title: Regulation of corticotropin responsiveness in human fetal adrenal cells.
abstract: The human fetal adrenal gland exhibits a high rate of steroidogenesis during fetal development and produces the majority of steroids used by the placenta for estrogen synthesis. Corticotropin appears to be the principal hormonal regulator of steroidogenesis in the fetal adrenal gland. However, little is known concerning the regulation of corticotropin receptors. In this study we examined the long-term regulation of corticotropin responsiveness as measured by the ability of human fetal adrenal gland cells to produce cyclic adenosine monophosphate after corticotropin treatment for 3 hours. We also examined the regulation of corticotropin receptors as determined by iodine 125-labeled corticotropin binding to fetal adrenal cells. Fetal adrenal glands were obtained from second-trimester abortuses. The two distinct zones of the fetal adrenal gland, the definitive zone and the fetal zone, were separated and the tissue mechanically dispersed. Freshly isolated cells responded to corticotropin with a sevenfold to tenfold increase in the production of cyclic adenosine monophosphate, indicating a functional corticotropin receptor-adenylate cyclase coupling. However, when either fetal zone or definitive zone cells were grown and passed in monolayer culture, corticotropin stimulation of cyclic adenosine monophosphate production dropped to only twofold. The loss of corticotropin stimulation of cyclic adenosine monophosphate production occurred with a loss of the steroid-metabolizing enzyme 17 alpha-hydroxylase (P-450(17 alpha]. Because P-450(17 alpha) expression can be stimulated after treatment of fetal adrenal gland cells with corticotropin or forskolin, we attempted to increase the ability of corticotropin to stimulate cyclic adenosine monophosphate production in a similar manner. After cells were pretreated with corticotropin (0.1 to 100 nmol/L) or forskolin (0.1 to 100 mumol/L) for 4 days, their ability to produce cyclic adenosine monophosphate in response to corticotropin was examined. Pretreatment with both corticotropin and forskolin caused a dose-dependent increase in the ability of corticotropin to stimulate the production of cyclic adenosine monophosphate. Cells stimulated with corticotropin after pretreatment with forskolin exhibited a 35- to 50-fold increase in cyclic adenosine monophosphate production compared with nontreated cells (approximately twofold). Corticotropin pretreatment increased responsiveness to a lesser extent than forskolin pretreatment. The increase in corticotropin responsiveness occurred along with an induction of P-450(17 alpha) enzyme levels. The effect of pretreatment with corticotropin and forskolin on the binding of iodine 125-labeled corticotropin to definitive zone cells was also investigated. Corticotropin pretreatment increased corticotropin receptor binding 2.8 times; forskolin pretreatment increased corticotropin binding by seven times.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Obstetrics and Gynecology, UT Southwestern Medical Center, Dallas 75235-9032.
authors.forename: W E
authors.initials: WE
authors.lastname: Rainey
authors.forename: J M
authors.initials: JM
authors.lastname: McAllister
authors.forename: E W
authors.initials: EW
authors.lastname: Byrd
authors.forename: J I
authors.initials: JI
authors.lastname: Mason
authors.forename: B R
authors.initials: BR
authors.lastname: Carr
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis*; D005333:Fetus; D006801:Humans; D018043:Receptors, Corticotropin; D011979:Receptors, Pituitary Hormone / Q000378:metabolism*; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism
chemical_list: D018043:Receptors, Corticotropin; D011979:Receptors, Pituitary Hormone; D005576:Colforsin; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D013254:Steroid 17-alpha-Hydroxylase