ORCID Profile
0000-0002-6793-3601
Current Organisation
University of Nottingham
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Publisher: Springer Science and Business Media LLC
Date: 27-06-2007
Abstract: Ghrelin is an orexigenic hormone principally produced by the stomach, but also by numerous peripheral tissues including the placenta. Ghrelin acts via growth hormone secretagogue receptors (GHSR-1a) to alter food intake, fat utilization, and cellular proliferation, and has been suggested to play a role in the developmental growth of the fetoplacental unit. The placental expression of ghrelin and its role in ruminant species is not known. We tested the hypotheses that ghrelin and its functional receptor, GHSR-1a, are present in tissues of the ovine placenta, and that their expression is linked to the stage of development. Antibodies raised against ghrelin and GHSR-1a were used in standard immunohistochemical protocols on placental tissues collected from pregnant ewes (n = 6 per gestational time point) at days 50, 80, 100, 128 and 135 of gestation (term ≈ day 145). Immunostaining for ghrelin and GHSR-1a was quantified using computer-aided image analysis. Image analysis data were subjected to one-way ANOVA, with differences in immunostaining between time-points determined by Fisher's least significant difference. Positive immunostaining for ghrelin was detected in ovine placentae at all gestational time points, with staining localized to the maternal epithelium, caruncle and trophectoderm. There was a significant effect of gestational age (p 0.001) on the placental expression of ghrelin, with maximal levels at gestational day 80. GHSR-1a immunostaining was detected in the fetal trophectoderm at all time points. In contrast to the gestational pattern of ghrelin expression, there was no effect of gestational age on placental GHSR-1a immunoexpression. Ghrelin and GHSR-1a are both present in the ovine placenta, and ghrelin displays a developmentally-related pattern of expression. Therefore, these data strongly suggest that the ghrelin system may have a role in feto-placental development in sheep.
Publisher: Oxford University Press (OUP)
Date: 23-04-2008
Publisher: Bioscientifica
Date: 12-2001
Abstract: Gonad development in female sheep fetuses is thought to occur in a number of key stages. The aim of this study was to determine the effects of maternal undernutrition, applied at one or more of these critical stages, on fetal ovarian development. Groups of ewes (n = 11-19) were fed rations providing either 100% (high H) or 50% (low L) of energy requirements for live weight maintenance during selected 'windows' during gestation. Control ewes (HH and HHH) were fed the H ration from mating until they were killed at days 50, 65 (HH) or 110 (HHH) of gestation, whereas ewes of other groups were fed the L ration for the periods between day 0 and day 30 of gestation (LH and LHH), day 31 and day 50 or 65 of gestation (HL and HLH), day 65 and day 110 of gestation (HHL) or day 0 of gestation until the animals were killed (LL and LLL). At day 50 of gestation, there was no effect of nutritional treatment on mean fetal mass but compared with HH animals, mean fetal ovarian mass was significantly lower in HL (P 0.05) and LL (P 0.001) animals. At day 65 of gestation, there were significantly fewer germ cells (P 0.05) at the resting, diplotene stage of initial meiosis in LL animals than there were in HH animals, indicating delayed germ cell maturation and onset of meiosis. Qualitative assessment of proliferative cell nuclear antigen immunostaining indicated that, at day 50 of gestation, staining was located predominantly in the germ cells, whereas by day 65 of gestation, staining was confined predominantly to somatic cells. Undernutrition in each one of these windows was associated with delayed ovarian follicular development (P 0.05-0.001) as measured by development of the granulosa cell layer at day 110 of gestation. This study demonstrates that undernutrition before and during folliculogenesis can delay fetal follicular development.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2005
Abstract: The gut hormone, ghrelin, is involved in the neuroendocrine and metabolic responses to hunger. In monogastric species, circulating ghrelin levels show clear meal-related and body weight-related changes. The pattern of secretion and its role in ruminant species is less clear. Ghrelin acts via growth hormone secretagogue receptors (GHSR-1a) to alter food intake, fat utilization, and cellular proliferation. There is also evidence that ghrelin is involved in reproductive function. In the present study we used immunohistochemistry to investigate the presence of ghrelin and GHSR-1a in sheep reproductive tissues. In addition, we examined whether ghrelin and GHSR-1a protein expression is developmentally regulated in the adult and fetal ovine testis, and whether there is an association with markers of cellular proliferation, i.e. stem cell factor (SCF) and proliferating cell nuclear antigen (PCNA). Antibodies raised against ghrelin and its functional receptor, GHSR-type 1a, were used in standard immunohistochemical protocols on various reproductive tissues collected from adult and fetal sheep. GHSR-1a mRNA presence was also confirmed by in situ hybridisation. SCF and PCNA immunoexpression was investigated in fetal testicular s les. Adult and fetal testicular immunostaining for ghrelin, GHSR-1a, SCF and PCNA was analysed using computer-aided image analysis. Image analysis data were subjected to one-way ANOVA, with differences in immunostaining between time-points determined by Fisher's least significant difference. In adult sheep tissue, ghrelin and GHSR-1a immunostaining was detected in the stomach (abomasum), anterior pituitary gland, testis, ovary, and hypothalamic and hindbrain regions of the brain. In the adult testis, there was a significant effect of season (photoperiod) on the level of immunostaining for ghrelin (p 0.01) and GHSR-1a (p 0.05). In the fetal sheep testis, there was a significant effect of gestational age on the level of immunostaining for ghrelin (p 0.001), GHSR-1a (p 0.05), SCF (p 0.05) and PCNA (p 0.01). Evidence is presented for the presence of ghrelin and its receptor in various reproductive tissues of the adult and fetal sheep. In addition, the data indicate that testicular expression of ghrelin and its receptor is physiologically regulated in the adult and developmentally regulated in the fetus. Therefore, the ghrelin ligand/receptor system may have a role (endocrine and/or paracrine) in the development (cellular proliferation) and function of the reproductive axis of the sheep.
Publisher: Wiley
Date: 03-2002
DOI: 10.1034/J.1600-0897.2002.1O049.X
Abstract: Vitamin A is important for immune function and deficiency is associated with adverse pregnancy outcome. In the rat, vitamin A deficiency reduces both foetal number and neonatal survival. The role of the placenta is uncertain. The effects of maternal vitamin A deficiency on placental cytokines and apoptosis have been investigated. Pregnant rats were fed either control or vitamin A free (VAF) diets (n = 4/group) from 8 weeks prior to and throughout pregnancy. Day 20 placentas from viable foetuses were examined for immunoexpression of (a) cytokines: tumour necrosis factor-alpha (TNF-alpha), TNFR1 receptor (p55), leptin and leptin receptor, (b) apoptosis: TdT-mediated dUTP nick end-labelling (TUNEL) positive cells, bax and bcl-2. Placentas from VAF rats, but not controls, exhibited an infiltrate of neutrophils positive for TNF-alpha and leptin. The number of TNFR1 (p55) and TUNEL positive trophoblast cells was increased specifically in areas of neutrophil infiltration. Trophoblast giant cells in VAF placentas exhibited reduced bax but no change in bcl-2. Maternal vitamin A deficiency is associated with abnormal placental apoptosis induced by neutrophil derived TNF-alpha acting through the TNFR1 (p55) and/or a change in the bcl-2/bax ratio in the trophoblast giant cells. These changes may underlie the effects of vitamin A deficiency on foetal development.
Publisher: Bioscientifica
Date: 04-2007
DOI: 10.1530/REP-06-0294
Abstract: Overnourishing pregnant adolescent sheep promotes maternal growth but reduces placental mass, lamb birth weight and circulating progesterone. This study aimed to determine whether altered progesterone reflected transcript abundance for StAR (cholesterol transporter) and the steroidogenic enzymes ( Cyp11A1 , Hsd3b and Cyp17 ). Circulating and placental expression of ovine placental lactogen (oPL) was also investigated. Adolescent ewes with singleton pregnancies were fed high (H) or moderate (M) nutrient intake diets to restrict or support placental growth. Experiment 1: peripheral progesterone and oPL concentrations were measured in H ( n =7) and M ( n =6) animals across gestation (days 7–140). Experiment 2: progesterone was measured to mid- (day 81 M: n =11, H: n =13) or late gestation (day 130 M: n =21, H: n =22), placental oPL, StAR and steroidogenic enzymes were measured by qPCR and oPL protein by immunohistochemistry. Experiment 1: in H vs M animals, term placental ( P .05), total cotyledon ( P .01) and foetal size ( P .05) were reduced. Circulating oPL and progesterone were reduced at mid- ( P .001, P .01) and late gestation ( P .01, P .05) and oPL detection was delayed ( P .01). Experiment 2: placental oPL was not altered by nutrition. In day 81 H animals, progesterone levels were reduced ( P .001) but not related to placental or foetal size. Moreover, placental steroidogenic enzymes were unaffected. Day 130 progesterone ( P .001) and Cyp11A1 ( P .05) were reduced in H animals with intrauterine growth restriction (H+IUGR). Reduced mid-gestation peripheral oPL and progesterone may reflect altered placental differentiation and/or increased hepatic clearance respectively. Restricted placental growth and reduced biosynthesis may account for reduced progesterone in day 130 H+IUGR ewes.
Publisher: Proceedings of the National Academy of Sciences
Date: 04-12-2007
Abstract: A complex combination of adult health-related disorders can originate from developmental events that occur in utero . The periconceptional period may also be programmable. We report on the effects of restricting the supply of specific B vitamins (i.e., B 12 and folate) and methionine, within normal physiological ranges, from the periconceptional diet of mature female sheep. We hypothesized this would lead to epigenetic modifications to DNA methylation in the preovulatory oocyte and/or preimplantation embryo, with long-term health implications for offspring. DNA methylation is a key epigenetic contributor to maintenance of gene silencing that relies on a dietary supply of methyl groups. We observed no effects on pregnancy establishment or birth weight, but this modest early dietary intervention led to adult offspring that were both heavier and fatter, elicited altered immune responses to antigenic challenge, were insulin-resistant, and had elevated blood pressure–effects that were most obvious in males. The altered methylation status of 4% of 1,400 CpG islands examined by restriction landmark genome scanning in the fetal liver revealed compelling evidence of a widespread epigenetic mechanism associated with this nutritionally programmed effect. Intriguingly, more than half of the affected loci were specific to males. The data provide the first evidence that clinically relevant reductions in specific dietary inputs to the methionine/folate cycles during the periconceptional period can lead to widespread epigenetic alterations to DNA methylation in offspring, and modify adult health-related phenotypes.
Publisher: Bioscientifica
Date: 2006
DOI: 10.1530/REP.1.00844
Abstract: This study aimed to determine whether reduced fetal ovary folliculogenesis in ewes undernourished during early/midpregnancy is associated with altered ovarian cell proliferation and/or the expression of apoptosis-regulating genes. Groups of ewes ( n = 11–19) were fed either 100% (high H) or 50% (low L) of metabolisable energy requirements for live-weight maintenance during selected windows of gestation. All animals were killed at days 50, 65 or 110 of gestation. Between mating and slaughter, control animals were fed the H ration, while animals of other subgroups were fed the L ration from (a) mating to slaughter at 50, 65 or 110 days (b) 0 to 30 days (c) 31 to 50 or 65 days or (d), in the day 110 slaughter group only, from 66 to 110 days. Bouin’s-fixed fetal ovaries were examined for (a) Ki67 immunoexpression (proliferation) and (b) Bax and Mcl-1 (apoptosis-regulating genes) expression by in situ hybridisation (day 110) and immunohistochemistry (days 50, 65 and 110). At day 50, maternal nutrition had no effect on Ki67, predominant in germ cells, or Bax and Mcl-1, predominant in the oocytes. Restricted maternal food intake from 0 to 30 days significantly reduced staining for Ki67 in germ cells at day 65 ( P 0.05) but increased staining in granulosa cells at day 110 ( P 0.05). In animals fed the L ration for 110 days, primordial follicle Bax and Mcl-1 were significantly increased (Bax: P 0.01 Mcl-1: P 0.05). Granulosa cell Bax was also increased ( P 0.05). When the L ration was fed from 66 to 110 days, granulosa cell Bax ( P 0.05) and primordial follicle Mcl-1 ( P 0.01) were also significantly increased. In the fetal ovarian vasculature, animals underfed for 0–110 days had significantly elevated perivascular Mcl-1 ( P 0.001) and endothelial Bax expression ( P 0.05). Moreover, at day 110, endothelial Mcl-1 was increased by underfeeding from 0 to 30 days ( P 0.05). These data indicate that maternal undernutrition alters proliferation and the expression of apoptosis-regulating genes in the developing fetal ovary. The precise mechanism depends on the window of maternal food restriction.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Richard Lea.