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Department of Physiology, Eastern Virginia Medical School, Norfolk, Virginia 23501 (M.G.L., M.G.B., G.J.P.); Departments of Obstetrics/Gynecology/ Reproductive Studies and Physiology (G.W.A., E.D.A.), Center for Studies in Reproduction, The University of Maryland School of Medicine, Baltimore, Maryland 21201
Address all correspondence and requests for reprints to: Gerald J. Pepe, Ph.D., Department of Physiology, Eastern Virginia Medical School, P.O. Box 1980, Norfolk, Virginia 23501-1980. E-mail: gjp{at}borg.evms.edu
Throughout the majority of intrauterine development, the primate fetal
adrenal gland is comprised primarily of fetal zone cells and only late
in gestation do definitive zone cells, which express the enzyme
5-3ß-hydroxysteroid dehydrogenase/isomerase (3ß-HSD)
emerge to produce cortisol. The present study was designed to determine
whether the induction of definitive zone ACTH receptor messenger RNA
(mRNA) levels and components of the steroidogenic pathway known to be
expressed specifically in the definitive zone, e.g. the
3ß-HSD enzyme, are dependent upon fetal pituitary ACTH. Fetal
pituitaries and adrenal glands were obtained on day 165 (term =
day 184) from untreated controls (n = 7) and from baboons in which
betamethasone was administered im to the fetus (0.6 mg/100 µl; n
= 4) or to the fetus (0.6 mg) and mother (6 mg/ml; n = 4) every
other day between days 150 and 164 of gestation. Although fetal
pituitary weight was not altered by betamethasone, POMC mRNA levels
determined by in situ hybridization were lower
(P < 0.05) in betamethasone-treated (0.34 ±
0.07 arbitrary densitometric units) than in untreated controls
(0.63 ± 0.04). Associated with this decline in pituitary POMC,
levels of the major 3.4-kb mRNA transcript for the ACTH receptor
expressed as a ratio of ß-actin were approximately 80% lower
(P < 0.05) in fetal adrenals of
betamethasone-treated baboons (0.12 ± 0.02) than in untreated
controls (0.84 ± 0.05). In situ hybridization
indicated that ACTH receptor mRNA expression in the definitive zone
exceeded that in the fetal zone and was reduced by betamethasone.
Associated with the decrease in ACTH receptor expression, fetal adrenal
weight was suppressed (P < 0.05) by 50% and
reflected a marked reduction (P < 0.05) in the
size of the cells of the definitive and fetal zones. Betamethasone
treatment also induced a decrease (P < 0.05) in
the width (µm) of the definitive zone (183 ± 14
vs. 128 ± 7; determined by immunohistochemical
expression of 3ß-HSD), as well as the levels of the mRNA and protein
for 3ß-HSD. Levels of the mRNA for the LDL-receptor and the enzymes
17
-hydroxylase-C17,20 lyase and P450 cholesterol side
chain cleavage were also suppressed in adrenals of
betamethasone-treated baboons. These findings indicate that treatment
of the baboon fetus with betamethasone in late gestation suppressed
fetal pituitary POMC mRNA expression and ACTH receptor mRNA levels in
the fetal adrenal gland, as well as the hypertrophy and ACTH receptor
mRNA and 3ß-HSD mRNA/protein levels in the cells comprising the newly
emerging definitive zone. We conclude that ACTH is necessary for the
up-regulation of the mRNAs for the ACTH receptor and steroidogenic
enzymes in the definitive zone of the primate fetal adrenal gland in
late gestation.
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