Glucocorticoid exposure and tissue gene expression of 11β HSD-1, 11β HSD-2, and glucocorticoid receptor in a porcine model of differential fetal growth

Glucocorticoids play a critical role in fetal development, but inappropriate exposure is associated with reduced fetal growth. We investigated cortisol exposure and supply in a porcine model of differential fetal growth. This model compares the smallest fetus of a litter with an average-sized sibling at three stages of gestation. At day 45, small fetuses had reduced plasma cortisol (16.8 ± 3.4 ng/ml) relative to average fetuses (34.4 ± 3.4 ng/ml, P < 0.001). At day 65 levels had reduced in small and average fetuses to similar concentrations (5.7 ± 1.0 vs 4.8 ± 0.5 ng/ml, P = 0.128). By day 100, elevated levels were found in small fetuses (10.7 ± 1.5 vs 7.6 ± 0.7 ng/ml, P < 0.001). Maternal plasma cortisol was unchanged over gestation (day 45, 56.7 ± 21.6 ng/ml; day 65, 57.8 ± 14.4 ng/ml; day 100, 55.7 ± 6.5 ng/ml). We examined the cause of altered cortisol by investigating the fetal hypothalamic–pituitary–adrenal axis through the measurement of adrenocorticotropic hormone and assessing exposure to maternal cortisol by quantifying placental 11β-hydroxysteroid dehydrogenase-isoform 2 (11β HSD-2) gene expression. These data suggest that altered cortisol supply was of fetal origin. We examined organ glucocorticoid (GC) metabolism by the measurement of GC receptor (GR) and 11β-hydroxysteroid dehydrogenase-isoform 1 (11β HSD-1) gene expression. We found that fetal organs have different temporal patterns of 11β HSD-1 and GR expression, with the liver particularly sensitive to cortisol in late gestation. This study examines GC exposure in naturally occurring differential growth and simultaneously explores tissue GC sensitivity and handling, at three key stages of gestation.

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Cytokines and cytokine receptors in fetal growth and development

Biochemical Society Transactions ◽

10.1042/bst0290033 ◽

2001 ◽

Vol 29 (2) ◽

pp. 33-37 ◽

Cited By ~ 10

Author(s):

M. E. Symonds ◽

A. Mostyn ◽

T. Stephenson

Keyword(s):

Fetal Growth ◽

Fetal Development ◽

Early Stage ◽

Critical Role ◽

Late Gestation ◽

Cytokine Receptors ◽

Prolactin Receptors ◽

Factor I ◽

Specific Effects ◽

Pathological Conditions

The cytokine receptors for growth hormone (GH), prolactin and leptin have a critical role in regulating embryo, placental and/or fetal development, which is dependent on stage of gestation and species. GH and prolactin receptors are detectable from conception, and alterations in the maternal hormonal environment may impact on placental growth from this early stage of gestation. Leptin is critical for conception, but its role in fetal growth remains elusive. During late gestation, when fetal growth accelerates and organ maturation occurs, prolactin and insulin-like growth factor-I may have interactive roles in regulating the growth of specific tissues, including adipose tissue. Prolactin, leptin and GH all have specific effects on fetal and neonatal energy balance, which are mediated in part through promoting lipolysis and/or enhancing the expression of uncoupling proteins. An increased understanding of these interactions is likely to have important implications for a number of potentially pathological conditions, including infection, obesity and hypertension.

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Endocrine regulation of fetal growth

Reproduction Fertility and Development ◽

10.1071/rd9950351 ◽

1995 ◽

Vol 7 (3) ◽

pp. 351 ◽

Cited By ~ 163

Author(s):

AL Fowden

Keyword(s):

Gene Expression ◽

Growth Factors ◽

Fetal Growth ◽

Growth Regulation ◽

Fetal Liver ◽

In Utero ◽

Tissue Differentiation ◽

Late Gestation ◽

Endocrine Regulation ◽

Tissue Accretion

Hormones have an important role in the control of fetal growth. They act on both tissue accretion and differentiation and enable a precise and orderly pattern of growth to occur during late gestation. In part, their actions on growth may be mediated by other growth factors such as the insulin-like growth factors (IGFs). Insulin stimulates fetal growth by increasing the mitotic drive and nutrient availability for tissue accretion. It has little effect on tissue differentiation. In contrast, the main effects of cortisol in utero are on tissue differentiation and maturation. Cortisol appears to act directly on the cells to alter gene transcription or post-translational processing of the gene products. Cortisol may also initiate the transition from the fetal to the adult modes of growth regulation by inducing the switch from IGF-II to IGF-I gene expression in the fetal liver. Thyroxine affects both tissue accretion and differentiation in the fetus by a combination of metabolic and non-metabolic mechanisms. Pituitary growth hormone, on the other hand, appears to have little part in the control of fetal growth, unlike its role postnatally. Fetal hormones, therefore, promote growth and development in utero by altering both the metabolism and gene expression of the fetal tissues. These hormonal actions ensure that fetal growth rate is commensurate with the nutrient supply and that prepartum maturation occurs in preparation for extrauterine life.

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Does the ovine placenta secrete ACTH under normoxic or hypoxic conditions?

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1991.260.2.r389 ◽

1991 ◽

Vol 260 (2) ◽

pp. R389-R395 ◽

Cited By ~ 2

Author(s):

M. Keller-Wood ◽

C. E. Wood

Keyword(s):

Plasma Cortisol ◽

Adrenocorticotropic Hormone ◽

Late Pregnancy ◽

Maternal Plasma ◽

Late Gestation ◽

Fetal Circulation ◽

Fetal Plasma ◽

Hypoxic Conditions ◽

Ovine Placenta ◽

Arterial Po2

In the sheep, maternal plasma cortisol is increased in late pregnancy, and fetal plasma cortisol and adrenocorticotropic hormone (ACTH) rise precipitously in late gestation. In many species, the placenta contains ACTH. These experiments were designed to test whether the ovine placenta contains ACTH and whether there is net secretion of ACTH by the uteroplacental unit into either the maternal or fetal circulation. Pregnant ewes and their fetuses were prepared with maternal and fetal arterial and uterine and umbilical venous catheters. Arterial and venous samples were taken from both sides of the placenta before and during hypoxia induced by the ewe breathing 9-11% O2, and arteriovenous (a-v) differences in ACTH, PO2, PCO2, and progesterone were analyzed. A positive a-v difference in PO2 (48.2 +/- 3.4 mmHg) and negative a-v differences in PCO2 and progesterone (-3.5 +/- 0.7 mmHg and -25 +/- 5 ng/ml, respectively) were found across the placenta in the ewe, and a positive a-v difference in PCO2 (4.8 +/- 0.9 mmHg) and negative a-v differences in PO2 and progesterone (-8.1 +/- 1.5 mmHg and -13 +/- 3 ng/ml, respectively) were found across the placenta in the fetus, indicating that the umbilical and uterine venous catheters were properly placed. Hypoxia decreased fetal and maternal arterial PO2 from 22.8 +/- 1.3 to 13.8 +/- 0.7 and from 98.8 +/- 3.3 to 37.0 +/- 2.6 mmHg, respectively, and increased fetal and maternal arterial ACTH immunoreactivity from 95 +/- 60 to 2,676 +/- 795 and from 149 +/- 21 to 275 +/- 88 pg/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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Thyroid hormones and the mRNA of the GH receptor and IGFs in skeletal muscle of fetal sheep

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00284.2001 ◽

2002 ◽

Vol 282 (1) ◽

pp. E80-E86 ◽

Cited By ~ 16

Author(s):

A. J. Forhead ◽

J. Li ◽

R. S. Gilmour ◽

M. J. Dauncey ◽

A. L. Fowden

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Thyroid Hormones ◽

Gestational Age ◽

Plasma Cortisol ◽

Mrna Abundance ◽

Late Gestation ◽

Fetal Sheep ◽

Igf I ◽

I Gene

Thyroid hormones are required for the normal development of skeletal muscle in utero, although their mechanism of action is poorly understood. The present study examined the effects of the thyroid hormones on the gene expression of the growth hormone receptor (GHR) and the insulin-like growth factors (IGFs) IGF-I and IGF-II, in skeletal muscle of fetal sheep during late gestation (term 145 ± 2 days) and after manipulation of plasma thyroid hormone concentration. Thyroidectomy at 105–110 days of gestation suppressed muscle GHR and IGF-I gene expression in fetuses studied at 127–130 and 142–145 days. Muscle GHR mRNA abundance remained unchanged with increasing gestational age in intact and thyroidectomized fetuses. In the intact fetuses, a decrease in muscle IGF-I gene expression was observed between 127–130 and 142–145 days, which coincided with the normal prepartum surges in plasma cortisol and triiodothyronine (T3). At 127–130 days, downregulation of muscle IGF-I mRNA abundance was induced prematurely in intact fetuses by an infusion of cortisol for 5 days (2–3 mg · kg−1 · day−1 iv), which increased plasma cortisol and T3 concentrations to values seen near term. However, increasing plasma T3 alone by an infusion of T3 for 5 days (8–12 μg · kg−1 · day−1 iv) in intact fetuses at this age had no effect on GHR or IGF-I gene expression in skeletal muscle. In the thyroidectomized fetuses, no additional change in the low level of muscle IGF-I mRNA abundance was seen with increasing gestational age, but at 127–130 days, IGF-I gene expression was reduced further when plasma cortisol and T3 concentrations were increased by exogenous cortisol infusion. Muscle IGF-II mRNA abundance was not affected by thyroidectomy, gestational age, or exogenous hormone infusion. These findings show, in the sheep fetus, that thyroid hormones may influence the growth and development of skeletal muscle via changes in the local activity of the somatotrophic axis.

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Developmental regulation of preproenkephalin (PENK) gene expression in the adrenal gland of the ovine fetus and newborn lamb: effects of hypoxemia and exogenous cortisol infusion

Journal of Endocrinology ◽

10.1677/joe.0.1550143 ◽

1997 ◽

Vol 155 (1) ◽

pp. 143-149 ◽

Cited By ~ 7

Author(s):

M Fraser ◽

SG Matthews ◽

G Braems ◽

T Jeffray ◽

Keyword(s):

Gene Expression ◽

Adrenal Gland ◽

Plasma Cortisol ◽

Late Gestation ◽

Mrna Levels ◽

Fetal Sheep ◽

Adult Sheep ◽

Organ Systems ◽

Response To Stress ◽

In Pregnancy

Development of the fetal adrenal gland is crucial not only for maturation of several fetal organ systems and the initiation of parturition, but also for the development of the fetal response to stress. The enkephalin-related peptides are present in the chromaffin cells of the fetal adrenal medulla and are secreted in response to stress and with sympathetic stimulation. However, changes in expression of preproenkephalin (PENK) with gestation and in response to stress have not been studied in detail. Therefore we examined the developmental pattern of PENK gene expression in the adrenal gland of fetal and newborn lambs, and of adult sheep. We also determined whether levels of PENK mRNA in the fetal adrenal gland changed in response to exogenous glucocorticoids in late gestation, or in response to hypoxemia. Adrenal glands were removed from fetal sheep, lambs and adult sheep at different stages of development for measurement of PENK mRNA. Cortisol was infused (5 micrograms/min) for 12, 24 or 96 h beginning on day 124-129 of gestation. Moderate hypoxemia was induced for 48 h beginning on day 126-130, or at day 134-136 of gestation, by lowering the maternal fractional inspired oxygen. At the end of the treatment periods, the ewes and fetuses were euthanized. Adrenal PENK mRNA were measured by Northern blot analysis. PENK mRNA levels in fetal adrenals were significantly higher (P < 0.05) on days 140-141 of gestation than earlier in pregnancy, and then decreased significantly with the onset of parturition (days 142-146). After cortisol infusion to the fetus for 96 h there was a significant reduction in adrenal PENK mRNA levels. Hypoxemia resulted in a significant increase in PENK mRNA levels in fetuses at day 126-130 of gestation, but not at the later time in pregnancy when endogenous plasma cortisol concentrations were higher. We conclude that there is a decrease in levels of PENK mRNA in the fetal adrenal gland before parturition at the time of the endogenous prepartum rise in plasma cortisol. Hypoxemia led to an elevation of PENK mRNA levels in fetuses at less than 130 days, but after that time, when the basal and stimulated cortisol responses had risen, there was no significant effect of hypoxemia on PENK mRNA. Cortisol infusion to the fetus at this stage of pregnancy resulted in a decrease in adrenal PENK mRNA levels. We suggest that cortisol may play an important role in the regulation of fetal adrenal PENK mRNA levels and enkephalin synthesis by the adrenal gland of the fetal sheep.

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Prepartum adrenocortical maturation in the fetal foal: responses to ACTH1–24

Journal of Endocrinology ◽

10.1677/joe.0.1420417 ◽

1994 ◽

Vol 142 (3) ◽

pp. 417-425 ◽

Cited By ~ 64

Author(s):

M Silver ◽

A L Fowden

Keyword(s):

Amniotic Fluid ◽

Plasma Cortisol ◽

Critical Period ◽

Maternal Plasma ◽

Significant Rise ◽

Late Gestation ◽

Plasma Acth ◽

Fetal Plasma ◽

Period 2 ◽

Time To Delivery

Abstract The present study was carried out on 19 chronically catheterized mares and fetuses in late gestation (term >320 days). In six animals which were monitored up to the time of delivery of a live foal, plasma and amniotic fluid cortisol concentrations remained low until 4–5 days before parturition when there was a rapid, significant rise (P<0·05) which was not accompanied by any corresponding changes in maternal plasma cortisol. Circulating fetal ACTH concentrations became more variable close to delivery and ANOVA revealed no significant increases during this critical period, although a negative correlation between plasma ACTH and time to delivery was observed (P<0·05). Tests on fetal adrenal responsiveness to exogenous ACTH1–24 were carried out on ten animals. Before 295 days of gestation no significant increases in fetal plasma cortisol above its basal level of 20–30 nmol/l could be elicited by ACTH, administered as a single i.v. injection (1–2 μg/kg). By 304 ± 3 days (mean ± s.e.m.) small but significant (P<0·05) increments in plasma cortisol were detected after ACTH, while in the oldest group (313 ±2 days) significant (P<0·01) 50–60% increments were seen throughout the test period (2 h). Only one fetus was tested within 3 days of delivery and here a fourfold rise in plasma cortisol was evoked by ACTH. When changes in endogenous levels of circulating ACTH and cortisol were monitored every 15 min over 1·5- to 2-h periods in late gestation, rises in ACTH were only accompanied by concomitant increases in plasma cortisol in fetuses within 5 days of delivery (correlation coefficient r=0·58, P<0·01). Before this time, plasma cortisol concentrations remained at basal levels irrespective of any fluctuations in plasma ACTH. These findings indicate that the adrenal cortex of the fetal foal is relatively quiescent and insensitive to ACTH for most of the latter part of gestation, but that a short rapid escalation in circulating cortisol precedes its delivery. Journal of Endocrinology (1994) 142, 417–425

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Differences in Placental Imprinted Gene Expression across Preeclamptic and Non-Preeclamptic Pregnancies

Genes ◽

10.3390/genes11101146 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1146

Author(s):

Maya A. Deyssenroth ◽

Qian Li ◽

Carlos Escudero ◽

Leslie Myatt ◽

Jia Chen ◽

...

Keyword(s):

Gene Expression ◽

Fetal Growth ◽

Pregnancy Complications ◽

Fetal Growth Restriction ◽

Late Onset ◽

Critical Role ◽

Growth Restriction ◽

Imprinted Genes ◽

Imprinted Gene ◽

Expression Levels

Preeclampsia is a multi-systemic syndrome that presents in approximately 5% of pregnancies worldwide and is associated with a range of subsequent postpartum and postnatal outcomes, including fetal growth restriction. As the placenta plays a critical role in the development of preeclampsia, surveying genomic features of the placenta, including expression of imprinted genes, may reveal molecular markers that can further refine subtypes to aid targeted disease management. In this study, we conducted a comprehensive survey of placental imprinted gene expression across early and late onset preeclampsia cases and preterm and term normotensive controls. Placentas were collected at delivery from women recruited at the Magee-Womens Hospital prenatal clinics, and expression levels were profiled across 109 imprinted genes. We observed downregulation of placental Mesoderm-specific transcript (MEST) and Necdin (NDN) gene expression levels (false discovery rate (FDR) < 0.05) among early onset preeclampsia cases compared to preterm controls. No differences in placental imprinted gene expression were observed between late onset preeclampsia cases and term controls. While few studies have linked NDN to pregnancy complications, reductions in MEST expression levels, as observed in our study, are consistently reported in the literature in relation to various pregnancy complications, including fetal growth restriction, suggesting a potential role for placental MEST expression as a biosensor of an adverse in utero environment.

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A heretical view: rather than a solely placental protective function, placental 11β hydroxysteroid dehydrogenase 2 also provides substrate for fetal peripheral cortisol synthesis in obese pregnant ewes

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174420000112 ◽

2020 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Adel B. Ghnenis ◽

John F. Odhiambo ◽

Ashley M. Smith ◽

Chris L. Pankey ◽

Peter W. Nathanielsz ◽

...

Keyword(s):

Plasma Cortisol ◽

Fetal Liver ◽

Venous Blood ◽

National Research Council ◽

Hydroxysteroid Dehydrogenase ◽

Maternal Plasma ◽

Peripheral Tissue ◽

Protective Function ◽

System Components ◽

Perirenal Fat

Abstract Exposure to glucocorticoid levels higher than appropriate for current developmental stages induces offspring metabolic dysfunction. Overfed/obese (OB) ewes and their fetuses display elevated blood cortisol, while fetal Adrenocorticotropic hormone (ACTH) remains unchanged. We hypothesized that OB pregnancies would show increased placental 11β hydroxysteroid dehydrogenase 2 (11β-HSD2) that converts maternal cortisol to fetal cortisone as it crosses the placenta and increased 11β-HSD system components responsible for peripheral tissue cortisol production, providing a mechanism for ACTH-independent increase in circulating fetal cortisol. Control ewes ate 100% National Research Council recommendations (CON) and OB ewes ate 150% CON diet from 60 days before conception until necropsy at day 135 gestation. At necropsy, maternal jugular and umbilical venous blood, fetal liver, perirenal fat, and cotyledonary tissues were harvested. Maternal plasma cortisol and fetal cortisol and cortisone were measured. Fetal liver, perirenal fat, cotyledonary 11β-HSD1, hexose-6-phosphate dehydrogenase (H6PD), and 11β-HSD2 protein abundance were determined by Western blot. Maternal plasma cortisol, fetal plasma cortisol, and cortisone were higher in OB vs. CON (p < 0.01). 11β-HSD2 protein was greater (p < 0.05) in OB cotyledonary tissue than CON. 11β-HSD1 abundance increased (p < 0.05) in OB vs. CON fetal liver and perirenal fat. Fetal H6PD, an 11β-HSD1 cofactor, also increased (p < 0.05) in OB vs. CON perirenal fat and tended to be elevated in OB liver (p < 0.10). Our data provide evidence for increased 11β-HSD system components responsible for peripheral tissue cortisol production in fetal liver and adipose tissue, thereby providing a mechanism for an ACTH-independent increase in circulating fetal cortisol in OB fetuses.

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Inhibition of placental 11β-hydroxysteroid dehydrogenase type 2 by catecholamines via α-adrenergic signaling

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.6.r1966 ◽

2001 ◽

Vol 281 (6) ◽

pp. R1966-R1974 ◽

Cited By ~ 64

Author(s):

Sumita Sarkar ◽

Shu-Whei Tsai ◽

Tien T. Nguyen ◽

Michael Plevyak ◽

James F. Padbury ◽

...

Keyword(s):

Gene Expression ◽

Physiological Stress ◽

Promoter Sequence ◽

Hydroxysteroid Dehydrogenase ◽

Northern Blotting ◽

Late Gestation ◽

Mrna Levels ◽

Adrenergic Stimulation ◽

Trophoblastic Cells

The placenta expresses high levels of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) that converts cortisol into inactive 11-keto metabolites and effectively protects the developing fetus from maternal cortisol during pregnancy. Impairment of this glucocorticoid barrier has adverse effects on fetal outcomes. A similar spectrum of adverse fetal effects is induced by antenatal stress during pregnancy. To examine the hypothesis that physiological stress may regulate placental 11βHSD2 gene expression, we examined the effects of the catecholamines norepinephrine (NE) and epinephrine (E) on 11βHSD2 expression in human trophoblastic cells. With the use of Northern blotting and semiquantitative RT-PCR, we determined that NE and E rapidly downregulate 11βHSD2 steady-state mRNA levels in early- and late-gestation human trophoblasts and BeWo trophoblastic cells. Experiments using different adrenoceptor subtype-selective agonists and antagonists demonstrated that this catecholamine suppression of 11βHSD2 mRNA expression is mediated via both α1- and α2-adrenoceptors and is independent of β-adrenergic stimulation. To examine transcriptional regulation, BeWo cells were transiently transfected with a reporter construct in which an 11βHSD2 human promoter sequence was inserted upstream of the luciferase gene. Treatment with 10−7 M NE decreased luciferase activity by ∼60% ( n = 3, P < 0.01). These results suggest the NE/E-mediated decrease in placental 11βHSD2 gene expression is an instance of α-adrenoceptor-specific rapid transcriptional inhibition of an adrenergic target gene. This molecular mechanism may be involved in the deleterious effects of antenatal physiological stress on fetoplacental growth and development.

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Regulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in ovine placenta by fetal cortisol

Journal of Endocrinology ◽

10.1677/joe.0.1720527 ◽

2002 ◽

Vol 172 (3) ◽

pp. 527-534 ◽

Cited By ~ 43

Author(s):

KA Clarke ◽

JW Ward ◽

AJ Forhead ◽

DA Giussani ◽

AL Fowden

Keyword(s):

Plasma Cortisol ◽

Inverse Correlation ◽

Hydroxysteroid Dehydrogenase ◽

Plasma Cortisol Level ◽

Late Gestation ◽

Fetal Sheep ◽

Fetal Plasma ◽

Ovine Placenta ◽

Cortisol Levels

The effect of fetal cortisol on the activity of the type 2 isoform of the enzyme, 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD2), was examined in ovine placenta and fetal kidney by measuring tissue 11 beta-HSD2 activity during late gestation when endogenous fetal cortisol levels rise and after exogenous cortisol administration to immature fetuses before the prepartum cortisol surge. Placental 11 beta-HSD2 activity decreased between 128-132 days and term (approximately 145 days of gestation) in association with the normal prepartum increase in fetal plasma cortisol. Raising fetal cortisol levels to prepartum values in the immature fetus at 128--132 days of gestation reduced placental 11 beta-HSD2 activity to term values. In contrast, 11 beta-HSD2 activity in the fetal renal cortex was unaffected by gestational age or cortisol infusion. When all the data were combined, there was an inverse correlation between the log fetal plasma cortisol level at delivery and placental 11 beta-HSD2 activity, expressed both on a weight-specific basis and per mg placental protein. Fetal cortisol therefore appears to be a physiological regulator of placental, but not renal, 11 beta-HSD2 activity in fetal sheep during late gestation. These findings have important implications, not only for glucocorticoid exposure in utero, but also for the local actions of cortisol within the placental tissues that are involved in initiating parturition in the sheep.

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