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1.
Endocrinology ; 148(11): 5424-32, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17702852

RESUMEN

We investigated the effects of an intrafetal infusion of IGF-I on adrenal growth and expression of the adrenal steroidogenic and catecholamine-synthetic enzyme mRNAs in the sheep fetus during late gestation. Fetal sheep were infused for 10 d with either IGF-I (26 microg/kg.h; n = 14) or saline (n = 10) between 120 and 130 d gestation, and adrenal glands were collected for morphological analysis and determination of the mRNA expression of steroidogenic and catecholamine-synthetic enzymes. Fetal body weight was not altered by IGF-I infusion; however, adrenal weight was significantly increased by 145% after IGF-I infusion. The density of cell nuclei within the fetal adrenal cortex (the zona glomerulosa and zona fasciculata), and within the adrenaline synthesizing zone of the adrenal medulla, was significantly less in the IGF-I-infused fetuses compared with the saline-infused group. Thus, based on cell-density measurements, there was a significant increase in cell size in the zona glomerulosa and zona fasciculata of the adrenal cortex and in the adrenaline-synthesizing zone of the adrenal medulla. There was no effect of IGF-I infusion on the adrenal mRNA expression of the steroidogenic or catecholamine-synthetic enzymes or on fetal plasma cortisol concentrations. In summary, infusion of IGF-I in late gestation resulted in a marked hypertrophy of the steroidogenic and adrenaline-containing cells of the fetal adrenal in the absence of changes in the mRNA levels of adrenal steroidogenic or catecholamine-synthetic enzymes or in fetal plasma cortisol concentrations. Thus, IGF-I infusion results in a dissociation of adrenal growth and function during late gestation.


Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Feto/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/farmacología , Esteroides/metabolismo , Glándulas Suprarrenales/embriología , Glándulas Suprarrenales/crecimiento & desarrollo , Animales , Femenino , Sangre Fetal/química , Desarrollo Fetal/efectos de los fármacos , Desarrollo Fetal/genética , Peso Fetal/efectos de los fármacos , Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Edad Gestacional , Hidrocortisona/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Ovinos
2.
Biol Reprod ; 71(2): 620-8, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15265784

RESUMEN

It is not clear if an increase in intra-adrenal cortisol is required to mediate the actions of adrenocorticotropic hormone (ACTH) on adrenal growth and steroidogenesis during the prepartum stimulation of the fetal pituitary-adrenal axis. We infused metyrapone, a competitive inhibitor of cortisol biosynthesis, into fetal sheep between 125 and 140 days of gestation (term = 147 +/- 3 days) and measured fetal plasma cortisol, 11-desoxycortisol, and ACTH; pituitary pro-opiomelanocortin mRNA and adrenal expression of ACTH receptor (melanocortin type 2 receptor), steroidogenic acute regulatory protein (StAR), 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), cytochrome P450 17-hydroxylase (CYP17), 3beta-hydroxysteroid dehydrogenase, and cytochrome P450 21-hydroxylase mRNA; and StAR protein in the fetal adrenal gland. Plasma ACTH and 11-desoxycortisol concentrations were higher (P < 0.05), whereas plasma cortisol concentrations were not significantly different in metyrapone- compared with vehicle-infused fetuses. The ratio of plasma cortisol to ACTH concentrations was higher (P < 0.0001) between 136 and 140 days than between 120 and 135 days of gestation in both metyrapone- and vehicle-infused fetuses. The combined adrenal weight and adrenocortical thickness were greater (P < 0.001), and cell density was lower (P < 0.01), in the zona fasciculata of adrenals from the metyrapone-infused group. Adrenal StAR mRNA expression was lower (P < 0.05), whereas the levels of mature StAR protein (30 kDa) were higher (P < 0.05), in the metyrapone-infused fetuses. In addition, adrenal mRNA expression of 11betaHSD2, CYP11A1, and CYP17 were higher (P < 0.05) in the metyrapone-infused fetuses. Thus, metyrapone administration may represent a unique model that allows the investigation of dissociation of the relative actions of ACTH and cortisol on fetal adrenal steroidogenesis and growth during late gestation.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Metirapona/farmacología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/embriología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/genética , 3-Hidroxiesteroide Deshidrogenasas/genética , Glándulas Suprarrenales/anatomía & histología , Glándulas Suprarrenales/embriología , Glándulas Suprarrenales/fisiología , Hormona Adrenocorticotrópica/sangre , Animales , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Cortodoxona/sangre , Femenino , Edad Gestacional , Hidrocortisona/sangre , Tamaño de los Órganos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Sistema Hipófiso-Suprarrenal/fisiología , Embarazo , Proopiomelanocortina/genética , ARN Mensajero/análisis , Receptor de Melanocortina Tipo 2/genética , Ovinos , Esteroide 17-alfa-Hidroxilasa/genética , Esteroide 21-Hidroxilasa/genética
3.
Neuroscience ; 123(1): 167-78, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-14667451

RESUMEN

During development norepinephrine plays a role in determining the morphologic organization of the CNS and the density and future responsiveness of adrenergic receptors. alpha-2 Adrenergic receptors, one of three adrenergic receptor types, regulate important adult CNS functions and may have a distinct role during development. We examined alpha-2 receptor distribution and density in the rat brain at postnatal days 1, 5, 10, 15, 21, 28 and in adults using the antagonist [(3)H]RX821002 for autoradiography. Binding kinetics and pharmacology for alpha-2 adrenergic receptors were the same in adults and neonates. There was an overall increase in alpha-2 receptor levels during postnatal development with great variability in pattern and timing of receptor density changes among brain regions. Three major patterns were apparent. First, in many regions receptor density increased during postnatal development, generally reaching adult levels around postnatal day 15. Within this group there was variability in timing between regions and there were several regions with receptor densities higher than adult levels during the postnatal period. Second, there were regions with very high levels of receptors at birth and little or no change in density during the postnatal period. Third, some regions demonstrated decreasing or transient expression of alpha-2 adrenergic receptors in the course of postnatal development, including white matter regions, cerebellum and many brainstem nuclei, suggesting specific roles for alpha-2 receptors during development. This study investigates the development of alpha-2 adrenergic receptors in the rat CNS. It demonstrates there is region-specific regulation of alpha-2 receptor development and identifies brain regions where these receptors may play a specific and critical role in the regulation normal development.


Asunto(s)
Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Idazoxan/análogos & derivados , Receptores Adrenérgicos alfa 2/metabolismo , Animales , Animales Recién Nacidos , Autorradiografía , Sistema Nervioso Central/crecimiento & desarrollo , Sistema Nervioso Central/metabolismo , Idazoxan/metabolismo , Unión Proteica/fisiología , Ratas , Ratas Sprague-Dawley
4.
Endocr Res ; 30(4): 845-50, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15666835

RESUMEN

It is well established in the sheep, that the normal timing of parturition is dependent on a prepartum activation of the fetal pituitary-adrenal axis. We have recently demonstrated for the first time that embryo number, embryo sex, and alterations in the environment of the early embryo, including exposure to maternal undernutrition during the periconceptional period, alter the timing and level of activation of the pituitary-adrenal axis in the sheep fetus during late gestation. There is a delay in activation of the fetal HPA axis in twin fetuses and we speculate that the diminished adrenocortical responsiveness in the twin fetus may be an adaptive response, which counters the impact of the potential enhanced intrauterine stress experienced by a twin fetus, thereby reducing the possibility of preterm delivery. We have also reported that a moderate restriction of maternal nutrition to during the periconceptional period (from 60 days before and for one week after conception) resulted in an earlier activation of the pituitary-adrenal axis of twin, but not singleton, fetuses during late gestation. A series of studies using assisted reproductive technologies have also found that perturbation of the early embryonic environment results in a dysregulation of placental and fetal growth and development and in the timing of normal parturition. In summary, after several decades of work focussed on events in late gestation associated with the prepartum activation and stress responsiveness of the fetal HPA axis, our recent studies indicate that the environment of the early embryo may have a significant role to play in determining the timing and level of the prepartum activation of this axis and potentially on the functional capacity of the axis to respond to acute or chronic stress in later life.


Asunto(s)
Parto/fisiología , Sistema Hipófiso-Suprarrenal/embriología , Animales , Feto/fisiología , Ovinos/embriología , Ovinos/fisiología , Factores de Tiempo
5.
J Physiol ; 552(Pt 2): 621-33, 2003 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-14561842

RESUMEN

While the impact of exogenous glucocorticoids on the fetal cardiovascular system has been well defined, relatively few studies have characterised the role of endogenous fetal glucocorticoids in the regulation of arterial blood pressure (BP) during late gestation. We have therefore infused metyrapone, an inhibitor of cortisol biosynthesis, into fetal sheep from 125 days gestation (when fetal cortisol concentrations are low) and from 137 days gestation (when fetal cortisol concentrations are increasing) and measured fetal plasma cortisol, 11-desoxycortisol and ACTH, fetal systolic, diastolic and mean arterial BP, heart rate, and the fetal BP responses to increasing doses of angiotensin II (AII). At 125 days gestation, there was a significant increase in fetal plasma ACTH and 11-desoxycortisol by 24 h after (+24 h) the start of the metyrapone infusion, and plasma cortisol concentrations were not different at +24 h when compared with pre-infusion values. Whilst the initial fall in circulating cortisol concentrations may have been transient, systolic, diastolic and mean arterial BP were ~5-6 mmHg lower (P < 0.05) in metyrapone- than in vehicle-infused fetuses at 24-48 h after the start of the infusion. When metyrapone was infused from 137/138 days gestation, there was a significant decrease in plasma cortisol concentrations by +6 h, which was followed by an increase back to pre-infusion values. While cortisol concentrations decreased, there was no change in fetal mean arterial BP during the first 24 h after the start of metyrapone infusion. Mean fetal arterial BP values at 137-139 days gestation were not different in fetuses that had been infused with either vehicle or metyrapone from 125 days gestation or with metyrapone from 137/138 days gestation. At 137-139 days gestation, however, arterial BP responses to increasing doses of AII were significantly blunted in fetuses that had been infused with metyrapone from 125 days gestation, when compared with fetuses that had been infused with metyrapone from 137/138 days gestation or with vehicle from 125 days gestation. The dissociation of the gestational age increase in arterial BP and the effects of intrafetal AII on fetal arterial BP indicates that increase in fetal BP with gestational age is not entirely a result of an increased vascular responsiveness to endogenous AII. Furthermore there may be a critical window during late gestation when the actions of cortisol contribute to the development of vascular responsiveness to AII.


Asunto(s)
Angiotensina II/farmacología , Antimetabolitos/farmacología , Presión Sanguínea/efectos de los fármacos , Feto/fisiología , Metirapona/farmacología , Hormona Adrenocorticotrópica/sangre , Animales , Antimetabolitos/administración & dosificación , Análisis de los Gases de la Sangre , Glucemia/metabolismo , Cortodoxona/sangre , Femenino , Edad Gestacional , Frecuencia Cardíaca Fetal/efectos de los fármacos , Hormonas/sangre , Hidrocortisona/sangre , Inyecciones , Metirapona/administración & dosificación , Embarazo , Radioinmunoensayo , Ovinos
6.
Mol Cell Endocrinol ; 196(1-2): 1-10, 2002 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-12385820

RESUMEN

We have previously demonstrated that maternal undernutrition during either the 'periconceptional' (i.e. from 60 days (d) before until 7 d after mating) or 'gestational' periods (i.e. from 8 d after mating until the end of pregnancy) have differential effects on the subsequent development of the hypothalamo-pituitary-adrenocortical (HPA) axis and on adrenal growth and steroidogenesis in the sheep fetus during late gestation (term=147+/-3 d gestation). The specific mechanisms by which periconceptional or gestational undernutrition result in activation of the fetal HPA axis in late gestation are unclear. We have therefore investigated the impact of maternal nutrient restriction imposed either during the periconceptional period, or between 8 and 147 d gestation on the expression of specific genes in the fetal pituitary and adrenal which regulate adrenal steroidogenesis in late gestation. Ewes were maintained on either a Control (C) or Restricted (R, 70% of C) diet from 60 d before until 7 d after mating (periconceptional period) and then maintained on either a Control or Restricted diet from 8 d after mating for the remainder of pregnancy (gestational period). Four nutritional treatment groups were therefore generated (C-C, C-R, R-R and R-C). Whilst periconceptional undernutrition (R-R and R-C groups) resulted in higher fetal plasma adrenocorticotrophic hormone (ACTH) at 135-146 d gestation, there was no change in the relative level of expression of the ACTH receptor (MC2R), steroidogenic acute regulatory protein (StAR) or steroidogenic enzyme mRNAs in the fetal adrenal in late gestation. Exposure to gestational undernutrition (R-R and C-R groups), however, resulted in a stimulation in the relative level of expression of MC2R mRNA (P=0.001) and StAR mRNA (P=0.007) in the fetal adrenal during late gestation. This study provides new insights into the potential mechanisms by which alterations of the nutrient environment of the fetus at different stages of gestation may result in differential activation of the fetal HPA axis.


Asunto(s)
Glándulas Suprarrenales/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Fosfoproteínas/biosíntesis , Receptores de Corticotropina/biosíntesis , Glándulas Suprarrenales/embriología , Animales , Femenino , Feto , Edad Gestacional , Fosfoproteínas/genética , Hipófisis/embriología , Hipófisis/metabolismo , Embarazo , ARN Mensajero/análisis , Receptor de Melanocortina Tipo 2 , Receptores de Corticotropina/genética , Ovinos , Gemelos , Regulación hacia Arriba
7.
Arch Physiol Biochem ; 110(1-2): 99-105, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11935406

RESUMEN

During fetal life, it is critical that there is coordinate regulation of the growth, zonation and differentiation of the fetal adrenal cortex to ensure that cells in key tissues and organs are exposed in a programmed temporal sequence to the actions of glucocorticoids. Glucocorticoids are essential for maturation of key target organs before birth, including the lung, brain, liver, gut, kidney and adrenal, and the prepartum increase in glucocorticoid synthesis and secretion by the fetal adrenal gland is critical for the successful transition to postnatal life. It is also evident that premature or abnormal exposure of embryonic or fetal tissues to glucocorticoids during critical windows of development can irreversibly alter the programmed development of organ systems. Premature or abnormal exposure of the fetus to excess glucocorticoids may occur either as a consequence of endogenous stimulation of the fetal hypothalamo-pituitary-adrenal axis (HPAA) or as a consequence of exposure to exogenous glucocorticoids in a therapeutic context. Administration of synthetic glucocorticoids to women at risk of preterm labour, for example, is a routine clinical practice designed to improve respiratory function and neonatal outcome. It is clearly important to understand what endogenous factors regulate the growth and functional maturation of the adrenal cortex during development and the consequent likelihood of exposure of developing tissues to excess corticosteroids. To date, investigations have centred on the role of ACTH 1-39 in the stimulation of adrenal growth and steroidogenesis in long gestation species, such as the primate and sheep, where maturation and differentiation of organ systems occurs predominantly before birth. In this review, we will focus on the evidence that in addition to ACTH 1-39, other pro-opio-melanocortin (POMC) derived peptides, which are synthesized, processed and secreted by the fetal pituitary, play a role in the coordinate regulation of the specific phases of growth and functional development of the fetal adrenal gland in vivo. We will discuss our recent findings on the direct in vivo actions of N-POMC 1-77 and separately, insulin like growth factor II (IGF-II), as adrenal growth factors. These studies provide an understanding of the separate regulatory mechanisms which control activation of adrenal growth and stimulation of adrenal steroidogenesis in the late gestation fetus.


Asunto(s)
Glándulas Suprarrenales/embriología , Factor II del Crecimiento Similar a la Insulina/fisiología , Proopiomelanocortina/fisiología , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Animales , Biomarcadores , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Humanos , Péptidos/metabolismo , Ovinos , Esteroide 17-alfa-Hidroxilasa/genética
8.
Endocr Res ; 28(4): 625-9, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12530673

RESUMEN

In the sheep, there is a rapid increase in fetal adrenal growth and steroidogenesis during the last 10-15 days gestation. Recently, we have shown that infusion of POMC 1-77 increases fetal adrenal growth but does not significantly alter fetal plasma cortisol concentrations. Phosphorylation and inactivation of the pRB protein, which is required for progression into the DNA synthetic phase of the cell-cycle is conducted by a holoenzyme, for which cyclin D1 gene encodes the rate-limiting regulatory subunit. To further elucidate the mechanisms by which POMC 1-77 regulates adrenal growth, we therefore examined adrenal expression of the rate-limiting cell cycle protein, cyclin D1, from fetuses infused for 48 hr with POMC 1-77 (n = 6), POMC 1-49 or Saline (n = 6). There was no significant difference in the adrenal expression of cyclin D1 mRNA levels between POMC 1-77, 1-49 and saline infused fetuses. There was no significant correlation between cyclin D1 (4.0 Kb) and adrenal weight. In summary, these data do not demonstrate that the rate-limiting cell cycle protein, cyclin D1, is activated to stimulate adrenal growth following infusion of POMC 1-77 in the fetal sheep in late gestation.


Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/embriología , Ciclina D1/metabolismo , Fragmentos de Péptidos/farmacología , Proopiomelanocortina/farmacología , Animales , Ciclina D1/genética , Embrión de Mamíferos , Feto/anatomía & histología , Feto/metabolismo , Tamaño de los Órganos/efectos de los fármacos , ARN Mensajero/metabolismo , ARN Ribosómico 18S/metabolismo , Ovinos , Factores de Tiempo
9.
Neurosci Lett ; 316(2): 63-6, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11742716

RESUMEN

We have investigated the effect of lowering foetal arterial PO(2) either acutely or chronically on tyrosine hydroxylase (TH) protein content in the dorsal and ventral medullary regions of the brainstem of the sheep foetus during late gestation. TH protein content increased in both the dorsal and ventral medullary regions of the foetal brainstem after exposure to acute hypoxia when compared to normoxia. In contrast there was no increase in the TH protein content of either the dorsal or ventral medullary regions in the brainstem of foetal sheep which were chronically hypoxaemic throughout late gestation as a consequence of experimental restriction of placental growth. The differences between the TH responses to acute and chronic hypoxaemia in the foetal sheep brainstem may be important in the mediation of physiological adaptations to these intrauterine stimuli and for the generation of an appropriate physiological response to hypoxia in the newborn period.


Asunto(s)
Catecolaminas/metabolismo , Hipoxia Fetal/enzimología , Hipoxia Encefálica/enzimología , Bulbo Raquídeo/enzimología , Neuronas/enzimología , Tirosina 3-Monooxigenasa/metabolismo , Regulación hacia Arriba/fisiología , Enfermedad Aguda , Animales , Enfermedad Crónica , Femenino , Hipoxia Fetal/patología , Hipoxia Fetal/fisiopatología , Hipoxia Encefálica/patología , Hipoxia Encefálica/fisiopatología , Inmunohistoquímica , Bulbo Raquídeo/patología , Bulbo Raquídeo/fisiopatología , Neuronas/patología , Oxígeno/sangre , Embarazo , Ovinos , Fracciones Subcelulares
11.
Clin Exp Pharmacol Physiol ; 28(11): 938-41, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11703401

RESUMEN

1. A range of epidemiological studies has shown that poor intra-uterine growth is associated with an increased prevalence of cardiovascular disease, non-insulin-dependent diabetes mellitus and the Metabolic syndrome in adult life. 2. Because these associations are independent of adult lifestyle or current size, it has been postulated that a reduced intra- uterine nutrient supply perturbs fetal growth and, concomitantly, alters or programmes the structure and function of developing systems. 3. A reduced fetal nutrient supply may be a consequence of poor placental function or inadequate maternal nutrient intake. 4. It has been proposed that one outcome of either a suboptimal placental or maternal nutrient supply is exposure of the fetus to excess glucocorticoids, which act to restrict fetal growth and to programme permanent changes in the cardiovascular, endocrine and metabolic systems. 5. While a range of studies in the rat has investigated the impact of maternal undernutrition on arterial blood pressure in the offspring, there have been relatively few studies in species, such as the sheep, in which the responses of the cardiovascular and neuroendocrine systems to intra-uterine undernutrition can be measured before birth. 6. The present review summarizes recent evidence that poor placental function or inadequate maternal nutrition each results in an increased exposure of fetal sheep tissues to glucocorticoids and, in specific, changes in the regulation of fetal arterial blood pressure. 7. These studies are important in determining how the timing, type and duration of fetal nutrient restriction are each important in determining the nature of the fetal neuroendocrine and cardiovascular adaptive responses and their pathophysiological sequelae in later life.


Asunto(s)
Glucocorticoides/farmacología , Hipertensión/etiología , Insuficiencia Placentaria/fisiopatología , Preñez , Efectos Tardíos de la Exposición Prenatal , Animales , Presión Sanguínea , Femenino , Glucosa/metabolismo , Embarazo , Atención Prenatal , Ovinos
12.
Pediatr Res ; 50(2): 210-6, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11477205

RESUMEN

We determined the route of action of epidermal growth factor (EGF) [intraperitoneal (IP) versus intraamniotic administration] on adrenal development and whether its effects are mediated via the fetal hypothalamic-pituitary axis in the fetal rhesus monkey in vivo. EGF (40 microg) was administered IP (n = 9) or intraamniotic (n = 6) at 121, 123, 125, and 127 d gestation (term, approximately 165 +/- 10 d gestation). In addition, a competitive corticotropin-releasing factor antagonist ([D-phenylalanine(12), Norleucine(21,38)] corticotropin-releasing factor(12-41) to block fetal pituitary ACTH secretion; 400 microg IP) and metyrapone (11beta-hydroxylase inhibitor to block adrenal cortisol synthesis; 15 mg IP and 15 mg intraamniotic) were administered, in combination with EGF (EGF+BLOCK; 40 microg IP; n = 4 fetuses). Control fetuses (n = 6) received saline injections in an equivalent volume. On gestational d 128, a hysterotomy was performed, and fetal adrenals were collected for morphometric analyses and immunocytochemical localization of 3beta -hydroxysteroid dehydrogenase (3betaHSD) and cytochrome P-450 11beta -hydroxylase/aldosynthase. Definitive zone (DZ) width and cortical width of 3betaHSD staining were significantly greater (p < 0.05) in the EGF IP-treated fetuses compared with controls and EGF+BLOCK. With EGF IP, 3betaHSD was increased in the DZ and induced extensively in the transitional zone of the fetal adrenal cortex, and cytochrome P-450 11beta-hydroxylase/aldosynthase immunoreactivity was induced to detectable levels in the DZ. The administration of EGF+BLOCK inhibited the expression of 3betaHSD in the transitional zone, but 3betaHSD expression was still increased in the DZ and cytochrome P-450 11beta-hydroxylase/aldosynthase immunoreactivity was induced in the DZ. EGF intraamniotic administration had no significant effect on the width of the DZ or cortical width of 3betaHSD staining compared with controls. These data suggest that EGF acts via the hypothalamic-pituitary axis to modulate adrenal cortical growth and functional maturation of the transitional zone (the putative zona fasciculata), whereas EGF can act independently of the hypothalamic-pituitary axis to stimulate functional maturation of the DZ (the putative zona glomerulosa).


Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/embriología , Factor de Crecimiento Epidérmico/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiología , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Glándulas Suprarrenales/enzimología , Líquido Amniótico , Animales , Peso Corporal/efectos de los fármacos , Factor de Crecimiento Epidérmico/administración & dosificación , Femenino , Madurez de los Órganos Fetales/efectos de los fármacos , Inyecciones Intraperitoneales , Macaca mulatta , Tamaño de los Órganos/efectos de los fármacos , Embarazo
13.
Reproduction ; 122(2): 195-204, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11467970

RESUMEN

A range of pathophysiological factors can result in a perturbation or restriction of fetal growth, and the cardiovascular, neuroendocrine and metabolic adaptations of the fetus to these stimuli will depend on their nature, timing and intensity. The critical importance of these physiological adaptations for both immediate survival and long-term health outcomes has provided an impetus for experimental studies of the nature and consequences of specific fetal adaptations to a poor intrauterine environment. This review summarizes data from recent studies that have focused on the responses of the fetal cardiovascular, sympathoadrenal, hypothalamo-pituitary-adrenal and renin-angiotensin systems to experimental restriction of placental function in the sheep and discusses the consequences of these adaptations for fetal, neonatal and adult health.


Asunto(s)
Adaptación Fisiológica , Retardo del Crecimiento Fetal/fisiopatología , Glándulas Suprarrenales/embriología , Animales , Sistema Cardiovascular/embriología , Femenino , Retardo del Crecimiento Fetal/complicaciones , Glucocorticoides/fisiología , Humanos , Hipotálamo/embriología , Hipófisis/embriología , Placenta/fisiopatología , Embarazo , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático/embriología
14.
Biol Reprod ; 62(5): 1297-302, 2000 May.
Artículo en Inglés | MEDLINE | ID: mdl-10775180

RESUMEN

We have investigated the effect of intrafetal cortisol administration, before the normal prepartum cortisol surge, on the expression of 11beta hydroxysteroid dehydrogenase (11betaHSD) type 2 mRNA in the fetal adrenal. We also determined whether increased fetal cortisol concentrations can stimulate growth of the fetal adrenal gland or increase expression of adrenal steroidogenic enzymes. Cortisol (hydrocortisone succinate: 2.0-3.0 mg in 4.4 ml/24 h) was infused into fetal sheep between 109 and 116 days of gestation (cortisol infused; n = 12), and saline was administered to control fetuses (saline infused; n = 13) at the same age. There was no effect of cortisol infusion on the fetal adrenal:body weight ratio (cortisol: 101.7 +/- 5.3 mg/kg; saline: 108.2 +/- 4.3 mg/kg). The ratio of adrenal 11betaHSD-2 mRNA to 18S rRNA expression was significantly lower, however, in the cortisol-infused group (0.75 +/- 0.02) compared with the group receiving saline (1.65 +/- 0.14). There was no significant effect of intrafetal cortisol on the relative abundance of adrenal CYP11A1, CYP17, CYP21A1, and 3betaHSD mRNA. A premature elevation in fetal cortisol therefore resulted in a suppression of adrenal 11betaHSD-2. Increased intra-adrenal exposure to cortisol at this stage of gestation is, however, not sufficient to promote adrenal growth or steroidogenic enzyme gene expression.


Asunto(s)
Glándulas Suprarrenales/embriología , Glándulas Suprarrenales/metabolismo , Sangre Fetal/metabolismo , Hidrocortisona/sangre , Hidroxiesteroide Deshidrogenasas/genética , 11-beta-Hidroxiesteroide Deshidrogenasas , Glándulas Suprarrenales/anatomía & histología , Hormona Adrenocorticotrópica/sangre , Animales , Peso Corporal , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Sistema Enzimático del Citocromo P-450/genética , Enzimas/efectos de los fármacos , Enzimas/metabolismo , Femenino , Hidrocortisona/farmacología , Hidroxiesteroide Deshidrogenasas/efectos de los fármacos , Hidroxiesteroide Deshidrogenasas/metabolismo , Tamaño de los Órganos , Embarazo , ARN Mensajero/metabolismo , Ovinos/embriología , Esteroide 17-alfa-Hidroxilasa/genética
15.
Biol Reprod ; 62(3): 714-9, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10684814

RESUMEN

In the present study we investigated the ontogeny of the expression of the type 1 angiotensin receptor (AT(1)R mRNA) and the zonal localization of AT(1)R immunoreactivity (AT(1)R-ir) and cytochrome P450(c11) (CYP11B-ir) in the sheep adrenal gland. In the adult sheep and in the fetus from as early as 90 days gestation, intense AT(1)R-ir was observed predominantly in the zona glomerulosa and to a lesser extent in the zona fasciculata, and it was not detectable in the adrenal medulla. AT(1)R mRNA decreased 4-fold between 105 days and 120 days, whereas AT(1)R mRNA levels remained relatively constant between 120 days and the newborn period. In contrast, both in the adult sheep and in the fetal sheep from as early as 90 days gestation, intense CYP11B-ir was consistently detected throughout the adrenal cortex and in steroidogenic cells that surround the central adrenal vein. In conclusion, we speculate that the presence of AT(1)R in the zona fasciculata, and the higher levels of expression of AT(1)R at around 100 days gestation, may suggest that suppression of CYP17 is mediated via AT(1)R at this time. The abundant expression of AT(1)R-ir and CYP11B-ir in the zona glomerulosa of the fetal sheep adrenal gland would also suggest that lack of angiotensin II stimulation of aldosterone secretion is not due to an absence of AT(1)R or CYP11B in the zona glomerulosa.


Asunto(s)
Glándulas Suprarrenales/fisiología , Citocromo P-450 CYP11B2/metabolismo , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo , Ovinos/fisiología , Glándulas Suprarrenales/embriología , Aldosterona/biosíntesis , Animales , Northern Blotting , Citocromo P-450 CYP11B2/inmunología , Femenino , Regulación del Desarrollo de la Expresión Génica , Edad Gestacional , Hidrocortisona/biosíntesis , Embarazo , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Receptores de Angiotensina/inmunología
16.
Endocrinology ; 141(2): 539-43, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10650933

RESUMEN

We have investigated the effects of fetal growth restriction, induced by restriction of placental growth and function (PR), on 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD-1) and 11betaHSD-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 11betaHSD-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 11betaHSD-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 11betaHSD-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 11betaHSD-2 mRNA. 11betaHSD-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 11betaHSD-2 mRNA in the fetal kidney. In summary, 11betaHSD-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 11betaHSD-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.


Asunto(s)
Desarrollo Embrionario y Fetal , Retardo del Crecimiento Fetal/fisiopatología , Regulación del Desarrollo de la Expresión Génica , Hidroxiesteroide Deshidrogenasas/genética , Placenta/fisiología , Transcripción Genética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1 , Glándulas Suprarrenales/embriología , Glándulas Suprarrenales/enzimología , Animales , Peso Corporal , Femenino , Retardo del Crecimiento Fetal/enzimología , Regulación Enzimológica de la Expresión Génica , Edad Gestacional , Isoenzimas/genética , Riñón/embriología , Riñón/enzimología , Hígado/embriología , Hígado/enzimología , Placenta/enzimología , Embarazo , ARN Mensajero/genética , Ovinos
17.
Endocr Res ; 26(4): 523-9, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11196424

RESUMEN

In the sheep, there is a rapid increase in fetal adrenal growth and steroidogenesis during the last 10-15 days gestation. Recently, we have shown that infusion of POMC (1-77) increases fetal adrenal growth and expression of CYP17 mRNA but does not significantly alter fetal plasma cortisol concentrations [1]. We therefore investigated the effects of infusion of bovine POMC (1-77) and its biosynthetic derivative POMC (1-49) on adrenal StAR mRNA expression. At 136d gestation, POMC (1-77) (n=5 fetuses; 2microg/ml/h), POMC (1-49) (n=5 fetuses, 2microg/ml/h) or Saline (n=5 fetuses, 1ml/h) was infused for 48h. At 138d, fetal adrenal glands were collected and frozen in liquid N2 until RNA was extracted. Northern blot analyses demonstrated a major transcript for StAR mRNA at 3.0kb in fetal adrenal glands from all treatments. The membrane was stripped and re-probed with a P-labelled rat 18S rRNA oligo-probe to verify equal RNA loading. Infusion of POMC (1-77), but not POMC (1-49), resulted in a suppression of fetal adrenal StAR mRNA:18S rRNA when compared to adrenal StAR mRNA:18S rRNA from saline-infused controls. Our data suggest POMC (1-77) may act via separate mechanisms to increase fetal adrenal growth and to limit adrenal steroidogenesis through suppression of StAR mRNA.


Asunto(s)
Glándulas Suprarrenales/embriología , Feto/metabolismo , Fragmentos de Péptidos/farmacología , Fosfoproteínas/genética , Proopiomelanocortina/farmacología , ARN Mensajero/antagonistas & inhibidores , Animales , Northern Blotting , Feto/efectos de los fármacos , Ovinos
18.
Mol Cell Endocrinol ; 154(1-2): 71-7, 1999 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-10509802

RESUMEN

The aim of this study was to investigate the ontogeny of localization of 11betaHSD-2 protein in the human adrenal gland. In addition, we have investigated the effects of abnormal adrenal function on 11betaHSD-2 by determining the pattern of localization of 11betaHSD-2 protein, and the amount and level of expression of 11betaHSD-2 mRNA and protein in human adrenal cortical carcinoma and adenoma. In the human foetal adrenal gland 11betaHSD-2 immunoreactivity (11betaHSD-2-ir) was detected in the foetal zone, whereas in normal adult adrenal glands 11betaHSD-2-ir was not detected by immunocytochemistry. In adrenal cortical carcinoma and adenoma, 11betaHSD-2-ir was detectable in specific regions, which have been identified as steroid synthesizing cells using 3betaHSD-ir as a marker. In adrenal cortical carcinoma and adenoma, 11betaHSD-2 mRNA and 11betaHSD-2 protein were detected by nuclease protection analysis and by western blot analysis, respectively. In summary, 11betaHSD-2-ir was detected in the foetal zone of the mid-gestation human foetal adrenal, whereas, 11betaHSD-2-ir was not detectable in the postnatal or normal adult adrenal gland. 11BetaHSD-2 protein and mRNA was induced in adult human adrenal cortical carcinoma and adenoma. The induction of expression of 11betaHSD-2 in the adrenal cortex suggests a possible role in regulating abnormal adrenal steroidogenic function in these patients.


Asunto(s)
Glándulas Suprarrenales/embriología , Glándulas Suprarrenales/enzimología , Adenoma Corticosuprarrenal/enzimología , Carcinoma Corticosuprarrenal/enzimología , Hidroxiesteroide Deshidrogenasas/biosíntesis , 11-beta-Hidroxiesteroide Deshidrogenasas , Glándulas Suprarrenales/química , Glándulas Suprarrenales/citología , Adulto , Western Blotting , Feto/química , Feto/citología , Humanos , Hidroxiesteroide Deshidrogenasas/genética , Inmunohistoquímica , Recién Nacido , Riñón/enzimología , Métodos , ARN Mensajero/análisis , Ribonucleasas/análisis
19.
Endocrinology ; 139(12): 5144-50, 1998 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9832454

RESUMEN

Previous studies in the primate fetal adrenal gland have indicated that the gland is comprised of three functional zones: 1) the inner fetal zone (FZ), which has the enzymes necessary for dehydroepiandrosterone sulfate (DHEAS) production beginning early in gestation; 2) the transitional zone (TZ), which possesses enzymes necessary for cortisol production; and 3) the outer, definitive zone (DZ), which appears to function as a reservoir of progenitor cells that may populate the remainder of the gland and does not acquire a steroidogenic phenotype with the capacity to produce mineralocorticoids until near term. The enzymes CYP21A2 (P450 21 hydroxylase, or P450c21), CYP11B1 (11beta hydroxylase or P450c11) and CYP11B2 (aldosterone synthase) are necessary for glucocorticoid and mineralocorticoid synthesis but have not been localized previously in an ontogenic manner in the primate fetal adrenal gland. Therefore, we used immunocytochemistry (ICC) to assess specific zonal localization and developmental regulation of CYP21A2 and CYP11B1/CYP11B2 in the human (13-24 weeks' gestation) and rhesus monkey (109 d-term) fetal adrenal gland. In the fetal rhesus, ICC was performed with and without metyrapone administration to the fetus to assess the effects of endogenously increased fetal ACTH. In the human fetal adrenal, CYP21A2 immunoreactivity (IR) was present in only a few isolated cells in the DZ but was detectable in almost all cells in the TZ and FZ. In the fetal rhesus, CYP21A2-IR was present in cells throughout the DZ and TZ and, to a lesser degree, in the FZ. Staining intensity increased with advancing gestational age and was up-regulated in the DZ and TZ, but not the FZ, of the metyrapone-treated fetuses. In the human fetal adrenal gland, CYP11B1/CYP11B2-IR was absent in the DZ but present in the TZ and FZ. In the fetal rhesus monkey adrenal, CYP11B1/CYP11B2-IR was present in all cells of the TZ and FZ but was absent from the DZ until near term. After metyrapone, CYP11B1/CYP11B2-IR was induced in the DZ and was up-regulated in the TZ and FZ. Taken together, these data indicate that in the primate fetal adrenal gland, the FZ has the capacity to synthesize DHEA and DHEAS beginning early in development, the TZ has the capacity to synthesize cortisol after midgestation, and the DZ has the capacity to synthesize mineralocorticoids, but not until near term. The spatial localization of steroid metabolizing enzymes and steroid products in the human and rhesus monkey fetal adrenal suggests analogies of the three functional zones of the fetus (DZ, TZ, and FZ) to their adult counterparts (zona glomerulosa, zona fasciculata, and zona reticularis) and their steroid products (mineralocorticoids, glucocorticoids and androgens, respectively), although the reason for the presence of CYP11B1/CYP11B2- and CYP21A2-IR in the FZ remains to be elucidated.


Asunto(s)
Glándulas Suprarrenales/embriología , Citocromo P-450 CYP11B2/metabolismo , Primates/embriología , Esteroide 11-beta-Hidroxilasa/metabolismo , Esteroide 21-Hidroxilasa/metabolismo , Esteroides/biosíntesis , Animales , Desarrollo Embrionario y Fetal/fisiología , Humanos , Inmunohistoquímica , Macaca mulatta , Factores de Tiempo , Distribución Tisular
20.
Pediatr Res ; 44(5): 656-62, 1998 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9803446

RESUMEN

The aims of this study were to determine whether placental restriction (PR) alters the pattern of localization of the catecholamine-synthesizing enzymes, dopamine-beta-hydroxylase and phenylethanolamine N-methyltransferase, and enkephalin (ENK)-containing peptides in the adrenal gland of the midgestation sheep fetus. We also determined the effect of PR on the content and profile of the molecular mass forms of ENK-containing peptides in the fetal adrenal medulla. Placental growth was restricted by removal of most of the placental implantation sites in the uterus before mating. In midgestation, placental and fetal body weight were reduced (p < 0.05) in the PR group (n = 8; 237.9 +/- 39.5 g, 564.7 +/- 41.6 g, respectively) when compared with the control group (n = 9; 479.1 +/- 36.9 g, 721.2 +/- 22.8 g, respectively). However, combined fetal adrenal weight and adrenal cortical and medullary area were similar in the PR and control fetuses. In PR fetuses, distribution of staining for dopamine-beta-hydroxylase, phenylethanolamine N-methyltransferase, and ENK-containing peptides in the adrenal medulla was similar when compared with the control group; however, staining was less intense and not all adrenomedullary cells were stained. The total adrenal content of ENK-containing peptides was also significantly (p < 0.05) less in the PR group (103.4 +/- 18.6 ng/adrenal) than in the control group (243.6 +/- 24.8 ng/adrenal). However, the molecular mass profile of ENK-containing peptides was not altered in the PR fetuses compared with controls. These data suggest that placental restriction in utero may alter the synthesis and/or secretion of catecholamines and ENK-containing peptides from the fetal adrenal medulla from as early as 90 d gestation.


Asunto(s)
Médula Suprarrenal/embriología , Placenta/fisiología , Animales , Constricción , Dopamina beta-Hidroxilasa/metabolismo , Encefalinas/metabolismo , Femenino , Inmunohistoquímica , Tamaño de los Órganos , Feniletanolamina N-Metiltransferasa/metabolismo , Embarazo , Ovinos
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