CBG in part by increased hepatic biosynthesis. It may also be accentuated by a change in the glycosylation of CBG, bu t cannot be attributed to transplacental transfer. Furthermore, glucoc orticoid treatment exerts opposite effects on CBG biosynthesis in feta l and adult sheep.