I. McMillen - Academia.edu (original) (raw)
Book Chapters by I. McMillen
During fetal life, it is critical that there is coordinate regulation of the growth, zonation and... more 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 post-natal 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 glucocor-ticoids 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.
Papers by I. McMillen
AJP: Endocrinology and Metabolism, 2014
This study aimed to determine whether exposure of the oocyte and/or embryo to maternal undernutri... more This study aimed to determine whether exposure of the oocyte and/or embryo to maternal undernutrition results in the later programming of insulin action in the liver and factors regulating gluconeogenesis. To do this, we collect livers from singleton and twin fetal sheep that were exposed to periconceptional (PCUN; -60 to 7 days) or preimplantation (PIUN; 0-7 days) undernutrition at 136-138 days of gestation (term = 150 days). The mRNA and protein abundance of insulin signaling and gluconeogenic factors were then quantified using qRT-PCR and Western blotting, respectively, and global microRNA expression was quantified using deep sequencing methodology. We found that hepatic PEPCK-C mRNA (P < 0.01) and protein abundance and the protein abundance of IRS-1 (P < 0.01), p110β (P < 0.05), PTEN (P < 0.05), CREB (P < 0.01), and pCREB (Ser(133); P < 0.05) were decreased in the PCUN and PIUN singletons. In contrast, hepatic protein abundance of IRS-1 (P…
The Journal of physiology, Jan 15, 1996
1. We have investigated the role of the fetal hypothalamo-pituitary axis in the control of adreno... more 1. We have investigated the role of the fetal hypothalamo-pituitary axis in the control of adrenocortical growth and steroidogenesis in the sheep fetus during late gestation. Plasma concentrations of ACTH(1-39) increased between 120-125 and 136-142 days (P < 0.05), but did not change after surgical disconnection of the fetal hypothalamus and pituitary (HPD) at 106-120 days gestation. There was no effect of either gestational age or HPD on the circulating concentrations of the ACTH-containing precursors pro-opiomelanocortin (POMC) and pro-ACTH (the 22 kDa N-terminal portion of POMC). 2. In the fetal sheep adrenal, the relative abundance of the mRNAs of the steroidogenic enzymes CYPIIA1 and CYP21A1 increased between 130-135 and 136-140 days gestation (P < 0.05) and remained high after 141 days, whereas that of CYP17 mRNA increased after 141 days gestation (P < 0.05). The abundance of adrenal 3 beta-HSD mRNA did not change between 130 and 145 days. 3. Hypothalamo-pituitary dis...
Sleep, 1993
We compared the effects of the demands of term and preterm infants on the daily rhythms of sleep ... more We compared the effects of the demands of term and preterm infants on the daily rhythms of sleep and wakefulness and salivary melatonin and cortisol concentrations in mothers for up to 5 months after either birth (term group) or arrival of the infant home (preterm group). Although there were relatively small differences between the term and preterm groups in the daily patterns of infant sleep-wake behavior, there were more marked differences in the maternal sleep-wake parameters. During the first 8 weeks after the arrival of the infant home, the mothers of preterm infants had significantly less time asleep and fewer sleep bouts per 24 hours than did the mothers of term infants. The mothers of preterm infants spent a significantly longer proportion of each night awake (30-40%) for the first 8 weeks than did the mothers of the term infants (20-30%). There was also a significant difference between the term and preterm groups in the effect of time of day on maternal salivary melatonin c...
Journal of Physiology-London, 2007
Restricted growth before birth is associated with impaired insulin secretion but with initially e... more Restricted growth before birth is associated with impaired insulin secretion but with initially enhanced insulin sensitivity in early postnatal life, which then progresses to insulin resistance and impaired glucose homeostasis by adulthood. This suggests that prenatal restraint impairs insulin secretion, but increases insulin sensitivity, before birth. Poor placental growth and function are major causes of restricted fetal growth in humans. We have therefore investigated the effects of restricted placental growth and function on plasma glucose, α-amino nitrogen and insulin concentrations and glucose-and arginine-stimulated insulin secretion in the fetal sheep at 120 and 140 days gestational age, and on insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp, at 130 days gestational age. Placental restriction decreased fetal blood pH and oxygen content, and weight in late gestation by ∼20%. Reduced fetal and placental weights and indices of poor placental function, in particular fetal hypoxia and hypoglycaemia, were associated with impaired glucose-and arginine-stimulated insulin secretion, but not with changes in insulin sensitivity in the fetal sheep. We conclude that the impaired insulin secretion capacity reported in children and adults after intrauterine growth restriction, and in the neonatal and young adult sheep which is small at birth, is present in utero and persists. Whether this reflects the actions of the adverse intrauterine environment or changes to intrinsic capacity is unclear, but in utero interventions may be necessary to improve postnatal insulin secretion in the infant who is growth-restricted before birth.
The Journal of Physiology, 2005
In the present study, our aim was to determine whether intrafetal glucose infusion increases feta... more In the present study, our aim was to determine whether intrafetal glucose infusion increases fetal adiposity, synthesis and secretion of leptin and regulates gene expression of the 'appetite regulatory' neuropeptides neuropepetide Y (NPY), agouti-related peptide (AGRP), pro-opiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART) and receptors (leptin receptor (OB-Rb) and melancortin 3 receptor (MC3R)) within the fetal hypothalamus. Glucose (50% dextrose in saline) or saline was infused (7.5 ml h −1 ) into fetal sheep between 130 and 140 days gestation (term = 150 ± 3 days gestation). Glucose infusion increased circulating glucose and insulin concentrations, mean lipid locule size (532.8 ± 3.3 µm 2 versus 456.7 ± 14.8 µm 2 ) and total unilocular fat mass (11.7 ± 0.6 g versus 8.9 ± 0.6 g) of the perirenal fat depot. The expression of OB-Rb mRNA was higher in the ventromedial nucleus compared to the arcuate nucleus of the hypothalamus in both glucose and saline infused fetuses (F = 8.04; P < 0.01) and there was a positive correlation between expression of OB-Rb and MC3R mRNA in the arcuate nucleus (r = 0.81; P < 0.005). Glucose infusion increased mRNA expression for POMC, but not for the anorectic neuropeptide CART, or the orexigenic neuropeptides NPY and AGRP, in the arcuate nucleus of the fetal hypothalamus. These findings demonstrate that increased circulating glucose and insulin regulate gene expression of the neuropeptides within the fetal hypothalamus that are part of the neural network regulating energy balance in adult life.
Reproduction, 2007
The efficiency of cloning by somatic cell nuclear transfer (SCNT) is poor in livestock with appro... more The efficiency of cloning by somatic cell nuclear transfer (SCNT) is poor in livestock with approximately 5% of transferred cloned embryos developing to term. SCNT is associated with gross placental structural abnormalities. We aimed to identify defects in placental histology and gene expression in failing ovine cloned pregnancies to better understand why so many clones generated by SCNT die in utero. Placentomes from SCNT pregnancies (n = 9) and age matched, naturally mated controls (n = 20) were collected at two gestational age ranges (105-134 days and 135-154 days; term = 147 days). There was no effect of cloning on total placental weight. However, cloning reduced the number of placentomes at both gestational ages (105-134 days: control 55.0 +/- 4.2, clone 44.7 +/- 8.0 and 135-154 days: control 72.2 +/- 5.1, clone 36.6 +/- 5.1; P < 0.001) and increased the mean individual placentome weight (105-134 days: control 10.6 +/- 1.3 g, clone 18.6 +/- 2.8 g and 135-154 days: control 6.6 +/- 0.6 g, clone 7.0 +/- 2.0 g; P < 0.02). Placentomes from cloned pregnancies had a significant volume of shed trophoblast and fetal villous hemorrhage, absent in controls, at both gestational age ranges (P < 0.001) that was shown to be apoptotic by activated caspase-3 immunoreactivity. Consequently, the volume of intact trophoblast was reduced and the arithmetic mean barrier thickness of trophoblast through which exchange occurs was altered (P < 0.001) at both gestational age ranges in clones. In addition, cloning reduced placental expression of key genes in placental differentiation and function. Thus, cloning by SCNT results in both gross and microscopic placental abnormalities. We speculate that trophoblast apoptosis, shedding, and hemorrhage may be causal in fetal death in ovine clones.
Organogenesis, 2008
The increasing incidence of obesity in the developed and developing world in the last decade has ... more The increasing incidence of obesity in the developed and developing world in the last decade has led to a need to define our understanding of the physiological mechanisms which can predispose individuals to weight gain in infancy, childhood and adulthood. There is now a considerable body of evidence which has shown that the pathway to obesity may begin very early in life, and that exposure to an inappropriate level of nutrition during prenatal and/or early postnatal development can predispose individuals to obesity in later life The brain is at the heart of the regulation of appetite and food preferences, and it is increasingly being recognized that the development of central appetitive structures is acutely sensitive to the nutritional environment both before and immediately after birth. This review will summarize the body of work which has highlighted the critical role of the brain in the early origins of obesity and presents some perspectives as to the potential application of these research findings in the clinical setting.
Journal of Pineal Research, 1994
Effect of two weeks of continuous light on the development of the circadian melatonin newborn lam... more Effect of two weeks of continuous light on the development of the circadian melatonin newborn lambs Fielke SI, Young IR, Walker DW, McMillen IC. Effect of two weeks of continuous light on the development of the circadian melatonin rhythm in newborn lambs.
Journal of Pharmaceutical and Biomedical Analysis, 2011
This paper describes the development of a sensitive high performance liquid chromatography (HPLC)... more This paper describes the development of a sensitive high performance liquid chromatography (HPLC) method for quantification of rosiglitazone in sheep plasma and amniotic fluid. Samples were prepared by liquid-liquid extraction using tert-butyl methyl ether, and rosiglitazone was quantitated by HPLC using a C18 column and fluorescence detector with an excitation wavelength of 247 nm and emission wavelength of 367 nm. The mobile phase consisted of ammonium acetate (10 mM, pH 5.2) and acetonitrile (56.5:43.5, v/v) with a flow rate of 1 ml/min. Ketoconazole was used as the internal standard (IS).
Journal of Neuroendocrinology, 2004
In the adult, a hypothalamic neural network acts to maintain energy balance in response to nutrit... more In the adult, a hypothalamic neural network acts to maintain energy balance in response to nutritional feedback from the periphery. Although there is an immediate requirement for this system to be functional at birth, it is unknown whether the components of this central neural network are expressed in the developing brain before birth. We therefore examined in the fetal sheep hypothalamus during late gestation gene expression for leptin receptor (OB-Rb) and neuropeptides that regulate energy balance in the adult. Brains were collected from fetal sheep at 110 days (n ¼ 12) and 140 days of gestation (n ¼ 5) (term ¼ 150 days) and gene expression was detected in all hypothalami using in situ hybridization with radiolabelled riboprobes for OB-Rb, neuropeptide Y (NPY), agouti-related peptide, pro-opiomelanocortin and cocaine-and amphetamine-regulated transcript (CART). All mRNAs were expressed in the arcuate nucleus of fetuses at both time points. Additional sites of mRNA expression were the dorsomedial hypothalamus (DMH) for NPY, the paraventricular nucleus (PVN), ventromedial hypothalamus (VMH) and lateral hypothalamic area for CART, and the DMH, PVN and VMH for OB-Rb. We have therefore demonstrated that adult-like localization of gene expression for OB-Rb and key appetite regulatory neuropeptides is established in the ovine hypothalamus before birth. Thus, the fetus possesses a central appetite regulatory neural network with the potential to respond to changes in nutrient supply, which could impact on energy balance regulation both before and after birth.
Journal of Neuroendocrinology, 1996
The neuroendocrine control of prolactin synthesis and secretion before birth is not well understo... more The neuroendocrine control of prolactin synthesis and secretion before birth is not well understood. We have measured the changes in the level of prolactin mRNA in the anterior pituitary of the fetal sheep throughout the last 15 days of pregnancy (term=147f3 days gestation). We have also investigated the effects of surgical disconnection of the fetal hypothalamus and pituitary (HPD) with or without long term cortisol infusion on pituitary prolactin mRNA levels and plasma prolactin concentrations in the late gestation sheep fetus. Prolactin mRNA levels were measured in anterior pituitaries collected from a series of fetal sheep (130-134 days, n=6; 135-140 days, n =6; 141 -1 45 days, n = 6) in late gestation. HPD was carried out in ten fetal sheep at 105-1 15 days gestation and five intact fetal sheep were used as controls. In the HPD group, either saline (HPD+saline group, n=5) or cortisol was infused (3.5mg/24 h) for 5 days from 134-136 days gestation (HPD+cortisol group, n=5). There was an increase in the ratio of prolactin mRNA: 18s rRNA in the fetal pituitary between 130-1 34 days (0.46 f 0.08, n = 6) and 135-1 40 days (1.27 f 0.1 7 n = 6) which was maintained after 141 days gestation, (1.27 + 0.1 1, n=6). The mean prolactin mRNA: 18 S rRNA ratio was significantly higher (P<O.O5) in intact fetal sheep (1.41 kO.16, n=4) than in the HPD fetal sheep after either saline (0.54k0.14, n =4) or cortisol (0.74k0.24, n =5) administration. The mean plasma concentration of prolactin was also higher in the intact group (28.3 k 3.9 ng/ml) when compared with the HPD + saline group (8.0 3.3 ng/ml) or the HPD +cortisol group (5.6 f 1.9 ng/ml). We have demonstrated that there is a strong hypothalamic drive to prolactin synthesis and secretion in the fetus and that cortisol does not act directly at the fetal pituitary to stimulate prolactin synthesis and secretion in late gestation.
Journal of Endocrinology, 1995
We have used a perifusion system and slices of the anterior pituitary of the fetal sheep combined... more We have used a perifusion system and slices of the anterior pituitary of the fetal sheep combined with specific immunoradiometric assays to investigate the effect of increasing gestational age and cortisol infusion on the output of ACTH(1-39) and the ACTH precursors, pro-ACTH and pro-opiomelanocortin, from the fetal sheep pituitary. Two slices from each fetal anterior pituitary at 106-113 days (n = 3), 120-136 days (n = 5) and 140-143 days (n = 5) of gestation were used. Slices from each anterior pituitary were perifused with the perifusion buffer for at least 120 min prior to the infusion of cortisol (100 nM) for 30 min or buffer alone (control). The anterior pituitary output (fmol/5 min per mg pituitary) of ACTH(1-39) and the ACTH precursors were measured using specific immunoradiometric assays. There was a significant increase in the anterior pituitary secretion rate of ACTH(1-39) between 120 and 136 days (1.04 +/- 0.23 fmol/5 min per mg) and between 140 and 143 days of gestation (3.08 +/- 0.33 fmol/5 min per mg). In contrast, there was no change in the secretory rate of the ACTH precursors between 105 and 143 days of gestation. The ratio of the anterior pituitary output of the ACTH precursors:ACTH(1-39) therefore decreased between 120 and 143 of days gestation from 19.10 +/- 2.05 to 6.36 +/- 0.58. There was no effect of cortisol infusion on the anterior pituitary secretion of either ACTH(1-39) or the ACTH precursors before 116 days of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Endocrinology, 1990
We have monitored the 24-h profiles of plasma melatonin concentrations between birth and 10 weeks... more We have monitored the 24-h profiles of plasma melatonin concentrations between birth and 10 weeks of age, in lambs which were delivered to, and suckled, either pineal-intact (control group) or pinealectomized (pinealectomized group) ewes. Between 0 and 2 weeks of age, plasma concentrations of melatonin in lambs suckling either intact or pinealectomized ewes were highest at 01.00 h. At this age, however, there was no significant difference in the mean plasma concentrations of melatonin between the entire dark and light phases in lambs in either the control group (dark, 39.7 +/- 6.0 (S.E.M.) pmol/l; light, 39.5 +/- 8.1 pmol/l) or the pinealectomized group (dark, 79.8 +/- 43.3 pmol/l; light, 60.9 +/- 8.7 pmol/l). Between 3 and 4 weeks of age, however, a diurnal rhythm in plasma melatonin concentrations was clearly present in the lambs in both the control and pinealectomized groups (control group: dark, 164.1 +/- 5.6 pmol/l; light 26.2 +/- 2.5 pmol/l; pinealectomized group: dark, 52.7 +/- 8.0 pmol/l; light, 19.1 +/- 5.3 pmol/l; P less than 0.001). Between 3 and 10 weeks of age, plasma concentrations of melatonin in the dark phase were significantly (P less than 0.05) lower in the lambs suckling pinealectomized ewes than in the control group. In both the control lambs and lambs suckling pinealectomized ewes, the mean plasma concentrations of melatonin in the dark and light phases increased significantly (P less than 0.05) between 3 and 6 weeks after birth. In conclusion, we have demonstrated that a clear diurnal plasma rhythm in melatonin concentrations does not emerge until 3-4 weeks of age in lambs suckling either pinealectomized or intact ewes.(ABSTRACT TRUNCATED AT 250 WORDS)
European Journal of Endocrinology, 1993
We have measured the relative levels of proopiomelanocortin (POMC), prolactin (PRL) and growth ho... more We have measured the relative levels of proopiomelanocortin (POMC), prolactin (PRL) and growth hormone (GH) messenger ribonucleic acid (mRNA) in the anterior and neurointermediate lobes of the fetal pituitary during the last 2-3 weeks of gestation. The mean POMC mRNA/18S RNA ratio in the fetal anterior pituitary was significantly greater (p < 0.02) at 130-136 days (0.90 +/- 0.08; N = 9) than at 141-143 days of gestation (0.67 +/- 0.07; N = 6). In contrast, the mean PRL mRNA/18S RNA ratio increased significantly (p < 0.02) between 130 and 136 days (0.31 +/- 0.05; N = 9) when compared with 141-143 days of gestation (0.58 +/- 0.10; N = 6). There was no significant difference, however, between the mean GH mRNA/18S RNA ratio in fetal anterior pituitaries at 130-136 days (0.95 +/- 0.04; N = 9) when compared with 141-143 days of gestation (1.08 +/- 0.14; N = 6). The POMC mRNA/18S RNA ratio in the neurointermediate lobes was seven-, five- and tenfold higher than anterior pituitaries at 130-134, 135-136 and 141-143 days of gestation, respectively. We hypothesize that elevated circulating cortisol levels after 140 days of gestation act in the slow time domain (i.e. over days) to suppress POMC gene expression and that the increase in fetal pituitary PRL mRNA levels may be a consequence of oestrogen stimulation in late gestation.
Endocrinology, 1988
We have measured plasma melatonin (MT) concentrations in the pregnant ewe and fetal sheep during ... more We have measured plasma melatonin (MT) concentrations in the pregnant ewe and fetal sheep during 24-h periods between 114 and 142 days gestation. There was a clear diurnal rhythm in the plasma MT concentrations in both the ewe and fetus from 114 days gestation. Blood samples were also collected from the pregnant ewe and fetus during the day every 2-3 days from 112 days gestation to term. There was no gestational age trend in maternal or fetal day time plasma MT concentrations during late pregnancy. To establish whether there was transplacental transfer of MT, pregnant ewes were injected with [3H]MT, and total radioactivity (disintegrations per min) was measured in maternal and fetal arterial plasma and in amniotic fluid collected before and for 1 h after the [3H]MT injection. Two minutes after [3H]MT injection, radioactivity was detected in both maternal and fetal sheep plasma. Extraction of fetal plasma with chloroform indicated that [3H]MT accounted for 48.0 +/- 7.2 (SE) % of total radioactivity at 2 min after the injection. In one pregnant ewe infused with unlabeled MT (0.3 microgram/ml saline.min for 20 min) maternal and fetal plasma MT concentrations increased within 6 min after the start of the MT infusion. We conclude that there is a diurnal rhythm in the plasma concentrations of MT in the fetal lamb and pregnant ewe between 114 and 142 days gestation, and that MT crosses the ovine placenta from the maternal to the fetal circulation. Therefore, the MT present in the fetal sheep circulation may be solely of maternal origin or it may be derived from both fetal and maternal sources.
AJP: Regulatory, Integrative and Comparative Physiology, 2004
It has been proposed that maternal nutrient restriction may alter the functional development of t... more It has been proposed that maternal nutrient restriction may alter the functional development of the adipocyte and the synthesis and secretion of the adipocyte-derived hormone, leptin, before birth. We have investigated the effects of restricted periconceptional undernutrition and/or restricted gestational nutrition on fetal plasma leptin concentrations and fetal adiposity in late gestation. There was no effect of either restricted periconceptional or gestational nutrition on maternal or fetal plasma leptin concentrations in singleton or twin pregnancies during late gestation. In ewes carrying twins, but not singletons, maternal plasma leptin concentrations in late gestation were directly related to the change in ewe weight that occurred during the 60 days before mating [maternal leptin ϭ 0.9 (change in ewe weight) ϩ 7.8; r ϭ 0.6, P Ͻ 0.05]. In twin, but not singleton, pregnancies, there was also a significant relationship between maternal and fetal leptin concentrations (maternal leptin ϭ 0.5 fetal leptin ϩ 4.2, r ϭ 0.63, P Ͻ 0.005). The relative mass of perirenal fat was also significantly increased in twin fetal sheep in the control-restricted group (6.0 Ϯ 0.5) compared with the other nutritional groups (controlcontrol: 4.
AJP: Lung Cellular and Molecular Physiology, 2010
Pulmonary surfactant is synthesized by type II alveolar epithelial cells to regulate the surface ... more Pulmonary surfactant is synthesized by type II alveolar epithelial cells to regulate the surface tension at the air-liquid interface of the air-breathing lung. Developmental maturation of the surfactant system is controlled by many factors including oxygen, glucose, catecholamines, and cortisol. The intrauterine growth-restricted (IUGR) fetus is hypoxemic and hypoglycemic, with elevated plasma catecholamine and cortisol concentrations. The impact of IUGR on surfactant maturation is unclear. Here we investigate the expression of surfactant protein (SP) A, B, and C in lung tissue of fetal sheep at 133 and 141 days of gestation (term 150 +/- 3 days) from control and carunclectomized Merino ewes. Placentally restricted (PR) fetuses had a body weight &amp;lt;2 SD from the mean of control fetuses and a mean gestational Pa(O(2)) &amp;lt;17 mmHg. PR fetuses had reduced absolute, but not relative, lung weight, decreased plasma glucose concentration, and increased plasma cortisol concentration. Lung SP-A, -B, and -C protein and mRNA expression was reduced in PR compared with control fetuses at both ages. SP-B and -C but not SP-A mRNA expression and SP-A but not SP-B or -C protein expression increased with gestational age. Mean gestational Pa(O(2)) was positively correlated with SP-A, -B, and -C protein and SP-B and -C mRNA expression in the younger cohort. SP-A and -B gene expression was inversely related to plasma cortisol concentration. Placental restriction, leading to chronic hypoxemia and hypercortisolemia in the carunclectomy model, results in significant inhibition of surfactant maturation. These data suggest that IUGR fetuses are at significant risk of lung complications, especially if born prematurely.
Reproduction (Cambridge, England), 2011
Changes in maternal nutrient intake during gestation alter IGF receptor abundance and leptin (LEP... more Changes in maternal nutrient intake during gestation alter IGF receptor abundance and leptin (LEP) mRNA expression in fetal adipose tissue. It is not known whether such changes persist into adult life and whether they are associated with an effect on phenotype. We investigated the effect of high (240%) and low (70%) levels of recommended daily crude protein intake for beef heifers during the first and second trimesters of gestation on singleton progeny (n=68): subcutaneous (SC) adipose tissue depth at rump (P8) and rib (RF) sites from 65 until 657 days of age; plasma leptin concentrations from birth until 657 days and expression of IGF1 and IGF2, their receptors (IGF1R and IGF2R) and LEP mRNA in perirenal (PR), omental (OM) and SC adipose tissue at 680 days of age. High-protein diets during the first trimester increased LEP and IGF1 mRNA in PR of males and females, respectively, compared with low-protein diets, and decreased IGF1R mRNA in SC of all progeny but increased RF depth of ...
Nutrients, 2015
Assisted Reproductive Technologies (ARTs) have revolutionised reproductive medicine; however, rep... more Assisted Reproductive Technologies (ARTs) have revolutionised reproductive medicine; however, reports assessing the effects of ARTs have raised concerns about the immediate and long-term health outcomes of the children conceived through ARTs. ARTs include manipulations during the periconceptional period, which coincides with an environmentally sensitive period of gamete/embryo development and as such may alter cardiovascular development and health of the offspring in postnatal life. In order to identify the association between ARTs and cardiovascular health outcomes, it is important to understand the events that occur during the periconceptional period and how they are affected by procedures involved in ARTs. This review will highlight the emerging evidence implicating adverse cardiovascular outcomes before and after birth in offspring conceived through ARTs in both human and animal studies. In addition, it will identify the potential underlying causes and molecular mechanisms respo...
During fetal life, it is critical that there is coordinate regulation of the growth, zonation and... more 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 post-natal 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 glucocor-ticoids 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.
AJP: Endocrinology and Metabolism, 2014
This study aimed to determine whether exposure of the oocyte and/or embryo to maternal undernutri... more This study aimed to determine whether exposure of the oocyte and/or embryo to maternal undernutrition results in the later programming of insulin action in the liver and factors regulating gluconeogenesis. To do this, we collect livers from singleton and twin fetal sheep that were exposed to periconceptional (PCUN; -60 to 7 days) or preimplantation (PIUN; 0-7 days) undernutrition at 136-138 days of gestation (term = 150 days). The mRNA and protein abundance of insulin signaling and gluconeogenic factors were then quantified using qRT-PCR and Western blotting, respectively, and global microRNA expression was quantified using deep sequencing methodology. We found that hepatic PEPCK-C mRNA (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01) and protein abundance and the protein abundance of IRS-1 (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), p110β (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), PTEN (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), CREB (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01), and pCREB (Ser(133); P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) were decreased in the PCUN and PIUN singletons. In contrast, hepatic protein abundance of IRS-1 (P…
The Journal of physiology, Jan 15, 1996
1. We have investigated the role of the fetal hypothalamo-pituitary axis in the control of adreno... more 1. We have investigated the role of the fetal hypothalamo-pituitary axis in the control of adrenocortical growth and steroidogenesis in the sheep fetus during late gestation. Plasma concentrations of ACTH(1-39) increased between 120-125 and 136-142 days (P < 0.05), but did not change after surgical disconnection of the fetal hypothalamus and pituitary (HPD) at 106-120 days gestation. There was no effect of either gestational age or HPD on the circulating concentrations of the ACTH-containing precursors pro-opiomelanocortin (POMC) and pro-ACTH (the 22 kDa N-terminal portion of POMC). 2. In the fetal sheep adrenal, the relative abundance of the mRNAs of the steroidogenic enzymes CYPIIA1 and CYP21A1 increased between 130-135 and 136-140 days gestation (P < 0.05) and remained high after 141 days, whereas that of CYP17 mRNA increased after 141 days gestation (P < 0.05). The abundance of adrenal 3 beta-HSD mRNA did not change between 130 and 145 days. 3. Hypothalamo-pituitary dis...
Sleep, 1993
We compared the effects of the demands of term and preterm infants on the daily rhythms of sleep ... more We compared the effects of the demands of term and preterm infants on the daily rhythms of sleep and wakefulness and salivary melatonin and cortisol concentrations in mothers for up to 5 months after either birth (term group) or arrival of the infant home (preterm group). Although there were relatively small differences between the term and preterm groups in the daily patterns of infant sleep-wake behavior, there were more marked differences in the maternal sleep-wake parameters. During the first 8 weeks after the arrival of the infant home, the mothers of preterm infants had significantly less time asleep and fewer sleep bouts per 24 hours than did the mothers of term infants. The mothers of preterm infants spent a significantly longer proportion of each night awake (30-40%) for the first 8 weeks than did the mothers of the term infants (20-30%). There was also a significant difference between the term and preterm groups in the effect of time of day on maternal salivary melatonin c...
Journal of Physiology-London, 2007
Restricted growth before birth is associated with impaired insulin secretion but with initially e... more Restricted growth before birth is associated with impaired insulin secretion but with initially enhanced insulin sensitivity in early postnatal life, which then progresses to insulin resistance and impaired glucose homeostasis by adulthood. This suggests that prenatal restraint impairs insulin secretion, but increases insulin sensitivity, before birth. Poor placental growth and function are major causes of restricted fetal growth in humans. We have therefore investigated the effects of restricted placental growth and function on plasma glucose, α-amino nitrogen and insulin concentrations and glucose-and arginine-stimulated insulin secretion in the fetal sheep at 120 and 140 days gestational age, and on insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp, at 130 days gestational age. Placental restriction decreased fetal blood pH and oxygen content, and weight in late gestation by ∼20%. Reduced fetal and placental weights and indices of poor placental function, in particular fetal hypoxia and hypoglycaemia, were associated with impaired glucose-and arginine-stimulated insulin secretion, but not with changes in insulin sensitivity in the fetal sheep. We conclude that the impaired insulin secretion capacity reported in children and adults after intrauterine growth restriction, and in the neonatal and young adult sheep which is small at birth, is present in utero and persists. Whether this reflects the actions of the adverse intrauterine environment or changes to intrinsic capacity is unclear, but in utero interventions may be necessary to improve postnatal insulin secretion in the infant who is growth-restricted before birth.
The Journal of Physiology, 2005
In the present study, our aim was to determine whether intrafetal glucose infusion increases feta... more In the present study, our aim was to determine whether intrafetal glucose infusion increases fetal adiposity, synthesis and secretion of leptin and regulates gene expression of the 'appetite regulatory' neuropeptides neuropepetide Y (NPY), agouti-related peptide (AGRP), pro-opiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART) and receptors (leptin receptor (OB-Rb) and melancortin 3 receptor (MC3R)) within the fetal hypothalamus. Glucose (50% dextrose in saline) or saline was infused (7.5 ml h −1 ) into fetal sheep between 130 and 140 days gestation (term = 150 ± 3 days gestation). Glucose infusion increased circulating glucose and insulin concentrations, mean lipid locule size (532.8 ± 3.3 µm 2 versus 456.7 ± 14.8 µm 2 ) and total unilocular fat mass (11.7 ± 0.6 g versus 8.9 ± 0.6 g) of the perirenal fat depot. The expression of OB-Rb mRNA was higher in the ventromedial nucleus compared to the arcuate nucleus of the hypothalamus in both glucose and saline infused fetuses (F = 8.04; P < 0.01) and there was a positive correlation between expression of OB-Rb and MC3R mRNA in the arcuate nucleus (r = 0.81; P < 0.005). Glucose infusion increased mRNA expression for POMC, but not for the anorectic neuropeptide CART, or the orexigenic neuropeptides NPY and AGRP, in the arcuate nucleus of the fetal hypothalamus. These findings demonstrate that increased circulating glucose and insulin regulate gene expression of the neuropeptides within the fetal hypothalamus that are part of the neural network regulating energy balance in adult life.
Reproduction, 2007
The efficiency of cloning by somatic cell nuclear transfer (SCNT) is poor in livestock with appro... more The efficiency of cloning by somatic cell nuclear transfer (SCNT) is poor in livestock with approximately 5% of transferred cloned embryos developing to term. SCNT is associated with gross placental structural abnormalities. We aimed to identify defects in placental histology and gene expression in failing ovine cloned pregnancies to better understand why so many clones generated by SCNT die in utero. Placentomes from SCNT pregnancies (n = 9) and age matched, naturally mated controls (n = 20) were collected at two gestational age ranges (105-134 days and 135-154 days; term = 147 days). There was no effect of cloning on total placental weight. However, cloning reduced the number of placentomes at both gestational ages (105-134 days: control 55.0 +/- 4.2, clone 44.7 +/- 8.0 and 135-154 days: control 72.2 +/- 5.1, clone 36.6 +/- 5.1; P < 0.001) and increased the mean individual placentome weight (105-134 days: control 10.6 +/- 1.3 g, clone 18.6 +/- 2.8 g and 135-154 days: control 6.6 +/- 0.6 g, clone 7.0 +/- 2.0 g; P < 0.02). Placentomes from cloned pregnancies had a significant volume of shed trophoblast and fetal villous hemorrhage, absent in controls, at both gestational age ranges (P < 0.001) that was shown to be apoptotic by activated caspase-3 immunoreactivity. Consequently, the volume of intact trophoblast was reduced and the arithmetic mean barrier thickness of trophoblast through which exchange occurs was altered (P < 0.001) at both gestational age ranges in clones. In addition, cloning reduced placental expression of key genes in placental differentiation and function. Thus, cloning by SCNT results in both gross and microscopic placental abnormalities. We speculate that trophoblast apoptosis, shedding, and hemorrhage may be causal in fetal death in ovine clones.
Organogenesis, 2008
The increasing incidence of obesity in the developed and developing world in the last decade has ... more The increasing incidence of obesity in the developed and developing world in the last decade has led to a need to define our understanding of the physiological mechanisms which can predispose individuals to weight gain in infancy, childhood and adulthood. There is now a considerable body of evidence which has shown that the pathway to obesity may begin very early in life, and that exposure to an inappropriate level of nutrition during prenatal and/or early postnatal development can predispose individuals to obesity in later life The brain is at the heart of the regulation of appetite and food preferences, and it is increasingly being recognized that the development of central appetitive structures is acutely sensitive to the nutritional environment both before and immediately after birth. This review will summarize the body of work which has highlighted the critical role of the brain in the early origins of obesity and presents some perspectives as to the potential application of these research findings in the clinical setting.
Journal of Pineal Research, 1994
Effect of two weeks of continuous light on the development of the circadian melatonin newborn lam... more Effect of two weeks of continuous light on the development of the circadian melatonin newborn lambs Fielke SI, Young IR, Walker DW, McMillen IC. Effect of two weeks of continuous light on the development of the circadian melatonin rhythm in newborn lambs.
Journal of Pharmaceutical and Biomedical Analysis, 2011
This paper describes the development of a sensitive high performance liquid chromatography (HPLC)... more This paper describes the development of a sensitive high performance liquid chromatography (HPLC) method for quantification of rosiglitazone in sheep plasma and amniotic fluid. Samples were prepared by liquid-liquid extraction using tert-butyl methyl ether, and rosiglitazone was quantitated by HPLC using a C18 column and fluorescence detector with an excitation wavelength of 247 nm and emission wavelength of 367 nm. The mobile phase consisted of ammonium acetate (10 mM, pH 5.2) and acetonitrile (56.5:43.5, v/v) with a flow rate of 1 ml/min. Ketoconazole was used as the internal standard (IS).
Journal of Neuroendocrinology, 2004
In the adult, a hypothalamic neural network acts to maintain energy balance in response to nutrit... more In the adult, a hypothalamic neural network acts to maintain energy balance in response to nutritional feedback from the periphery. Although there is an immediate requirement for this system to be functional at birth, it is unknown whether the components of this central neural network are expressed in the developing brain before birth. We therefore examined in the fetal sheep hypothalamus during late gestation gene expression for leptin receptor (OB-Rb) and neuropeptides that regulate energy balance in the adult. Brains were collected from fetal sheep at 110 days (n ¼ 12) and 140 days of gestation (n ¼ 5) (term ¼ 150 days) and gene expression was detected in all hypothalami using in situ hybridization with radiolabelled riboprobes for OB-Rb, neuropeptide Y (NPY), agouti-related peptide, pro-opiomelanocortin and cocaine-and amphetamine-regulated transcript (CART). All mRNAs were expressed in the arcuate nucleus of fetuses at both time points. Additional sites of mRNA expression were the dorsomedial hypothalamus (DMH) for NPY, the paraventricular nucleus (PVN), ventromedial hypothalamus (VMH) and lateral hypothalamic area for CART, and the DMH, PVN and VMH for OB-Rb. We have therefore demonstrated that adult-like localization of gene expression for OB-Rb and key appetite regulatory neuropeptides is established in the ovine hypothalamus before birth. Thus, the fetus possesses a central appetite regulatory neural network with the potential to respond to changes in nutrient supply, which could impact on energy balance regulation both before and after birth.
Journal of Neuroendocrinology, 1996
The neuroendocrine control of prolactin synthesis and secretion before birth is not well understo... more The neuroendocrine control of prolactin synthesis and secretion before birth is not well understood. We have measured the changes in the level of prolactin mRNA in the anterior pituitary of the fetal sheep throughout the last 15 days of pregnancy (term=147f3 days gestation). We have also investigated the effects of surgical disconnection of the fetal hypothalamus and pituitary (HPD) with or without long term cortisol infusion on pituitary prolactin mRNA levels and plasma prolactin concentrations in the late gestation sheep fetus. Prolactin mRNA levels were measured in anterior pituitaries collected from a series of fetal sheep (130-134 days, n=6; 135-140 days, n =6; 141 -1 45 days, n = 6) in late gestation. HPD was carried out in ten fetal sheep at 105-1 15 days gestation and five intact fetal sheep were used as controls. In the HPD group, either saline (HPD+saline group, n=5) or cortisol was infused (3.5mg/24 h) for 5 days from 134-136 days gestation (HPD+cortisol group, n=5). There was an increase in the ratio of prolactin mRNA: 18s rRNA in the fetal pituitary between 130-1 34 days (0.46 f 0.08, n = 6) and 135-1 40 days (1.27 f 0.1 7 n = 6) which was maintained after 141 days gestation, (1.27 + 0.1 1, n=6). The mean prolactin mRNA: 18 S rRNA ratio was significantly higher (P<O.O5) in intact fetal sheep (1.41 kO.16, n=4) than in the HPD fetal sheep after either saline (0.54k0.14, n =4) or cortisol (0.74k0.24, n =5) administration. The mean plasma concentration of prolactin was also higher in the intact group (28.3 k 3.9 ng/ml) when compared with the HPD + saline group (8.0 3.3 ng/ml) or the HPD +cortisol group (5.6 f 1.9 ng/ml). We have demonstrated that there is a strong hypothalamic drive to prolactin synthesis and secretion in the fetus and that cortisol does not act directly at the fetal pituitary to stimulate prolactin synthesis and secretion in late gestation.
Journal of Endocrinology, 1995
We have used a perifusion system and slices of the anterior pituitary of the fetal sheep combined... more We have used a perifusion system and slices of the anterior pituitary of the fetal sheep combined with specific immunoradiometric assays to investigate the effect of increasing gestational age and cortisol infusion on the output of ACTH(1-39) and the ACTH precursors, pro-ACTH and pro-opiomelanocortin, from the fetal sheep pituitary. Two slices from each fetal anterior pituitary at 106-113 days (n = 3), 120-136 days (n = 5) and 140-143 days (n = 5) of gestation were used. Slices from each anterior pituitary were perifused with the perifusion buffer for at least 120 min prior to the infusion of cortisol (100 nM) for 30 min or buffer alone (control). The anterior pituitary output (fmol/5 min per mg pituitary) of ACTH(1-39) and the ACTH precursors were measured using specific immunoradiometric assays. There was a significant increase in the anterior pituitary secretion rate of ACTH(1-39) between 120 and 136 days (1.04 +/- 0.23 fmol/5 min per mg) and between 140 and 143 days of gestation (3.08 +/- 0.33 fmol/5 min per mg). In contrast, there was no change in the secretory rate of the ACTH precursors between 105 and 143 days of gestation. The ratio of the anterior pituitary output of the ACTH precursors:ACTH(1-39) therefore decreased between 120 and 143 of days gestation from 19.10 +/- 2.05 to 6.36 +/- 0.58. There was no effect of cortisol infusion on the anterior pituitary secretion of either ACTH(1-39) or the ACTH precursors before 116 days of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Endocrinology, 1990
We have monitored the 24-h profiles of plasma melatonin concentrations between birth and 10 weeks... more We have monitored the 24-h profiles of plasma melatonin concentrations between birth and 10 weeks of age, in lambs which were delivered to, and suckled, either pineal-intact (control group) or pinealectomized (pinealectomized group) ewes. Between 0 and 2 weeks of age, plasma concentrations of melatonin in lambs suckling either intact or pinealectomized ewes were highest at 01.00 h. At this age, however, there was no significant difference in the mean plasma concentrations of melatonin between the entire dark and light phases in lambs in either the control group (dark, 39.7 +/- 6.0 (S.E.M.) pmol/l; light, 39.5 +/- 8.1 pmol/l) or the pinealectomized group (dark, 79.8 +/- 43.3 pmol/l; light, 60.9 +/- 8.7 pmol/l). Between 3 and 4 weeks of age, however, a diurnal rhythm in plasma melatonin concentrations was clearly present in the lambs in both the control and pinealectomized groups (control group: dark, 164.1 +/- 5.6 pmol/l; light 26.2 +/- 2.5 pmol/l; pinealectomized group: dark, 52.7 +/- 8.0 pmol/l; light, 19.1 +/- 5.3 pmol/l; P less than 0.001). Between 3 and 10 weeks of age, plasma concentrations of melatonin in the dark phase were significantly (P less than 0.05) lower in the lambs suckling pinealectomized ewes than in the control group. In both the control lambs and lambs suckling pinealectomized ewes, the mean plasma concentrations of melatonin in the dark and light phases increased significantly (P less than 0.05) between 3 and 6 weeks after birth. In conclusion, we have demonstrated that a clear diurnal plasma rhythm in melatonin concentrations does not emerge until 3-4 weeks of age in lambs suckling either pinealectomized or intact ewes.(ABSTRACT TRUNCATED AT 250 WORDS)
European Journal of Endocrinology, 1993
We have measured the relative levels of proopiomelanocortin (POMC), prolactin (PRL) and growth ho... more We have measured the relative levels of proopiomelanocortin (POMC), prolactin (PRL) and growth hormone (GH) messenger ribonucleic acid (mRNA) in the anterior and neurointermediate lobes of the fetal pituitary during the last 2-3 weeks of gestation. The mean POMC mRNA/18S RNA ratio in the fetal anterior pituitary was significantly greater (p < 0.02) at 130-136 days (0.90 +/- 0.08; N = 9) than at 141-143 days of gestation (0.67 +/- 0.07; N = 6). In contrast, the mean PRL mRNA/18S RNA ratio increased significantly (p < 0.02) between 130 and 136 days (0.31 +/- 0.05; N = 9) when compared with 141-143 days of gestation (0.58 +/- 0.10; N = 6). There was no significant difference, however, between the mean GH mRNA/18S RNA ratio in fetal anterior pituitaries at 130-136 days (0.95 +/- 0.04; N = 9) when compared with 141-143 days of gestation (1.08 +/- 0.14; N = 6). The POMC mRNA/18S RNA ratio in the neurointermediate lobes was seven-, five- and tenfold higher than anterior pituitaries at 130-134, 135-136 and 141-143 days of gestation, respectively. We hypothesize that elevated circulating cortisol levels after 140 days of gestation act in the slow time domain (i.e. over days) to suppress POMC gene expression and that the increase in fetal pituitary PRL mRNA levels may be a consequence of oestrogen stimulation in late gestation.
Endocrinology, 1988
We have measured plasma melatonin (MT) concentrations in the pregnant ewe and fetal sheep during ... more We have measured plasma melatonin (MT) concentrations in the pregnant ewe and fetal sheep during 24-h periods between 114 and 142 days gestation. There was a clear diurnal rhythm in the plasma MT concentrations in both the ewe and fetus from 114 days gestation. Blood samples were also collected from the pregnant ewe and fetus during the day every 2-3 days from 112 days gestation to term. There was no gestational age trend in maternal or fetal day time plasma MT concentrations during late pregnancy. To establish whether there was transplacental transfer of MT, pregnant ewes were injected with [3H]MT, and total radioactivity (disintegrations per min) was measured in maternal and fetal arterial plasma and in amniotic fluid collected before and for 1 h after the [3H]MT injection. Two minutes after [3H]MT injection, radioactivity was detected in both maternal and fetal sheep plasma. Extraction of fetal plasma with chloroform indicated that [3H]MT accounted for 48.0 +/- 7.2 (SE) % of total radioactivity at 2 min after the injection. In one pregnant ewe infused with unlabeled MT (0.3 microgram/ml saline.min for 20 min) maternal and fetal plasma MT concentrations increased within 6 min after the start of the MT infusion. We conclude that there is a diurnal rhythm in the plasma concentrations of MT in the fetal lamb and pregnant ewe between 114 and 142 days gestation, and that MT crosses the ovine placenta from the maternal to the fetal circulation. Therefore, the MT present in the fetal sheep circulation may be solely of maternal origin or it may be derived from both fetal and maternal sources.
AJP: Regulatory, Integrative and Comparative Physiology, 2004
It has been proposed that maternal nutrient restriction may alter the functional development of t... more It has been proposed that maternal nutrient restriction may alter the functional development of the adipocyte and the synthesis and secretion of the adipocyte-derived hormone, leptin, before birth. We have investigated the effects of restricted periconceptional undernutrition and/or restricted gestational nutrition on fetal plasma leptin concentrations and fetal adiposity in late gestation. There was no effect of either restricted periconceptional or gestational nutrition on maternal or fetal plasma leptin concentrations in singleton or twin pregnancies during late gestation. In ewes carrying twins, but not singletons, maternal plasma leptin concentrations in late gestation were directly related to the change in ewe weight that occurred during the 60 days before mating [maternal leptin ϭ 0.9 (change in ewe weight) ϩ 7.8; r ϭ 0.6, P Ͻ 0.05]. In twin, but not singleton, pregnancies, there was also a significant relationship between maternal and fetal leptin concentrations (maternal leptin ϭ 0.5 fetal leptin ϩ 4.2, r ϭ 0.63, P Ͻ 0.005). The relative mass of perirenal fat was also significantly increased in twin fetal sheep in the control-restricted group (6.0 Ϯ 0.5) compared with the other nutritional groups (controlcontrol: 4.
AJP: Lung Cellular and Molecular Physiology, 2010
Pulmonary surfactant is synthesized by type II alveolar epithelial cells to regulate the surface ... more Pulmonary surfactant is synthesized by type II alveolar epithelial cells to regulate the surface tension at the air-liquid interface of the air-breathing lung. Developmental maturation of the surfactant system is controlled by many factors including oxygen, glucose, catecholamines, and cortisol. The intrauterine growth-restricted (IUGR) fetus is hypoxemic and hypoglycemic, with elevated plasma catecholamine and cortisol concentrations. The impact of IUGR on surfactant maturation is unclear. Here we investigate the expression of surfactant protein (SP) A, B, and C in lung tissue of fetal sheep at 133 and 141 days of gestation (term 150 +/- 3 days) from control and carunclectomized Merino ewes. Placentally restricted (PR) fetuses had a body weight &amp;lt;2 SD from the mean of control fetuses and a mean gestational Pa(O(2)) &amp;lt;17 mmHg. PR fetuses had reduced absolute, but not relative, lung weight, decreased plasma glucose concentration, and increased plasma cortisol concentration. Lung SP-A, -B, and -C protein and mRNA expression was reduced in PR compared with control fetuses at both ages. SP-B and -C but not SP-A mRNA expression and SP-A but not SP-B or -C protein expression increased with gestational age. Mean gestational Pa(O(2)) was positively correlated with SP-A, -B, and -C protein and SP-B and -C mRNA expression in the younger cohort. SP-A and -B gene expression was inversely related to plasma cortisol concentration. Placental restriction, leading to chronic hypoxemia and hypercortisolemia in the carunclectomy model, results in significant inhibition of surfactant maturation. These data suggest that IUGR fetuses are at significant risk of lung complications, especially if born prematurely.
Reproduction (Cambridge, England), 2011
Changes in maternal nutrient intake during gestation alter IGF receptor abundance and leptin (LEP... more Changes in maternal nutrient intake during gestation alter IGF receptor abundance and leptin (LEP) mRNA expression in fetal adipose tissue. It is not known whether such changes persist into adult life and whether they are associated with an effect on phenotype. We investigated the effect of high (240%) and low (70%) levels of recommended daily crude protein intake for beef heifers during the first and second trimesters of gestation on singleton progeny (n=68): subcutaneous (SC) adipose tissue depth at rump (P8) and rib (RF) sites from 65 until 657 days of age; plasma leptin concentrations from birth until 657 days and expression of IGF1 and IGF2, their receptors (IGF1R and IGF2R) and LEP mRNA in perirenal (PR), omental (OM) and SC adipose tissue at 680 days of age. High-protein diets during the first trimester increased LEP and IGF1 mRNA in PR of males and females, respectively, compared with low-protein diets, and decreased IGF1R mRNA in SC of all progeny but increased RF depth of ...
Nutrients, 2015
Assisted Reproductive Technologies (ARTs) have revolutionised reproductive medicine; however, rep... more Assisted Reproductive Technologies (ARTs) have revolutionised reproductive medicine; however, reports assessing the effects of ARTs have raised concerns about the immediate and long-term health outcomes of the children conceived through ARTs. ARTs include manipulations during the periconceptional period, which coincides with an environmentally sensitive period of gamete/embryo development and as such may alter cardiovascular development and health of the offspring in postnatal life. In order to identify the association between ARTs and cardiovascular health outcomes, it is important to understand the events that occur during the periconceptional period and how they are affected by procedures involved in ARTs. This review will highlight the emerging evidence implicating adverse cardiovascular outcomes before and after birth in offspring conceived through ARTs in both human and animal studies. In addition, it will identify the potential underlying causes and molecular mechanisms respo...