Developmental regulation of corticotrophin receptor gene expression in theadrenal gland of the ovine fetus and newborn lamb: Effects of hypoxia during late pregnancy

Responsiveness of the fetal Sheep adrenal gland to adrenocorticotrophin (AC TH) increases in late pregnancy, resulting in increased glucocorticoid prod uction. Development of this responsiveness is an important determinant of f etal hypothalamic-pituitary-adrenal function and depends, in part, on the p otential for ACTH binding to adrenal tissue. In the present study, we have examined the developmental pattern of ACTH receptor (ACTH-R) expression dur ing the latter half of pregnancy and in neonatal and adult life. As hypoxae mia induces increases in cortisol and ACTH secretion, in addition to increa sing fetal adrenal responsiveness, a further aim of this study was to inves tigate whether hypoxaemia was associated with altered expression of the ACT H-R gene. Whole adrenal glands were removed from fetal sheep, lambs and adult sheep a t different stages of development for measurement or ACTH-R mRNA. Moderate hypoxaemia was induced for 48 h beginning on days 124-128, or on days 131-1 34 of gestation, by decreasing the maternal fractional inspired oxygen. ACT H-R mRNA was detected northern blotting using a cDNA cloned in our laborato ry and by in situ bydridisation. ACTH-R mRNA (3.6 kb major transcript) was detected in adrenal tissue at day 63 of gestation. Its relative abundance increased significantly (P<0.05) b etween days 126-128 and 140-141 of pregnancy, increased further with the on set of spontaneous labour, and remained increased in newborn lambs at 7 h-7 days after birth. ACTH-R mRNA levels then decreased ill adrenal tissue fro m lambs and adult sheep (P<0.05). Hypoxaemia for 48 h significantly increas ed ACTH-R mRNA expression in adrenals of the older fetuses (days 134-136) c ompared with that in controls (P<0.05), but was without effect in younger f etuses. We conclude that levels of ACTH-R mRNA ill the fetal adrenal gland increase as term approaches, coincident with the endogenous prepartum surge in plas ma ACTH and cortisol. Sustained hypoxaemia resulted in an upregulation of m RNA encoding for ACTH-R, but only in older fetuses and in association with a sustained increase in plasma cortisol. These results are consistent with cortisol, ACTH, or both, contributing to increased fetal adrenal responsive ness, by increasing expression of fetal adrenal receptors for ACTH.