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

Abstract

Responsiveness of the fetal sheep adrenal gland to adrenocorticotrophin (ACTH) increases in late pregnancy, resulting in increased glucocorticoid production. Development of this responsiveness is an important determinant of fetal hypothalamic-pituitary-adrenal function and depends, in part, on the potential for ACTH binding to adrenal tissue. In the present study, we have examined the developmental pattern of ACTH receptor (ACTH-R) expression during the latter half of pregnancy and in neonatal and adult life. As hypoxaemia induces increases in cortisol and ACTH secretion, in addition to increasing fetal adrenal responsiveness, a further aim of this study was to investigate whether hypoxaemia was associated with altered expression of the ACTH-R gene.Whole adrenal glands were removed from fetal sheep, lambs and adult sheep at different stages of development for measurement of ACTH-R mRNA. Moderate hypoxaemia was induced for 48 h beginning on days 124-128, or on days 132-134 of gestation, by decreasing the maternal fractional inspired oxygen. ACTH-R mRNA was detected by northern blotting using a cDNA cloned in our laboratory 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) between days 126-128 and 140-141 of pregnancy, increased further with the onset of spontaneous labour, and remained increased in newborn lambs at 7 h-7 days after birth. ACTH-R mRNA levels then decreased in adrenal tissue from lambs and adult sheep (P<0·05). Hypoxaemia for 48 h significantly increased ACTH-R mRNA expression in adrenals of the older fetuses (days 134-136) compared with that in controls (P<0·05), but was without effect in younger fetuses.We conclude that levels of ACTH-R mRNA in the fetal adrenal gland increase as term approaches, coincident with the endogenous prepartum surge in plasma ACTH and cortisol. Sustained hypoxaemia resulted in an upregulation of mRNA 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 responsiveness, by increasing expression of fetal adrenal receptors for ACTH.

Interference RNA-based silencing of endogenous SMAD4 in porcine granulosa cells resulted in decreased FSH-mediated granulosa cells proliferation and steroidogenesis

“…In vitro, FSH-stimulated steroidogenesis is modulated by growth factors, including members of the BMP family. Recombinant BMP4, BMP6, BMP7, BMP15, and GDF9 inhibited FSH-induced P 4 secretion by rat GCs in culture (Shimasaki et al 1999, Otsuka et al 2000, Vitt et al 2000, Fraser et al 2001, Lee et al 2001, whereas BMP4 and BMP7 enhanced FSH-dependent E 2 production, suggesting that BMP factors may delay luteinization (Shimasaki et al 1999). In this study, SMAD4 knockdown inhibited FSH-induced E 2 secretion but did not affect FSH-induced P 4 secretion.…”

The effect of prenatal betamethasone administration on postnatal ovine hypothalamic-pituitary-adrenal function

“…This is followed by a period of relative quiescence (90-120 days of gestation) characterized by a decrease in responsiveness until 120 days gestational age, when adrenal sensitivity increases to a maximum at term (Rose et al 1982, Boshier & Holloway 1989, Wintour et al 1995. This increase in responsiveness has been associated with an increase in ACTH receptor mRNA levels (Fraser et al 2001). It is possible that an early single exposure to prenatal betamethasone at 104 days of gestation increased ACTH receptors and/or steroidogenic enzymes during this period of relative quiescence in a way that permanently increased the set point of adrenal responsiveness.…”

Nur77 Activated by Hypoxia-Inducible Factor-1α Overproduces Proopiomelanocortin in von Hippel-Lindau-Mutated Renal Cell Carcinoma

“…SK-N-SH cells were transiently transfected with different reporter constructs under the control of the wild-type and deletion mutants of Nur77 promoter along with HIF-1␣ expression vector (pCMV-HA-HIF-1␣). It was known previously that hypoxia activates hypothalamicpituitary-adrenal axis, resulting in increase of ACTH and ACTH receptor (26,27), suggesting that oxygen fluctuation may control the production of cellular hormone. However, little was known about the effect of oxygen tension on hormone homeostasis, despite the possibility that the hormone regulates metabolic homeostasis, proliferation, and differentiation in an oxygen concentration-dependent manner.…”