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Impact of Restriction of Placental and Fetal Growth on Expression of 11ß-Hydroxysteroid Dehydrogenase Type 1 and Type 2 Messenger Ribonucleic Acid in the Liver, Kidney, and Adrenal of the Sheep Fetus¹

Departments of Physiology and Obstetrics and Gynecology (J.S.R.), University of Adelaide, Adelaide, South Australia 5005, Australia

Address all correspondence and requests for reprints to: Dr. I. C. McMillen, Department of Physiology, Medical School Building, University of Adelaide, G.P.O. Box 498, North Terrace, Adelaide, South Australia 5005, Australia. E-mail: caroline.mcmillen{at}adelaide.edu.au

	Abstract

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We have investigated the effects of fetal growth restriction, induced by restriction of placental growth and function (PR), on 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD-1) and 11ßHSD-2 messenger RNA (mRNA) expression in fetal tissues in the sheep, using Northern blot analysis. Fetal liver, kidney, and adrenals were collected from normally grown fetuses at 90 days (n = 6), 125 days (n = 6), and 141–145 days (n = 7) and from PR fetuses at 141–145 days (n = 6). Expression of 11ßHSD-1 mRNA in the fetal liver increased significantly between 125 days (7.4 ± 0.8) and 141–145 days gestation (27 ± 5.3). There was also an approximately 2-fold increase in the ratio of 11ßHSD-1 mRNA/18S rRNA expression in the PR group (53.8 ± 7.9) compared with that in control animals at 141–145 days gestation. There was a significant decrease in 11ßHSD-2 mRNA in fetal adrenals between 125 days (41.6 ± 2.4) and 141–145 days (26.7 ± 1.1) gestation, but there was no effect of PR on the expression of adrenal 11ßHSD-2 mRNA. 11ßHSD-2 mRNA expression in the fetal kidney increased between 90 days (16.8 ± 1.7) and 141–145 days gestation (31.7 ± 4.3), but there was no effect of PR on the levels of 11ßHSD-2 mRNA in the fetal kidney. In summary, 11ßHSD-2 mRNA is differentially regulated in the fetal adrenal and kidney in the sheep fetus during late gestation. There is also a specific increase in the expression of 11ßHSD-1 mRNA in the liver of growth-restricted fetuses in late gestation. This suggests that there is increased hepatic exposure to cortisol in the growth-restricted fetus, which may be important in the reprogramming of hepatic physiology that occurs after growth restriction in utero.

	Introduction

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DURING THE PAST 10 yr, a worldwide series of epidemiological studies has shown that reduced birth weight is associated with an increase in hypertension, insulin resistance, noninsulin-dependent diabetes mellitus, and hyperlipidemia in adult life (1, 2). It has been proposed that overexposure of the fetus to excess glucocorticoids may be implicated in the association between fetal growth restriction and the programming of adult cardiovascular and metabolic diseases (3, 4). In the rat, the fetus is normally protected from the high levels of maternal corticosterone by the placental enzyme, 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD-2), a unidirectional NAD-dependent enzyme that catalyzes the conversion of the biologically active, corticosterone to the inert 11-dehydrocorticosterone (5). Treatment of pregnant rats with carbenoxolone, a potent inhibitor of 11ßHSD-2, throughout gestation reduces birth weight and predisposes the offspring to hypertension and hyperglycemia in adult life (6, 7). Similarly, treatment of pregnant rats with dexamethasone, which is a poor substrate for 11ßHSD-2, results in a lower mean birth weight, persistent elevations of arterial blood pressure, and fasting hyperglycemia in the adult offspring (8, 9). Although placental 11ßHSD-2 may act to limit fetal exposure to the actions of endogenous maternal glucocorticoids in the rat, its role in other species is more controversial (10, 11, 12). In the human and sheep during late gestation, the fetal hypothalamo-pituitary-adrenocortical axis responds to acute and chronic stress during late gestation, such that cortisol concentrations increase in the fetal circulation (13, 14, 15, 16). It has also been shown in these species, that there are two distinct isoforms of 11ßHSD present in fetal tissues during late gestation. In the sheep, 11ßHSD-2 messenger RNA (mRNA) is expressed in the fetal kidney where it acts as a dehydrogenase to convert cortisol to cortisone. In addition, the NADP(H)-dependent isoform, 11ßHSD-1, is expressed in the fetal liver, where it acts as a reductase to convert cortisone to cortisol (17, 18). It is therefore possible that in the sheep and human, the actions of cortisol in fetal target tissues such as the liver and kidney may be modulated by the levels of expression of 11ßHSD-1 and -2, respectively. Although it is clear that the tissue-specific pattern of expression of both isoforms of 11ßHSD may be developmentally regulated (17), there is no information on the impact of growth restriction in utero on the level of expression of 11ßHSD-1 or -2 in these key fetal tissues.

It is well established in the sheep fetus that there is an increase in adrenal growth and cortisol output during the last 2 weeks before delivery and that cortisol may act within the fetal adrenal to enhance growth and cellular maturation, and modulate expression of adrenal growth factors (18, 19, 20, 21, 22). Although 11ßHSD-2 mRNA is expressed in the adult sheep adrenal cortex (23), it is not known whether intraadrenal cortisol exposure in the fetus is modulated by changes in adrenal 11ßHSD-2 mRNA expression through late gestation. Furthermore, although we have reported previously that adrenal weight and circulating cortisol concentrations are increased in the growth-restricted sheep fetus (24), it is not known whether there are changes in adrenal 11ßHSD-2 mRNA expression, and hence intraadrenal exposure to cortisol, as a consequence of intrauterine growth restriction.

We have reported previously that restriction of placental growth and function from conception in the sheep is associated with chronic fetal hypoxemia, hypoglycemia, fetal growth restriction, and changes in hormonal profiles similar to those measured in cordocentesis studies in human fetuses that were growth restricted (15, 24). In the present study we investigated the effects of placental, and hence fetal, growth restriction on the expression of 11ßHSD-1 mRNA in the fetal liver and of 11ßHSD-2 mRNA in the fetal kidney and adrenal cortex. Our results demonstrate that there is a differential effect of increasing gestational age and placental restriction on the expression of 11ßHSD-1 and 11ßHSD-2 mRNA in these fetal tissues, which may be important in determining the level of exposure of the growth-restricted fetus to the potential programming actions of cortisol during late gestation.

	Materials and Methods

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Animals and surgery
All experiments in the study were carried out according to the guidelines of the standing committee of ethics and animal experimentation at the University of Adelaide (Adelaide, Australia). Pregnant Merino x Border Leicester ewes (n = 25) were used in these studies.

In six ewes, the majority of visible endometrial caruncles were removed under general anesthesia and aseptic conditions, as described previously, before mating (15). After surgical carunclectomy, the growth and functional development of the placenta are restricted (PR group) (15). In seven control ewes and six PR ewes, surgery was performed under general anesthesia between 110–115 days gestation to insert vascular catheters into the fetal and maternal carotid artery and jugular vein as described previously. Between 120–145 days gestation, fetal arterial blood samples (0·5 ml) were collected for measurement of fetal blood status using an ABL 520 acid/base analyzer (Radiometer, Copenhagen, Denmark).

Tissue collection
Ewes were killed with an iv overdose of sodium pentobarbitone (25 ml, 325 mg ml^-1, Lethobarb; Syntex, Castle Hill, Australia). The fetal sheep were anaesthetized by the maternal overdose of sodium pentobarbitone, then delivered via laparotomy, weighed, and killed by decapitation. Fetal liver, kidney, and adrenals were collected from 12 normally grown, noncatheterized fetuses at 90 days (n = 6) and 125 days (n = 6) gestation. The liver, kidney, and adrenals were also collected from six of the seven fetuses in the normally grown group and from all six fetuses in the PR group at 141–145 days gestation. Fetal tissues were quickly frozen in liquid nitrogen and stored at -80 C for RNA extraction and Northern blot analyses.

Northern blot analyses
Total RNA was extracted from fetal tissues from individual animals using Sigma TriReagent (TriReagent, Sigma-Aldrich Corp., Castle Hill, Australia) (20). Tissues (50–100 mg) were homogenized in ice-cold Tri-Reagent (1 ml) using a Polytron PT 3000 (Kinematica, Littall, Switzerland). The homogenate was incubated at room temperature for 5 min, and then 1-bromo-3-chloropropane (1:10 vol/vol) was added, and the samples were mixed thoroughly and incubated at room temperature for an additional 15 min. The samples were centrifuged at 12,000 x g for 15 min at 4 C, and the upper aqueous phase containing the RNA was collected. The RNA was precipitated by adding isopropanol (0.5 ml/ml TriReagent) and allowing the solution to stand at room temperature for 5 min before centrifuging at 12,000 x g (10 min at 4 C). The RNA pellet was washed with 75% ethanol, air-dried, and reconstituted in sterile water. The purity and yield of total RNA were quantitated by spectrophotometric measurement of the maximum absorbance of the samples at 260 and 280 nm. Northern blot analyses were performed as described previously (25). In brief, total RNA (20 µg) samples were subjected to gel electrophoresis. The RNA was transferred onto a Zeta-Probe nylon membrane (Bio-Rad Laboratories, Inc., Richmond, CA) by capillary blotting, and membranes were washed and then baked for 1 h at 80 C. Antisense oligonucleotide probes complementary to the coding nucleotides 97–137 of ovine 11ßHSD-1, 1066–1110 of ovine 11ßHSD-2, and 151–180 of rat 18S ribosomal RNA (rRNA) were end labeled using T4 polynucleotide kinase (Pharmacia, North Ryde, Australia) and [-³²P]ATP (4000 Ci/mmol; Geneworks, Adelaide, Australia). Membranes were hybridized sequentially with oligonucleotide probes to 11ßHSD-1, 11ßHSD-2, and 18S. After hybridization, the membranes were exposed to phosphorimager plates (Fuji-MacBAS MP2040, Fuji Photo Film Co. Ltd., Tokyo, Japan). The autoradiographs were visualized using a Fuji-BAS 1000 phosphorimager, and the signals were quantitated using Fuji-MacBAS software (V2.21), with the 11ßHSD signal being expressed as a ratio to the 18S rRNA.

Statistics
All data are presented as the mean ± SEM. Mean gestational arterial PO₂ values were calculated for each catheterized fetus in the PR and control groups. Mean fetal body weight and arterial PO₂ were compared between PR and age-matched control animals using unpaired Student’s t test. The ratio of 11ßHSD mRNA to 18S rRNA was multiplied by 10³ and compared across age and treatment groups using one-way ANOVA. P < 0.05 was considered significant.

	Results

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Fetal outcomes
Restriction of placental growth and function resulted in a reduction (P < 0.001) in fetal arterial PO₂ (PR, 14.7 ± 1.8 mm Hg; control, 22.5 ± 0.9 mm Hg) and fetal body weight (PR, 3.02 ± 0.46 kg; control, 5.07 ± 0.19 kg) at 141–145 days gestation.

Expression of 11ßHSD-1 in fetal liver
In fetal liver, 11ßHSD-1 mRNA was detectable by Northern blot analysis at the expected size of 1.8 kb. In normally grown fetal sheep, there was no change in the relative expression of 11ßHSD-1 mRNA/18S rRNA ratio in the fetal liver between 90 and 125 days gestation, but the liver 11ßHSD-1 mRNA/18S rRNA ratio increased between 125 days (7.4 ± 0.8) and 141–145 days (27.2 ± 5.3) gestation (Fig. 1). There was an approximately 2-fold (P < 0.05) increase in the ratio of 11ßHSD-1 mRNA/18S rRNA expression in the PR group (53.8 ± 7.9) compared with that in the age-matched control animals at 141–145 days gestation (Fig. 1). 11ßHSD-2 mRNA was not detected in total RNA extracted from the fetal liver.

View larger version (28K): [in this window] [in a new window]   Figure 1. Top panel, Northern blot analysis of total RNA extracted from samples of individual livers collected from normally grown fetal sheep at 90, 125, and 141–145 days gestation and from PR fetal sheep at 141–145 days gestation probed with oligonucleotide probes for 11ß HSD-1 and 18S rRNA. Bottom panel, The mean (±SEM) expression of 11ßHSD-1 mRNA/18S rRNA in the liver of normally grown fetal sheep at 90, 125, and 141–145 days gestation and in PR fetal sheep. Different superscripts indicate significant differences (P < 0.05) between mean values.

View larger version (38K): [in this window] [in a new window]   Figure 2. Top panel, Northern blot analysis of total RNA from samples of individual kidneys collected from normally grown fetal sheep at 90, 125, and 141–145 days and from PR fetal sheep at 141–145 days probed with oligonucleotide probes for 11ßHSD-2 and 18S rRNA. Bottom panel, The mean (±SEM) expression of 11ßHSD-2 mRNA/18S rRNA in the kidney of normally grown fetal sheep at 90, 125, and 141–145 days gestation and in PR fetal sheep. Different superscripts indicate significant differences (P < 0.05) between mean values.

View larger version (42K): [in this window] [in a new window]   Figure 3. Top panel, Northern blot analysis of total RNA from samples from individual adrenals collected from normally grown fetal sheep at 90, 125, and 141–145 days and from PR fetal sheep at 141–145 days probed with oligonucleotide probes for 11ßHSD-2 and 18S rRNA. Bottom panel, The mean (±SEM) expression of 11ßHSD-2 mRNA/18S rRNA ratio in the adrenal of normally grown fetal sheep at 90, 125, and 141–145 days gestation and in PR fetal sheep. Different superscripts indicate significant differences (P < 0.05) between mean values.

	Discussion

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Our finding of an increase in 11ßHSD-1 mRNA expression in the fetal liver in late gestation confirms the findings of Yang and co-workers (17), who reported a 4-fold increase in 11ßHSD-1 mRNA expression in the fetal liver at term, which was associated with a concomitant increase in 11ßHSD enzyme activity. These workers also found that the reductase activity of 11ßHSD-1, the capacity of the fetal liver to convert cortisone to cortisol, always exceeded the dehydrogenase activity in the fetal liver, suggesting that intrahepatic production of cortisol also increases before delivery. In the present study we found a further 2-fold increase in hepatic 11ßHSD-1 mRNA expression in growth-restricted compared with normally grown fetal sheep after 140 days gestation. Given the previously established relationship between 11ßHSD-1 mRNA expression and isoenzyme activity, it therefore appears likely that there is an increase in 11ßHSD-1 reductase activity in the liver of growth-restricted fetal sheep. Previously, it has been shown that dexamethasone administration stimulates an increase in 11ßHSD-1 mRNA expression and enzyme activity in the immature fetal sheep liver (26). One possibility, therefore, is that hepatic 11ßHSD-1 mRNA expression is stimulated by the increase in fetal cortisol concentrations that occurs in normally grown fetal sheep and to a greater extent in growth-restricted fetal sheep in the week before delivery (24). It has also been demonstrated that there is a progressive increase in glycogen deposition and gluconeogenesis in the fetal sheep liver and that circulating cortisol concentrations correlate positively with the activity of the hepatic gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK) in late gestation (27). Furthermore, the induction of gluconeogenic enzyme expression is reduced in mice with a targeted disruption of the 11ßHSD-1 gene (28). Thus, the increase in intrahepatic 11ßHSD-1 expression in the sheep fetus in late gestation may play a role in glucocorticoid-mediated increases in glycogen deposition and gluconeogenesis in the liver that occur immediately before birth.

We demonstrated that there is a greater increase in the expression of 11ßHSD-1 mRNA in the liver of the growth-restricted fetus in late gestation, which suggests that there may be greater intrahepatic exposure to the actions of glucocorticoids in the growth-restricted fetus compared with that in normally grown animals at the same gestational age. In the growth-restricted fetus, intrahepatic exposure to excess glucocorticoids may be important in the context of epidemiological evidence that has demonstrated an association between growth restriction in utero and noninsulin-dependent diabetes (2, 29). Treatment of pregnant rats with dexamethasone in late pregnancy resulted in an increased hepatic expression of glucocorticoid receptor and PEPCK mRNAs, an associated increase in hepatic PEPCK activity, and fasting hyperglycemia in the adult offspring (9). As PEPCK is the rate-limiting enzyme of gluconeogenesis, it was postulated that the increased hepatic PEPCK expression resulted in increased hepatic glucose production and impaired glucose tolerance (9). It should be noted, however, that in these studies, dexamethasone treatment of the pregnant rat did not alter hepatic 11ßHSD-1 mRNA expression in the newborn or adult offspring. Thus, although the mechanisms by which excess glucocorticoids act on the immature liver may differ depending on the nature of the glucocorticoid (synthetic vs. endogenous) and species (rat vs. sheep or human), the outcomes in later life, including a persistent increase in hepatic gluconeogenic enzyme expression and glucose production, may be similar.

The finding of an increase in 11ßHSD-2 mRNA expression in the kidney between 90–140 days gestation is consistent with earlier studies that also measured an increase in 11ßHSD-2 mRNA and dehydrogenase activity in the fetal kidney after 140 days gestation (17). This increase in kidney 11ßHSD-2 expression and activity occurs in parallel with the prepartum increase in fetal cortisol concentrations, and it is possible that the increased dehydrogenase activity protects the renal mineralocorticoid receptors from occupancy by the high cortisol concentrations. It is interesting that 11ßHSD-2 mRNA expression was not altered in the kidneys of the chronically hypoxemic, growth-restricted fetal sheep. This is in contrast to the suppression of kidney 11ßHSD-2 expression that occurs in fetuses in which chronic hypoxemia was induced by repeated placental embolization (30). The difference in findings between these two studies may be related to the different effects of intermittent vs. sustained changes in fetal oxygenation on renal blood flow and adrenocortical function.

Although 11ßHSD-2 mRNA expression increased in the fetal kidney, there was a concomitant decrease in 11ßHSD-2 mRNA expression in the fetal adrenal in the week before delivery. In the adult sheep, 11ßHSD-2 mRNA is localized exclusively to the adrenal cortex and is expressed highly in the zona fasiculata and reticularis, with relatively low expression in the zona glomerulosa (23). It is interesting that in the mouse, there is also a developmental regulation of adrenal 11ßHSD-2 mRNA expression. Using in situ hybridization, Brown and co-workers (31) demonstrated that 11ßHSD-2 mRNA was expressed up until embryonic day 14.5 and was undetectable for the remainder of gestation. Previous studies have also shown that there is a high level of 11ßHSD-2 activity in the human fetal adrenal at midgestation, and in contrast, there is no detectable 11ßHSD-2 activity in the postnatal or adult human adrenal (32, 33, 34).

It may be that in the sheep fetus, adrenal 11ßHSD-2 acts to protect the adrenocortical cells from the high levels of locally produced glucocorticoids up until 125 days gestation, but that the increases in adrenocortical growth and steroid output that occur after this stage of gestation require intraadrenal exposure to glucocorticoids. Administration of cortisol to hypophysectomized fetal sheep results in an increase in adrenocortical cytodifferentiation (21), and cortisol replacement in fetal sheep after disconnection of the fetal hypothalamo-pituitary axis restores adrenal weight to values similar to those measured in intact fetuses (20). Further functional studies are required to determine the role of 11ßHSD-2 in the fetal adrenal throughout late gestation and to determine whether there is a positive feedback mechanism within the fetal adrenal whereby an increase in adrenal cortisol production would lead to a decrease in 11ßHSD-2 mRNA expression and a further enhancement of the actions of cortisol to promote adrenocortical growth and cytodifferentiation. It was interesting that there was no further change in adrenal 11ßHSD-2 mRNA expression in the growth-restricted fetal sheep. This suggests that the increase in adrenal growth and circulating cortisol that occurs in the growth-restricted fetus is not dependent on a further fall in 11ßHSD-2 expression in adrenocortical cells during late gestation.

In summary, we found a significant increase in hepatic 11ßHSD-1 mRNA expression in growth-restricted compared with normally grown fetal sheep after 140 days gestation. This suggests that there is increased hepatic exposure to cortisol in the growth-restricted fetus during late gestation. This is important in the context of the epidemiological and experimental evidence that indicates that reprogramming of hepatic physiology occurs after growth restriction in utero or after exposure of the developing fetus to excess glucocorticoids (7, 9, 35). We found an increase in 11ßHSD-2 mRNA expression in the fetal kidney and a decrease in 11ßHSD-2 mRNA expression in the fetal adrenal, respectively, during late gestation. This indicates that tissue-specific factors are important in determining the degree of exposure to glucocorticoids during the period of development that is critical in ensuring a successful transition from intrauterine to extrauterine life. We also demonstrated that there was no additional impact of placental and fetal growth restriction on 11ßHSD-2 mRNA expression in the fetal kidney and adrenal, which suggests that the physiological changes that occur in these tissues in response to growth restriction are not dependent on further changes in the expression of 11ßHSD-2 mRNA .

	Acknowledgments

 
We acknowledge the expert research assistance of Anne Jurisevic and Simon Fielke in the care and maintenance of the chronically catheterized sheep preparations. We are also grateful to Mark Salkeld for his help with the preparation of the figures.

	Footnotes

 
¹ Presented in part, at the 42nd Annual Scientific Meeting of The Endocrine Society of Australia, Melbourne, Australia, 1999. This work was supported by the National Heart Foundation of Australia and the National Health and Medical Research Council.

Received August 27, 1999.

	References

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				C. Bertram, A. R. Trowern, N. Copin, A. A. Jackson, and C. B. Whorwood The Maternal Diet during Pregnancy Programs Altered Expression of the Glucocorticoid Receptor and Type 2 11{beta}-Hydroxysteroid Dehydrogenase: Potential Molecular Mechanisms Underlying the Programming of Hypertension in Utero Endocrinology, July 1, 2001; 142(7): 2841 - 2853. [Abstract] [Full Text] [PDF]

				C. B. Whorwood, K. M. Firth, H. Budge, and M. E. Symonds Maternal Undernutrition during Early to Midgestation Programs Tissue-Specific Alterations in the Expression of the Glucocorticoid Receptor, 11{beta}-Hydroxysteroid Dehydrogenase Isoforms, and Type 1 Angiotensin II Receptor in Neonatal Sheep Endocrinology, July 1, 2001; 142(7): 2854 - 2864. [Abstract] [Full Text] [PDF]

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