Gestational age-dependent changes in the levels of mRNAs encoding cortisol biosynthetic enzymes and IGF-II in the adrenal gland of fetal sheep during prolonged hypoxemia

Braems, G. A.; Han, VK; Challis,

doi:10.1677/joe.0.1590257

Cited by 21 publications

(16 citation statements)

References 44 publications

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“…In contrast, 24 h of restricted uterine blood flow (RUBF) in ovine fetuses aged between 115 and 120 days of gestation resulted in a significant decline in liver IGF-I mRNA and only a tendency for IGF-II mRNA to decrease (McLellan et al 1992). We observed no changes in tissue IGF-I or -II mRNA levels in the near-term group in response to UCO, although previous work in late-gestation (126-130 and 134-136 days of gestation) ovine fetuses has shown that 48 h of acute isocapnic hypoxia reduced IGF-II mRNA expression in the adrenal gland (Braems et al 1998). Our results suggest a greater susceptibility of IGF-II gene expression to UCO in younger fetuses, in which IGF-II mRNA levels are higher (Delhanty & Han 1993).…”

Section: Discussioncontrasting

confidence: 75%

“…These changes are associated with a reduction in the rate of DNA synthesis in specific organs and tissues (Hooper et al 1991, Asano et al 1997. A reduction in fetal growth, with associated changes in IGFs and IGFBPs, is likely to constitute tissue-specifc energy expenditure adaptations in the face of an altered substrate and/or oxygen supply and could be mediated, in part, by endocrine changes involving catecholamines (Hooper et al 1994) or cortisol (Braems et al 1998), for example.…”

Section: Introductionmentioning

confidence: 99%

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The effect of intermittent umbilical cord occlusion on insulin-like growth factors and their binding proteins in preterm and near-term ovine fetuses

Green

Kawagoe²,

Hill³

et al. 2000

Journal of Endocrinology

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Intermittent umbilical cord compression with resultant fetal hypoxia can have a negative impact on fetal growth and development. Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are the most important regulators of fetal growth. In preterm (107-108 days of gestation) and near-term (128-131 days of gestation) ovine fetuses, we have determined the effect of intermittent umbilical cord occlusion (UCO) over a period of 4 days on the profile and expression of IGFs and IGFBPs. In experimental group animals (preterm n=7; near term n=7) UCOs were carried out by complete inflation of an occluder cuff (duration 90 s) every 30 min for 3-5 h each day, while control fetuses (preterm n=7; near term n=7) received no UCOs. Ewes were euthanized at the end of day 4, and fetal heart, lung, kidney, liver, skeletal muscle and placenta were collected. During UCOs, PO 2 fell (by 13 mmHg), pH fell (by 0·05) and PCO 2 increased (by 7 mmHg), and changed to a similar extent in both preterm and near-term groups. In both preterm and near-term groups, there was no difference in fetal body or organ weight between UCO and control fetuses. No significant changes were observed in plasma IGF-I and -II concentrations or IGFBP-1, -2, -3 or -4 levels throughout the 4-day study at either gestational age. In the preterm group UCO fetuses, IGF-II mRNA (1·2-6·0 kb) levels were lower in fetal lung (33%, P<0·05), heart (54%, P<0·01) and skeletal muscle (29%, P<0·05), but there were no differences in IGF-I mRNA levels (7·3 kb); IGFBP-2 mRNA (1·5 kb) levels were lower in the right lobe of the liver (42%, P<0·05) and kidney (22%, P<0·01), but higher in the heart (72%, P<0·01), while IGFBP-4 (2·4 kb) levels were lower in skeletal muscle (21%, P<0·01). In the near-term group UCO fetuses, IGFBP-2 mRNA levels were greater in the placenta (39%, P<0·05). Thus, intermittent UCO as studied has a greater effect on the expression of genes encoding certain peptides of the fetal IGF system in selected tissues in preterm fetuses than that in near-term fetuses. Altered IGFBP-2 mRNA levels with reduced IGF-II mRNA levels in selected tissues may mediate changes in growth and/or differentiation that might become apparent if the length of the UCO study were extended.

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Section: Discussioncontrasting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

The effect of intermittent umbilical cord occlusion on insulin-like growth factors and their binding proteins in preterm and near-term ovine fetuses

Green

Kawagoe²,

Hill³

et al. 2000

Journal of Endocrinology

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“…In 1998, Braems et al (6) showed that, in the older sheep fetuses, hypoxemia resulted in significantly increased levels of mRNAs encoding P450scc, P450C21, and 3␤-HSD (6). These results are similar to ours.…”

Section: Discussionsupporting

confidence: 85%

“…Sustained hypoxemia activates adrenal steroidogenesis in the older fetal sheep. The resultant increase in cortisol synthesis is associated with decreased expression of adrenal IGF-II mRNA (6).…”

Section: Discussionmentioning

confidence: 99%

Effects of hypoxia on testosterone release in rat Leydig cells

Hwang

Chen

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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The aim of this study was to explore the effect and action mechanisms of intermittent hypoxia on the production of testosterone both in vivo and in vitro. Male rats were housed in a hypoxic chamber (12% O(2) + 88% N(2), 1.5 l/ml) 8 h/day for 4 days. Normoxic rats were used as control. In an in vivo experiment, hypoxic and normoxic rats were euthanized and the blood samples collected. In the in vitro experiment, the enzymatically dispersed rat Leydig cells were prepared and challenged with forskolin (an adenylyl cyclase activator, 10(-4) M), 8-Br-cAMP (a membrane-permeable analog of cAMP, 10(-4) M), hCG (0.05 IU), the precursors of the biosynthesis testosterone, including 25-OH-C (10(-5) M), pregnenolone (10(-7) M), progesterone (10(-7) M), 17-OH-progesterone (10(-7) M), and androstendione (10(-7)-10(-5) M), nifedipine (L-type Ca(2+) channel blocker, 10(-6)-10(-4) M), nimodipine (L-type Ca(2+) channel blocker, 10(-5) M), tetrandrine (L-type Ca(2+) channel blocker, 10(-5) M), and NAADP (calcium-signaling messenger causing release of calcium from intracellular stores, 10(-6)-10(-4) M). The concentrations of testosterone in plasma and medium were measured by radioimmunoassay. The level of plasma testosterone in hypoxic rats was higher than that in normoxic rats. Enhanced testosterone production was observed in rat Leydig cells treated with hCG, 8-Br-cAMP, or forskolin in both normoxic and hypoxic conditions. Intermittent hypoxia resulted in a further increase of testosterone production in response to the testosterone precursors. The activity of 17β-hydroxysteroid dehydrogenase was stimulated by the treatment of intermittent hypoxia in vitro. The intermittent hypoxia-induced higher production of testosterone was accompanied with the influx of calcium via L-type calcium channel and the increase of intracellular calcium via the mechanism of calcium mobilization. These results suggested that the intermittent hypoxia stimulated the secretion of testosterone at least in part via stimulatory actions on the activities of adenylyl cyclase, cAMP, L-type calcium channel, and steroidogenic enzymes.

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“…It is possible that the increase in cortisol contributes to regulation of ACTH-R mRNA expression. Alternatively, increased ACTH-R could enhance adrenal responsiveness and cortisol output, as mRNA levels encoding key steroidogenic enzymes were also increased in these fetuses (Braems et al 1998). Thus, with hypoxaemia, a feed-forward loop may be established, with increased cortisol synthesis driving enhanced adrenal responsiveness (Lye & Challis 1984), potentially resulting in preterm birth.…”

Section: Discussionmentioning

confidence: 99%

Developmental regulation of corticotrophin receptor gene expression in the adrenal gland of the ovine fetus and newborn lamb: effects of hypoxia during late pregnancy

Fraser

Braems²,

Challis³

2001

Journal of Endocrinology

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Responsiveness of the fetal sheep adrenal gland to adrenocorticotrophin (ACTH) increases in late pregnancy, resulting in increased glucocorticoid production. Development of this responsiveness is an important determinant of fetal hypothalamic-pituitary-adrenal function and depends, in part, on the potential for ACTH binding to adrenal tissue. In the present study, we have examined the developmental pattern of ACTH receptor (ACTH-R) expression during the latter half of pregnancy and in neonatal and adult life. As hypoxaemia induces increases in cortisol and ACTH secretion, in addition to increasing fetal adrenal responsiveness, a further aim of this study was to investigate whether hypoxaemia was associated with altered expression of the ACTH-R gene.Whole adrenal glands were removed from fetal sheep, lambs and adult sheep at different stages of development for measurement of ACTH-R mRNA. Moderate hypoxaemia was induced for 48 h beginning on days 124-128, or on days 132-134 of gestation, by decreasing the maternal fractional inspired oxygen. ACTH-R mRNA was detected by northern blotting using a cDNA cloned in our laboratory and by in situ bydridisation.ACTH-R mRNA (3·6 kb major transcript) was detected in adrenal tissue at day 63 of gestation. Its relative abundance increased significantly (P<0·05) between days 126-128 and 140-141 of pregnancy, increased further with the onset of spontaneous labour, and remained increased in newborn lambs at 7 h-7 days after birth. ACTH-R mRNA levels then decreased in adrenal tissue from lambs and adult sheep (P<0·05). Hypoxaemia for 48 h significantly increased ACTH-R mRNA expression in adrenals of the older fetuses (days 134-136) compared with that in controls (P<0·05), but was without effect in younger fetuses.We conclude that levels of ACTH-R mRNA in the fetal adrenal gland increase as term approaches, coincident with the endogenous prepartum surge in plasma ACTH and cortisol. Sustained hypoxaemia resulted in an upregulation of mRNA encoding for ACTH-R, but only in older fetuses and in association with a sustained increase in plasma cortisol. These results are consistent with cortisol, ACTH, or both, contributing to increased fetal adrenal responsiveness, by increasing expression of fetal adrenal receptors for ACTH.

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Gestational age-dependent changes in the levels of mRNAs encoding cortisol biosynthetic enzymes and IGF-II in the adrenal gland of fetal sheep during prolonged hypoxemia

Cited by 21 publications

References 44 publications

The effect of intermittent umbilical cord occlusion on insulin-like growth factors and their binding proteins in preterm and near-term ovine fetuses

The effect of intermittent umbilical cord occlusion on insulin-like growth factors and their binding proteins in preterm and near-term ovine fetuses

Effects of hypoxia on testosterone release in rat Leydig cells

Developmental regulation of corticotrophin receptor gene expression in the adrenal gland of the ovine fetus and newborn lamb: effects of hypoxia during late pregnancy

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