Spontaneous and Adrenocorticotropin (ACTH)-Induced Maturation of the Responsiveness of Ovine Fetal Adrenal Cells to in Vitro Stimulation by ACTH and Cholera Toxin*

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Abstract
Isolated adrenal cells from fetal (119–144 days old) neonatal, and adult sheep were tested for their in vitro ability to produce cAMP and corticosteroids in response to stimulation by ACTH-(1–24), αMSH, and cholera toxin. Basal cAMP production by isolated fetal adrenal cells remained stable up to the end of gestation (15.8 ± 1.0 pmo½12 × 105 cells-24 h). Under ACTH-(1–24) and cholera toxin stimulation, the response remained at a relatively low level (2-fold increase) between 1 ISIS? days of gestation. Maximal stimulation (5-fold) by cholera toxin was reached in prepartum animals (143–144 days of gestation), while the maximal response to ACTH-(1–24) was observed in newborn lambs. Basal corticoid output was low between 119–137 days of gestation (1.4 ± 0.2 ng × 2 × 105 cells-2 h) and increased significantly from day 143 on (3.8 ± 0.6 ng), reaching 15.9 ± 3.6 ng early post partum. The stimulation of corticosteroid out ut induced by ACTH-(1–24) and cholera toxin was very small (2-fold) in fetuses of 119–130 days of age, began to increase on days 136–137 (6-fold), and reached a maximum (24-fold) in newborn lambs. In adult animals, the output of corticosteroids under basal conditions and after stimulation with ACTH-(l–24) and cholera toxin was similar to that in 143- to 144-day-old fetuses, but lower than that in newborn animals. No variation in the ED50 of ACTH-Q-24) was observed at any age. aMSH was unable at any age to stimulate either cAMP or corticosteroid output. Perfusion of fetuses 133 and 115 days old with ACTH-Q-24) for 4 and 5 days, respectively, significantly enhanced the subsequent in vitro response of adrenal cells to ACTH-(1–24) and cholera toxin in terms of both cAMP and corticosteroid production. These results and others showing that fetal adrenal maturation is associated with an increase in the in vitro responsiveness of the adrenal adenylate cyclase to several stimuli provide evidence that the development of the steroidogenic response to ACTH-(1–24) of fetal adrenal cells during late gestation involves modifications at different steps of the mechanism of ACTH action: one located at the cell membrane level, resulting in variations in the capacity to produce cAMP, and another at a step distal to cAMP. Also, our results show that maturation of these biochemical steps can be induced by perfusion of fetuses with ACTH.