Fetal Corticosteroid-binding Globulin Research Articles

Developmental regulation of corticosteroid-binding globulin biosynthesis in the baboon fetus.

The present study determined the roles of estrogen and cortisol in maternal and fetal corticosteroid-binding globulin (CBG) levels and fetal hepatic messenger RNA (mRNA) expression in the baboon. Samples of fetal liver, kidney, and brain were obtained from untreated control animals at early (day 60; n = 4), mid (day 100; n = 8), and late (day 165; n = 5) gestation (term = day 184). Maternal and umbilical blood samples were collected on day 100 from baboons in which betamethasone was administered sc to the mother (n = 6) on days 60-99 of gestation and on day 165 from animals (n = 4) in which the fetus was administered betamethasone on days 150-164 of gestation. Maternal serum cortisol concentrations were similar at mid (43 +/- 2 micrograms/dl) and late (42 +/- 3 micrograms/dl) gestation and decreased (P < 0.05) at midgestation (1 +/- 1 micrograms/dl) and term (31 +/- 4 micrograms/dl) after betamethasone treatment. Umbilical serum cortisol levels were also reduced (P < 0.05) at both mid (1 +/- 1 micrograms/dl) and late (14 +/- 5 micrograms/dl) gestation by betamethasone treatment. Fetal serum CBG levels in untreated animals were lower (P < 0.05) on day 165 (444 +/- 29 pmol/ml) than on day 100 (844 +/- 35 pmol/ml) and increased (P < 0.05) at midgestation (1098 +/- 64 pmol/ml), but not at term (551 +/- 24 pmol/ml), after betamethasone treatment. In contrast, maternal serum CBG levels (range, 528-770 pmol/ml) were not altered by gestational age or betamethasone. The human CBG complementary DNA hybridized to a single mRNA species of 1.8 kilobases in baboon fetal liver; however, CBG was not expressed in fetal kidney and was detectable in fetal brain and pancreas only by reverse transcription-PCR. In untreated baboon fetuses, the mRNA levels of hepatic CBG, expressed as a ratio of 18S RNA, progressively decreased (P < 0.05) in early (1.83 +/- 0.17), mid (0.97 +/- 0.12), and late (0.51 +/- 0.04) gestation. These results demonstrate that fetal hepatic CBG mRNA expression and serum CBG concentrations were elevated early in baboon gestation and exhibited a progressive decline during the course of advancing pregnancy. We suggest that the increased levels of fetal CBG in the early stages of gestation reflect stimulation of hepatic CBG synthesis by maternal cortisol, which we previously demonstrated to occur in the fetus as a result of preferential 11 beta-hydroxysteroid dehydrogenase-catalyzed glucocorticoid reduction across the placenta. The decline in fetal CBG may reflect the developmental increase in catabolism of cortisol to bioinactive cortisone in target tissues of the fetus such as the liver.

Ontogeny of Corticosteroid-Binding Globulin Biosynthesis in the Rat*

In plasma, glucocorticoids are transported by corticosteroid-binding globulin (CBG), which is synthesized primarily in the liver. Plasma levels of maternal and fetal CBG fluctuate during gestation, and this may be due to changes in the biosynthesis and/or clearance of the protein. We have, therefore, studied the ontogeny of CBG biosynthesis in the rat by using a solution hybridization assay to measure hepatic CBG mRNA levels. The results indicate that the concentration of CBG mRNA is exceptionally high in 15-day-old fetal livers (55.1 pg CBG mRNA/micrograms total RNA), but declines to very low levels at birth (day 21). During the same period, CBG mRNA levels in maternal livers remained relatively constant (18.9-23.1 pg CBG mRNA/micrograms total RNA). Hepatic CBG mRNA levels were barely detectable 1 week after birth, and a sex difference was apparent by 2 weeks of age, with higher levels in female livers. Although adult CBG mRNA levels were attained by 3 weeks of age, serum CBG concentrations did not reach adult values for an additional 3 weeks. To determine whether age-related differences in the clearance of CBG are responsible for this, CBG from infant or adult animals was radiolabeled and administered iv to infant and adult rats. When this was done, the half-life of CBG in infants (approximately 6.9 h) was consistently less than that in adults (approximately 14.5 h) regardless of the source of the labeled CBG, and we conclude that variations in CBG biosynthesis and clearance may influence glucocorticoid action during fetal and postnatal development.

Effect of adrenalectomy at different pregnancy stages on maternal and fetal serum corticosteroid binding globulin and corticosterone in the rat

The response of pregnant rat corticosteroid binding globulin to maternal adrenalectomy was studied as a function of the stage of pregnancy. Non-pregnant or pregnant rats were deprived of their adrenal glands during 4 days. In non-pregnant animals, adrenalectomy led to undetectable corticosterone levels and to the doubling of corticosteroid binding globulin. In pregnant rats adrenalectomized at 12 days and studied at 16 days, the serum corticosterone was likewise undetectable and the corticosteroid binding globulin was doubled as compared with pregnant rats of the corresponding age. In contrast, adrenalectomy from day 14 to 18 or from day 16 to 20 did not deplete the maternal serum corticosterone and the corticosteroid binding globulin remained unchanged. Under these conditions neither fetal corticosteroid binding globulin nor fetal corticosterone were modified. However, when the pregnant rats adrenalectomized from day 16 to 20 also received an injection of 30 mg of metyrapone on days 19 and 20 in order to inhibit fetal adrenal secretion, the maternal response was again a depletion of serum corticosterone together with an increase in corticosteroid binding globulin. Under these conditions, the fetus also reacted by a fall of corticosterone and a rise of corticosteroid binding globulin. Our results suggest that the maternal response of corticosteroid binding globulin to adrenalectomy depends on the pregnancy stage inasmuch as it may be influenced by a supply of corticosterone from the fetus during late pregnancy. Moreover, they show that in this late period, fetal corticosteroid binding globulin is regulated independently.

Ontogeny and regulation of corticosteroid binding globulin capacity in plasma of fetal and newborn lambs.

The developmental pattern for plasma corticosteroid binding globulin (CBG) and unbound corticoids was studied in fetal and newborn sheep. CBG capacity in the fetus increased progressively from a value of 1.6 micrograms cortisol bound/dl plasma at 75 days gestation to 7.1 micrograms/dl at 141 days (n = 249), with a greater rate of increase after 120 days. By contrast total plasma proteins increased by about 50% during the third trimester. There was an accelerated increase in the concentration of both CBG and total proteins with labor, apparently reflecting hemoconcentration. The rate of increase in total plasma corticoids was similar to that for CBG capacity; however, corticoids began their major rise later in gestation (approximately 130 days). The concentration of unbound corticoids was 0.09 micrograms/dl at 115 days and did not increase until after 135 days, reaching a maximal level of 1.87 micrograms/dl on the day before spontaneous term delivery. After birth, CBG capacity decreased from a prepartum value of 11.4 micrograms/dl to 0.6 micrograms/dl at 14 days of age, whereas total plasma proteins were constant. Total and free corticoid levels also decreased postnatally, but at a slower rate than for CBG. The expected rise in fetal CBG capacity during the third trimester did not occur in hydranencephalic, stalk-sectioned, and hypophysectomized fetuses with loss of pituitary function. Under the conditions used, there was no precocious increase in CBG concentrations with infusion of hydrocortisone, PRL, or 17 beta-estradiol to intact fetuses, and infusion of ACTH to a hypophysectomized fetus did not affect the level of CBG. Thus, there is a marked increase in CBG capacity prenatally and a rapid decrease after birth. These changes in CBG may be responsible, at least in part, for the similar changes in total corticoid concentrations. We conclude that pituitary hormone(s) regulate CBG in the sheep fetus and speculate that this effect involves the placenta.