ORCID Profile
0000-0002-1455-0615
Current Organisation
University of Southampton
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1016/J.PLACENTA.2021.05.009
Abstract: Placental oxidative stress features in pregnancy pathologies but in clinical trials antioxidant supplementation has not improved outcomes. N-acetylcysteine (NAC) stimulates glutathione production and is proposed as a therapeutic agent in pregnancy. However, key elements of N-acetylcysteine biology, including its cellular uptake mechanism, remains unclear. This study explores how the cystine/glutamate transporter xCT may mediate N-acetylcysteine uptake and how N-acetylcysteine alters placental redox status. The involvement of xCT in NAC uptake by the human placenta was studied in perfused placenta and Xenopus oocytes. The effect of short-term N-acetylcysteine exposure on the placental villous proteome was determined using LC-MS. The effect of N-acetylcysteine on Maxi-chloride channel activity was investigated in perfused placenta, villous fragments and cell culture. Maternoplacental N-acetylcysteine administration stimulated intracellular glutamate efflux suggesting a role of the exchange transporter xCT, which was localised to the microvillous membrane of the placental syncytiotrophoblast. Placental exposure to a bolus of N-acetylcysteine inhibited subsequent activation of the redox sensitive Maxi-chloride channel independently of glutathione synthesis. Stable isotope quantitative proteomics of placental villi treated with N-acetylcysteine demonstrated changes in pathways associated with oxidative stress, apoptosis and the acute phase response. This study suggests that xCT mediates N-acetylcysteine uptake into the placenta and that N-acetylcysteine treatment of placental tissue alters the placental proteome while regulating the redox sensitive Maxi-chloride channel. Interestingly N-acetylcysteine had antioxidant effects independent of the glutathione pathway. Effective placental antioxidant therapy in pregnancy may require maintaining the balance between normalising redox status without inhibiting physiological redox signalling.
Publisher: Elsevier BV
Date: 05-1999
DOI: 10.1016/S0002-9378(99)70624-1
Abstract: The purpose of the study was to determine the effects of selective prostaglandin synthase type 2 inhibitors on basal prostaglandin concentrations in the fetal and maternal circulations and on the labor-associated increase in prostaglandin production in sheep. The effects of maternal nimesulide (0.01, 0.1, and 1 mg/kg) and 6-methoxy-2-naphthylacetic acid (1, 5, and 10 mg/kg) administration were examined (n = 5) at 134 +/- 1 days' gestation. At 138 days' gestation premature labor was induced by fetal dexamethasone infusion (1 mg/d). Ewes were treated with either vehicle or nimesulide infusion (20 mg. d-1. kg-1, n = 5 per group). Nimesulide and 6-methoxy-2-naphthylacetic acid decreased basal prostaglandin production in a concentration-dependent manner. Delivery of nimesulide-treated ewes was delayed by >/=17 hours with respect to that of control ewes (53.9 +/- 2.6 hours). In 2 nimesulide-treated ewes labor did not progress to delivery despite membrane rupture. The increase in prostaglandin concentrations usually seen during dexamethasone-induced labor was abolished in nimesulide-treated ewes and also in their fetuses. Highly selective inhibitors of prostaglandin endoperoxidase H synthase 2 may be required to spare fetal prostaglandin production and limit potential side effects during the suppression of preterm labor.
Publisher: Cambridge University Press (CUP)
Date: 05-2008
Publisher: Springer Science and Business Media LLC
Date: 02-2004
DOI: 10.1007/S00125-003-1305-3
Abstract: We have previously demonstrated poor glucose tolerance in adult pigs of naturally occurring low birthweight. The aim of this study was to examine sensitivity to insulin in juvenile (3-month-old) and adult (12-month-old) pigs of low and high birthweight. Low ( 1.53 kg) birthweight piglets from 15 litters were studied at 3 (n=47) and 12 (n=17) months of age. At each age the selected pigs were tranquilised and catheters were inserted into the dorsal aorta and caudal vena cava under general anaesthesia. After recovery, insulin sensitivity was measured as the glucose decrement (mmol.l(-1).min(-1)) during the first 10 min after an intravenous insulin bolus (0.5 IU/kg). Data (means +/- SEM) were analysed by the Student's t test, ANOVA and linear regression. The body weight of low birthweight female, but not male, pigs remained smaller than that of high birthweight pigs at 3 and 12 months of age. At 3 months, thinness at birth and rapid catch-up growth in the first month of life were associated with increased insulin sensitivity in males. In females thinness at 3 months was associated with reduced sensitivity to insulin. At 12 months, early postnatal catch-up growth was associated with insulin resistance, irrespective of sex, when all data were combined. The glucose intolerance previously observed in young adult pigs of low birthweight is probably due to insulin resistance. Early catch-up growth in low birthweight pigs was the clearest predictor of adult insulin resistance.
Publisher: Wiley
Date: 14-06-2010
Publisher: Bioscientifica
Date: 03-2001
Abstract: To further understand the relative roles of the pituitary gland and ACTH in the regulation of mRNAs encoding proteins that are essential for adrenal development, we investigated the effects of, first, an ACTH infusion and labour in intact fetuses and, secondly, the effect of an ACTH infusion to fetuses with and without a pituitary gland, on the relative abundance of the mRNA encoding for the ACTH receptor (MC2R), steroidogenic factor 1 (SF-1), cholesterol side-chain cleavage enzyme (P450(scc)), 3beta-hydroxysteroid dehydrogenase (3betaHSD) and 17alpha-hydroxylase (P450(C17)) in the fetal adrenal gland. ACTH(1-24) infusion (14.7 pmol/kg per h) to intact fetuses was without effect on the abundance of mRNA encoding MC2R and SF-1, irrespective of whether the infusion was given for 18 (115-132 days of gestation) or 32 days (115 days to term (147 days of gestation)). Hypophysectomy (HX) did not alter the expression of MC2R mRNA however, the abundance of SF-1 mRNA fell by approximately 50% following the removal of the pituitary gland. ACTH(1-24) infusion to HX fetuses failed to restore levels of SF-1 mRNA to that seen in intact animals. P450(scc) and 3betaHSD mRNAs were increased by ACTH(1-24) infusion for 18 days in intact animals, although no effects of the infusion were seen on P450(C17) mRNA levels. For all three of these mRNAs, there was a significant increase in their abundance between 132 days of gestation and term in intact fetuses. By term, ACTH(1-24) infusion was without any additional effect on their abundance. HX decreased the expression of P450(scc), 3betaHSD and P450(C17) mRNAs, while ACTH(1-24) infusion to HX fetuses increased the expression of these mRNAs to levels seen in intact animals. There were significant correlations between the abundance of the mRNA for P450(scc), 3betaHSD and P450(C17), but not MC2R and SF-1, and premortem plasma cortisol concentrations. These results emphasise the importance of the pituitary gland and ACTH in the regulation of the enzymes involved in adrenal steroidogenesis. Factors in addition to ACTH may also play some role, as the infusion was not always effective in increasing the abundance of the mRNAs. Surprisingly, the mRNA for MC2R and SF-1 did not appear to be regulated by ACTH in the late-gestation ovine fetus, though a pituitary-dependent factor may be involved in the regulation of SF-1 mRNA abundance.
Publisher: Springer Science and Business Media LLC
Date: 04-07-2002
DOI: 10.1007/S00125-002-0849-Y
Abstract: The aim of this study was to examine the effect of birth weight on glucose tolerance in juvenile and adult pigs. Low ( 1.53 kg) birth weight piglets from 15 litters were studied at 3 ( n=47) and 12 ( n=17) months of age. At each age, selected pigs were tranquilised and catheters were inserted into the dorsal aorta and caudal vena cava under general anaesthesia. After recovery, glucose (0.5 g/kg i.v.) was administered and regular arterial blood s les were taken for 2 h for plasma glucose and insulin measurements. Hepatic gluconeogenic enzyme activities were measured at post mortem. At 12, but not at 3 months of age, the area under the glucose and insulin curves after glucose administration were greater ( p<0.05) in low rather than in high birth weight pigs. The glucose area at 12 months was negatively correlated with body weight and BMI at birth. Disproportionate shape at birth was associated with reduced hepatic gluconeogenic enzyme concentrations and low birth weight pigs had reduced basal glucose concentrations at 12 months of age. This study has shown an association between low birth weight and thinness at birth and glucose intolerance at 12 months of postnatal age, but not at 3 months. This effect was not due to insulin deficiency or increased hepatic gluconeogenic enzyme activity.
Publisher: Wiley
Date: 08-11-2002
Publisher: Public Library of Science (PLoS)
Date: 06-03-2014
Publisher: Cambridge University Press (CUP)
Date: 22-03-2017
DOI: 10.1017/S2040174417000149
Abstract: Placental transport of vitamin D and other nutrients (e.g. amino acids, fats and glucose) to the fetus is sensitive to maternal and fetal nutritional cues. We studied the effect of maternal calorific restriction on fetal vitamin D status and the placental expression of genes for nutrient transport [aromatic T-type amino acid transporter-1 (TAT-1) triglyceride hydrolase/lipoprotein uptake facilitator lipoprotein lipase (LPL)] and vitamin D homeostasis [CYP27B1 vitamin D receptor (VDR)], and their association with markers of fetal cardiovascular function and skeletal muscle growth. Pregnant sheep received 100% total metabolizable energy (ME) requirements (control), 40% total ME requirements peri-implantation [PI40, 1–31 days of gestation (dGA)] or 50% total ME requirements in late gestation (L, 104–127 dGA). Fetal, but not maternal, plasma 25-hydroxy-vitamin D (25OHD) concentration was lower in PI40 and L maternal undernutrition groups ( P .01) compared with the control group at 0.86 gestation. PI40 group placental CYP27B1 messenger RNA (mRNA) levels were increased ( P .05) compared with the control group. Across all groups, higher fetal plasma 25OHD concentration was associated with higher skeletal muscle myofibre and capillary density ( P .05). In the placenta, higher VDR mRNA levels were associated with higher TAT-1 ( P .05) and LPL ( P .01) mRNA levels. In the PI40 maternal undernutrition group only, reduced fetal plasma 25OHD concentration may be mediated in part by altered placental CYP27B1. The association between placental mRNA levels of VDR and nutrient transport genes suggests a way in which the placenta may integrate nutritional cues in the face of maternal dietary challenges and alter fetal physiology.
Publisher: Informa UK Limited
Date: 06-2019
DOI: 10.2147/DMSO.S203700
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.BBI.2010.09.005
Abstract: The prevalence of the metabolic syndrome, which represents a spectrum of metabolic and cardiovascular disorders, continues to increase at an alarming rate in contemporary society. Inadequate responses of an in idual to environmental challenges such as unbalanced diet or lack of physical exercise during their life course has been recognised to increase risk of this pathological condition. Recent evidence suggests that this may involve alterations in the settings of the circadian clock system, which consists of oscillating molecular pacemakers found not only in the hypothalamic region of the brain but also in most peripheral tissues, and of the hypothalamic-pituitary-adrenal (HPA) axis which regulates stress responses. These two systems are now known to interact to produce an integrated response to environmental challenges. In this review, we highlight the importance of environmental cues during early development in establishing the homeostatic set-points of the circadian clock and HPA stress systems. These effects can operate within the normal range and are not in themselves pathological, but can nevertheless affect an in idual's response to environmental challenges in adult life and thus their risk of the metabolic syndrome.
Publisher: American Physiological Society
Date: 2007
DOI: 10.1152/AJPENDO.00253.2006
Abstract: The early-life environment has implications for risk of adult-onset diseases, such as glucose intolerance, insulin insensitivity, and obesity, effects that may occur with or without reduced birth weight. We determined the consequences of nutrient restriction in early gestation and early postnatal life and their interactions on postnatal growth, body composition, and glucose handling. Ewes received 100% (C, n = 39) or 50% nutritional requirements (U, n = 41) from 1 to 31 days gestation and 100% thereafter. Male and female offspring (singleton/twin) from C and U ewes were then fed either ad libitum (CC n = 22, UC n = 19) or to reduce body weight to 85% of target from 12 to 25 wk of age (CU n = 17, UU n = 22) and ad libitum thereafter. At 1.5 and 2.5 yr, glucose handling was determined by area under the curve (AUC) for glucose and insulin concentrations following intravenous glucose (0.5 g/kg body wt). Insulin sensitivity was determined at 2.5 yr following intravenous insulin (0.5 IU/kg). In females, postnatal undernutrition reduced ( P 0.05) glucose AUC at both ages, regardless of prenatal nutrition. Postnatal undernutrition did not affect insulin secretion in females but enhanced insulin-induced glucose disappearance in singletons. Poor early postnatal growth was associated with increased fat in females. In males, glucose tolerance was unaffected by undernutrition despite changes in insulin AUC dependent on age, treatment, and single/twin birth. Nutrition in early postnatal life has long-lasting, sex-specific effects on glucose handling in sheep, likely due, in females, to enhanced insulin sensitivity. Improved glucose utilization may aid weight recovery but have negative implications for glucose homeostasis and body composition over the longer term.
Publisher: Wiley
Date: 14-03-2003
Publisher: Elsevier BV
Date: 09-2000
Abstract: The aim of this study was to compare the effects of the selective prostaglandin synthase type 2 inhibitor nimesulide, alone or in combination with the oxytocin receptor antagonist atosiban, on the progression of glucocorticoid-induced premature labor in sheep. Effects on circulating maternal and fetal prostaglandin concentrations and on fetal well-being were also examined. Premature labor was induced in ewes with long-term catheterized fetuses by infusion of dexamethasone (1 mg/d) starting at 138 +/- 1 days' gestation. Ewes also received an infusion of either nimesulide and atosiban (20.0 and 4.12 mg/kg per day, respectively n = 5), nimesulide alone (20.0 mg/kg per day n = 5), or vehicle only (n = 9). Plasma 13,14-dihydro-15-keto-prostaglandin F(2)(alpha) and prostaglandin E(2) concentrations were measured before and during infusions in plasma s les obtained from the maternal and fetal carotid arteries and the utero-ovarian vein. No fetuses from ewes treated with nimesulide and atosiban were delivered during treatment. These animals were killed electively 98.0 +/- 6.8 hours after the commencement of dexamethasone induction. This was significantly longer than the delivery times for those ewes treated with nimesulide alone (71.2 +/- 3.9 hours n = 5) and for vehicle-treated ewes (51.4 +/- 1.7 hours n = 9). Both maternal and fetal plasma 13, 14-dihydro-15-keto-prostaglandin F(2alpha) and prostaglandin E(2) concentrations in nimesulide and atosiban-treated ewes and in nimesulide-treated ewes decreased during treatment. In contrast, vehicle-treated ewes showed a significant increase in maternal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F(2alpha) and prostaglandin E(2) concentrations during dexamethasone induction. Uterine electromyographic activity observed in nimesulide and atosiban-treated ewes was significantly suppressed with respect to activities in both vehicle- and nimesulide-treated ewes during the treatment period. All fetuses were alive at delivery or scheduled death. These results indicate that the combination of an inhibitor of prostaglandin endoperoxidase H synthase type 2 with an oxytocin receptor antagonist is more effective in inhibition of preterm labor than is treatment with a prostaglandin endoperoxidase H synthase type 2 inhibitor alone. The clinical use of atosiban to prevent the oxytocin-stimulated increase in uterine activity associated with labor in combination with nimesulide may permit reduction of the dose of nimesulide used to a level that has minimal impact on fetal well-being.
Publisher: Wiley
Date: 09-09-2015
DOI: 10.1113/JP270743
Publisher: Elsevier BV
Date: 06-2006
Publisher: Wiley
Date: 14-08-2009
DOI: 10.1113/EXPPHYSIOL.2009.047340
Abstract: The nutritional environment during development and even prior to conception may contribute to cardiovascular risk. In mature adult female sheep, we investigated the effect of preconceptional and periconceptional maternal nutritional restriction on the vascular reactivity of arteries from four vascular beds supplying the heart, thorax, kidney and hindlimb. Welsh Mountain ewes received 100% of nutrient requirements throughout gestation (control group, C, n = 18), or 50% of nutrient requirements for 30 days prior to conception (preconceptional group, PRE, n = 20) or for 15 days either side of conception (periconceptional group, PERI, n = 31) and 100% thereafter. In 3.5‐year‐old female offspring, the left anterior descending coronary (LAD), left internal thoracic (LITA), right renal and second and third order femoral arteries were dissected and their reactivity was assessed by organ bath or wire myography. Vasoconstrictor responses were greater in both LAD and LITA from PERI offspring compared with C ( P 0.01), while vasoconstriction was unaffected by maternal diet in arteries from the renal and femoral circulations ( P = n.s.). Endothelium‐dependent and ‐independent vasodilatation was attenuated in third order femoral arteries of PRE and PERI groups compared with C ( P 0.05). Endothelium‐independent vasodilatation was attenuated in both the LAD and renal arteries in the PERI group compared with C ( P 0.05). These data show that moderate maternal undernutrition either prior to or around conception affects vascular function of adult offspring. The effect depends on the timing of the insult, but also on the vascular bed studied and vessel hierarchy in the vascular tree.
Publisher: The Endocrine Society
Date: 07-2013
DOI: 10.1210/EN.2013-1412
Publisher: Wiley
Date: 03-2002
DOI: 10.1113/JPHYSIOL.2001.012926
Abstract: In man, epidemiological studies have shown that low birth weight (BW) is associated with an increased risk of cardiovascular disease in later life. In this study, the long-term consequences of variations in natural BW on basal cardiovascular function were investigated in pigs at 3 months of postnatal age. Low ( 1.52 kg n = 20) BW Large White piglets were selected from a total of 12 litters for study at 3 months of age. Basal mean arterial pressure (MAP) and heart rate (HR) were recorded for approximately 30 min using standard recording equipment and basal arterial blood s les were taken for hormone analyses. Concentrations of angiotensin-converting enzyme (ACE) were also measured in kidney, lung and plasma. Basal MAP, but not HR, in 3-month-old pigs was significantly inversely related to BW and positively related to the ratio of head length to BW. Postnatal growth rate of low BW pigs was slower than that of high BW pigs such that low BW piglets remained significantly smaller at 3 months of age. There were no differences in basal plasma adrenaline or cortisol concentrations between low and high BW pigs. However, basal plasma noradrenaline concentrations were significantly elevated in low BW compared to high BW pigs. Renal and pulmonary ACE levels were significantly reduced in low BW compared to high BW pigs. These data show that basal MAP in 3-month-old pigs is negatively associated with BW and positively correlated to disproportionate size at birth. This effect was associated with an increase in basal plasma noradrenaline concentrations.
Publisher: Wiley
Date: 05-1999
DOI: 10.1046/J.1365-2826.1999.00340.X
Abstract: Ovine parturition results from an increase in foetal cortisol secretion in late gestation which is dependent on an intact hypothalamo-pituitary connection. The cortisol surge and parturition fails in hypothalamo-pituitary disconnected (HPD) foetuses but, paradoxically, immunoreactive (ir)-ACTH concentrations and secretory dynamics appear normal. This study compares the occurrence and timing of labour, basal ir-ACTH and cortisol concentrations and adrenal responsiveness in HPD foetuses (HPD/ACTH) receiving constant ACTH(1-24) infusion (43 ng/h/kg) from surgery (114+/-1 days gestational age (GA)) with those of saline-infused HPD or intact foetuses (HPD/SAL and INT/SAL). HPD/ACTH foetuses initiated labour at 147+/-2 days GA, which was not significantly different from INT/SAL foetuses (149+/-1 day GA). HPD/SAL foetuses were killed electively at 146+/-3 days GA with no signs of labour. Foetal ir-ACTH concentrations in all groups were indistinguishable, but only HPD/ACTH and INT/SAL foetuses had a significant cortisol surge. Adrenal responsiveness to ACTH(1-24)(1 microg/kg) was greater in HPD/ACTH foetuses than in HPD/SAL or INT/SAL foetuses at all GAs studied. Adrenal responsiveness in HPD/SAL foetuses exceeded that in INT/SAL foetuses at 120 and 130 days GA but did not change with GA. In summary, the basal cortisol and parturition defect in HPD foetuses was reversed by low-dose ACTH(1-24) infusion. Basal cortisol concentrations were unrelated to adrenal responsiveness. HPD/SAL foetuses had hyper-responsive adrenals compared to those of INT/SAL foetuses until 130 days GA, suggesting that the foetal hypothalamus exerts a negative influence on adrenal cortisol responses before 130 days GA, after which time stimulatory influences predominate.
Publisher: Proceedings of the National Academy of Sciences
Date: 29-05-2007
Abstract: The early life environment has long-term implications for the risk of developing cardiovascular (CV) disease in adulthood. Fetal responses to changes in maternal nutrition may be of immediate benefit to the fetus, but the long-term effects of these adaptations may prove detrimental if nutrition in postnatal life does not match that predicted by the fetus on the basis of its prenatal environment. We tested this predictive adaptive response hypothesis with respect to CV function in sheep. We observed that a mismatch between pre- and postnatal nutrient environments induced an altered CV function in adult male sheep that was not seen when environments were similar. Sheep that received postnatal undernutrition alone had altered growth, CV function, and basal hypothalamo–pituitary–adrenal axis activity in adulthood. Prenatal undernutrition induced greater weight gain by weaning compared with the prenatal control diet, which may provide a reserve in the face of a predicted poor diet in later life. In an adequate postnatal nutrient environment (i.e., relatively mismatched), these offspring exhibited cardiac hypertrophy and altered CV function in adulthood. These data support the concept that adult CV function can be determined by developmental responses to intrauterine nutrition made in expectation of the postnatal nutritional environment, and that if these predictions are not met, the adult may be maladapted and at greater risk of CV disease. Our findings have substantial implications for devising strategies to reduce the impact of a mismatch in nutrition levels in humans undergoing rapid socio-economic transitions in both developing and developed societies.
Publisher: Wiley
Date: 07-01-2005
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S0303-7207(01)00623-2
Abstract: The present study investigated the ontogeny of pulmonary and renal angiotensin-converting enzyme (ACE) in foetal and postnatal pigs, and examined the effect of cortisol on tissue ACE in utero. Data were compared with those in sheep at similar ages. Under anaesthesia, tissues and umbilical blood were collected from pig foetuses between 81-115 days of gestation (term, 115+/-2 days). Twelve foetuses delivered at 97+/-2 days were infused with saline or cortisol (3-6 mgkg(-1)day(-1)) using osmotic mini-pumps implanted 6 days previously. Tissues were collected from newborn piglets, and from pigs at 2-4 weeks, 10-12 weeks and 10-12 months of age. Unlike in sheep, gestational age and exogenous cortisol had no effect on pulmonary or renal ACE in pigs. After birth, pulmonary ACE decreased to a nadir at 2-4 weeks and remained low thereafter. Renal ACE increased between 10-12 weeks and 10-12 months. Postnatal changes in tissue ACE may have consequences for cardiovascular, pulmonary and renal function in pigs.
Publisher: Elsevier BV
Date: 08-2017
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.MAM.2022.101095
Abstract: The placental exposome represents the sum of all placental exposures, and through its influence on placental function can affect an in idual's susceptibility to cardio-metabolic disease later in life. The placental exposome includes direct exposures during gestation, as well as those prior to gestation that affect the gametes or aspects of maternal physiology that influence placental function. This review will discuss the evidence for placental responses to environmental signals and its involvement in programming offspring health. A wide range of exposures may influence the placenta including maternal metabolic and endocrine status, nutrition, stress and toxins. Epigenetic changes within the placenta induced by these exposures may mediate persistent effects on placental function. Identifying which exposures are most influential in terms of placental function and offspring health is key to focusing future research and developing stratified and personalised interventions.
Publisher: Wiley
Date: 24-06-2004
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Kirsten Poore.