Maternal undernutrition during the first week after conception results in decreased expression of glucocorticoid receptor mRNA in the absence of GR exon 17 hypermethylation in the fetal pituitary in late gestation

2013 ◽  
Vol 4 (5) ◽  
pp. 391-401 ◽  
Author(s):  
S. Zhang ◽  
O. Williams-Wyss ◽  
S. M. MacLaughlin ◽  
S. K. Walker ◽  
D. O. Kleemann ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Mrna Expression ◽  
Hpa Axis ◽  
Early Embryo ◽  
Late Gestation ◽  
Control Group ◽  
Fetal Sheep ◽  
Maternal Undernutrition ◽  
Stress Responsiveness ◽  
Periconceptional Period

Exposure to maternal undernutrition during the periconceptional period results in an earlier prepartum activation of the fetal hypothalamo–pituitary–adrenal (HPA) axis and altered stress responsiveness in the offspring. It is not known whether such changes are a consequence of exposure of the oocyte and/or the early embryo to maternal undernutrition in the periconceptional period. We have compared the effects of ‘periconceptional’ undernutrition (PCUN: maternal undernutrition imposed from at least 45 days before until 6 days after conception), and ‘early preimplantation’ undernutrition (PIUN: maternal undernutrition imposed for only 6 days after conception) on the expression of genes in the fetal anterior pituitary that regulate adrenal growth and steroidogenesis, proopiomelanorcortin (POMC), prohormone convertase 1 (PC1), 11β-hydroxysteroid dehydrogenase type 1 and 2 (11βHSD1 and 2) and the glucocorticoid receptor (GR) in fetal sheep at 136–138 days of gestation. Pituitary GR mRNA expression was significantly lower in the PCUN and PIUN groups in both singletons and twins compared with controls, although this suppression of GR expression was not associated with hypermethylation of the exon 17 region of the GR gene. In twin fetuses, the pituitary 11βHSD1 mRNA expression was significantly higher in the PIUN group compared with the PCUN but not the control group. Thus, exposure of the single or twin embryo to maternal undernutrition for only 1 week after conception is sufficient to cause a suppression of the pituitary GR expression in late gestation. These changes may contribute to the increased stress responsiveness of the HPA axis in the offspring after exposure to poor nutrition during the periconceptional period.

Cardiovascular and hypothalamic-pituitary-adrenal axis development in late gestation fetal sheep and young lambs following modest maternal nutrient restriction in early gestation

2000 ◽  
Vol 12 (8) ◽  
pp. 443 ◽  
Author(s):  
P. Hawkins ◽  
C. Steyn ◽  
H. H. G. McGarrigle ◽  
N. A. Calder ◽  
T. Saito ◽  
...  
Keyword(s):  
Vascular Resistance ◽  
Hpa Axis ◽  
Femoral Artery ◽  
Cardiovascular Response ◽  
Late Gestation ◽  
Postnatal Life ◽  
Fetal Life ◽  
Fetal Sheep ◽  
Hypothalamic Pituitary Adrenal ◽  
Maternal Undernutrition

The effect of a 15% reduction in maternal nutrition for the first 70 days of gestation on cardiovascular and hypothalamic–pituitary–adrenal (HPA) axis responses to administration of corticotropin releasing hormone (CRH) + arginine vasopressin (AVP) was studied at 128 0.7 days gestation in fetal sheep and postnatally, at 85 4.5 days in young lambs. The effect on the fetal cardiovascular response to acute hypoxaemia was also examined. Under basal conditions, fetal heart rate (FHR) was reduced (P<0.05) and basal femoral artery vascular resistance (FVR) was increased (P<0.05) in fetuses of dietary-restricted (R) ewes compared with controls (C). Fetal mean arterial pressure (MAP) was similar in both groups. Femoral artery vascular resistance was also greater during hypoxaemia in R fetuses compared with C fetuses (P<0.05), suggesting that chemoreflex mechanisms were augmented in the R group. The fetal ACTH response to CRH + AVP was similar in both groups. However, cortisol responses to CRH + AVP were smaller in R fetuses compared with C fetuses (P<0.05). Postnatally, basal MAP (P<0.05), and ACTH (P<0.01) and cortisol (P<0.001) responses were greater in R lambs compared with C lambs. It was concluded that modest maternal undernutrition during pregnancy alters development of the cardiovascular system, producing elevated blood pressure in postnatal life. Development of the HPA axis is also altered, with reduced activity during fetal life, but increased activity postnatally. The data suggest that the HPA axis may play a role in mediating the elevation of MAP in R lambs.

Sexually dimorphic changes in the pancreas and skeletal muscle in young adulthood following intra-amniotic IGF-I treatment of growth-restricted fetal sheep

2021 ◽  
Author(s):  
Emma Jane Buckels ◽  
Frank Harry Bloomfield ◽  
Mark Hope Oliver ◽  
Ana-Mishel Spiroski ◽  
Jane Elizabeth Harding ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Young Adulthood ◽  
Endocrine Pancreas ◽  
Cell Mass ◽  
Late Gestation ◽  
Control Group ◽  
Sexually Dimorphic ◽  
Fetal Sheep ◽  
Igf I

Fetal growth restriction (FGR) is associated with decreased insulin secretory capacity and decreased insulin sensitivity in muscle in adulthood. We investigated whether intra-amniotic IGF-I treatment in late gestation mitigated the adverse effects of FGR on the endocrine pancreas and skeletal muscle at 18-months of age. Singleton-bearing ewes underwent uterine artery embolization between 103-107 days' gestational age, followed by five once-weekly intra-amniotic injections of 360 µg IGF-I (FGRI) or saline (FGRS), and were compared to an un-manipulated control group (CON). We measured offspring pancreatic endocrine cell mass and pancreatic and skeletal muscle mRNA expression at 18-months of age (n=7-9/sex/group). Total α-cell mass was increased ~225% in FGRI males vs. CON and FGRS males, while β-cell mass was not different between groups of either sex. Pancreatic mitochondria-related mRNA expression was increased in FGRS females vs. CON (NRF1, MTATP6, UCP2), and FGRS males vs. CON (TFAM, NRF1, UCP2), but was largely unchanged in FGRI males vs. CON. In skeletal muscle, mitochondria-related mRNA expression was decreased in FGRS females vs. CON (PPARGC1A, TFAM, NRF1, UCP2, MTATP6), FGRS males vs. CON (NRF1 and UCP2), and FGRI females vs. CON (TFAM and UCP2), with only MTATP6 expression decreased in FGRI males vs. CON. Although the window during which IGF-I treatment was delivered was limited to the final five weeks of gestation, IGF-I therapy of FGR altered the endocrine pancreas and skeletal muscle in a sex-specific manner in young adulthood.

Anemic Hypoxemia Reduces Myoblast Proliferation and Muscle Growth in Late Gestation Fetal Sheep

2021 ◽  
Author(s):  
Paul J. Rozance ◽  
Stephanie R Wesolowski ◽  
Sonnet S. Jonker ◽  
Laura D Brown
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Muscle Growth ◽  
Late Gestation ◽  
Whole Body ◽  
Myoblast Differentiation ◽  
Fetal Sheep ◽  
Body Protein ◽  
Skeletal Muscle Growth ◽  
Myoblast Proliferation

Fetal skeletal muscle growth requires myoblast proliferation, differentiation, and fusion into myofibers in addition to protein accretion for fiber hypertrophy. Oxygen is an important regulator of this process. Therefore, we hypothesized that fetal anemic hypoxemia would inhibit skeletal muscle growth. Studies were performed in late gestation fetal sheep that were bled to anemic, and therefore hypoxemic, conditions beginning at ~125 days of gestation (term = 148 days) for 9 ± 0 days (n=19) and compared to control fetuses (n=16). A metabolic study was performed on gestational day ~134 to measure fetal protein kinetic rates. Myoblast proliferation and myofiber area were determined in biceps femoris (BF), tibialis anterior (TA), and flexor digitorum superficialis (FDS) muscles. mRNA expression of muscle regulatory factors was determined in BF. Fetal arterial hematocrit and oxygen content were 28% and 52% lower, respectively, in anemic fetuses. Fetal weight and whole-body protein synthesis, breakdown, and accretion rates were not different between groups. Hindlimb length, however, was 7% shorter in anemic fetuses. TA and FDS muscles weighed less and FDS myofiber area was smaller in anemic fetuses compared to controls. The percentage of Pax7+ myoblasts that expressed Ki67 was lower in BF and tended to be lower in FDS from anemic fetuses indicating reduced myoblast proliferation. There was less MYOD and MYF6 mRNA expression in anemic vs. control BF consistent with reduced myoblast differentiation. These results indicate that fetal anemic hypoxemia reduced muscle growth. We speculate that fetal muscle growth may be improved by strategies that increase oxygen availability.

Genomic analysis of neuroendocrine development of fetal brain-pituitary-adrenal axis in late gestation

2006 ◽  
Vol 24 (3) ◽  
pp. 218-224 ◽  
Author(s):  
Maureen Keller-Wood ◽  
Melanie J. Powers ◽  
Jason A. Gersting ◽  
Nyima Ali ◽  
Charles E. Wood
Keyword(s):  
Brain Stem ◽  
Hpa Axis ◽  
Fetal Brain ◽  
Genomic Analysis ◽  
Brain Regions ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Genomic Expression ◽  
Feedback Sensitivity ◽  
Critical Components

The present study was performed to identify the changes in genomic expression of critical components of the hypothalamus-pituitary-adrenal (HPA) axis in the second half of gestation in fetal sheep. We isolated mRNA from pituitary, hypothalamus, hippocampus, and brain stem in fetal sheep at 80, 100, 120, 130, and 145 days of gestation and 1 and 7 days after delivery ( n = 4–5/group). Using real-time RT-PCR, we measured mRNA expression levels of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), serum- and glucocorticoid-induced kinase-1 (sgk1), proopiomelanocortin (POMC), CRF, and arginine vasopressin (AVP). Both MR and GR were highly expressed in pituitary and hippocampus; in all tissues GR was more highly expressed than MR. AVP was more highly expressed than CRF in hypothalamus. MR, GR, and sgk1 expression were increased postnatally in brain stem, and sgk1 expression was increased postnatally in hypothalamus. GR expression was reduced in pituitary in term fetuses compared with younger ages. Hypothalamic CRF expression was increased at the end of gestation compared with younger ages, and AVP expression was increased in newborn lambs. Pituitary POMC was increased at 100 days of gestation compared with 80 days; hypothalamic POMC was increased at 120 days. Overall, the results demonstrate the expression of both MR and GR in brain regions important for control of the HPA axis. Decreases in expression of GR in pituitary at the end of gestation might contribute to the decreased corticosteroid negative feedback sensitivity at term in this species.

scholarly journals Insulin Deficiency Alters the Metabolic and Endocrine Responses to Undernutrition in Fetal Sheep Near Term

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 4008-4018 ◽  
Author(s):  
Abigail L. Fowden ◽  
Alison J. Forhead
Keyword(s):  
Oxygen Consumption ◽  
Metabolic Response ◽  
Plasma Concentrations ◽  
Late Gestation ◽  
Similar Degree ◽  
Hepatic Glycogen ◽  
Insulin Deficiency ◽  
Fetal Sheep ◽  
Maternal Undernutrition ◽  
Significant Fall

Insulin deficiency affects the adult metabolic response to undernutrition, but its effects on the fetal response to maternal undernutrition remain unknown. This study examined the effects of maternal fasting for 48 h in late gestation on the metabolism of fetal sheep made insulin deficient by pancreatectomy (PX). The endocrine and metabolic responses to maternal fasting differed between intact, sham-operated and PX fetuses, despite a similar degree of hypoglycemia. Compared with intact fetuses, there was no increase in the plasma concentrations of cortisol or norepinephrine in PX fetuses during maternal fasting. In contrast, there was a significant fasting-induced rise in plasma epinephrine concentrations in PX but not intact fetuses. Umbilical glucose uptake decreased to a similar extent in both groups of fasted animals but was associated with a significant fall in glucose carbon oxidation only in intact fetuses. Pancreatectomized but not intact fetuses lowered their oxygen consumption rate by 15–20% during maternal fasting in association with increased uteroplacental oxygen consumption. Distribution of uterine oxygen uptake between the uteroplacental and fetal tissues therefore differed with fasting only in PX fetuses. Both groups of fetuses produced glucose endogenously after maternal fasting for 48 h, which prevented any significant fall in the rate of fetal glucose utilization. In intact but not PX fetuses, fasting-induced glucogenesis was accompanied by a lower hepatic glycogen content. Chronic insulin deficiency in fetal sheep therefore leads to changes in the counterregulatory endocrine response to hypoglycemia and an altered metabolic strategy in dealing with nutrient restriction in utero.

scholarly journals Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep

2016 ◽  
Vol 311 (1) ◽  
pp. R200-R208 ◽  
Author(s):  
Christine Culpepper ◽  
Stephanie R. Wesolowski ◽  
Joshua Benjamin ◽  
Jennifer L. Bruce ◽  
Laura D. Brown ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Late Gestation ◽  
Hepatic Glycogen ◽  
Plasma Glucagon ◽  
Low Oxygen ◽  
Fetal Sheep ◽  
Hepatic Glucose ◽  
Arterial Plasma

Hepatic glucose production (HGP) normally begins just prior to birth. Prolonged fetal hypoglycemia, intrauterine growth restriction, and acute hypoxemia produce an early activation of fetal HGP. To test the hypothesis that prolonged hypoxemia increases factors which regulate HGP, studies were performed in fetuses that were bled to anemic conditions (anemic: n = 11) for 8.9 ± 0.4 days and compared with control fetuses ( n = 7). Fetal arterial hematocrit and oxygen content were 32% and 50% lower, respectively, in anemic vs. controls ( P < 0.005). Arterial plasma glucose was 15% higher in the anemic group ( P < 0.05). Hepatic mRNA expression of phosphonenolpyruvate carboxykinase ( PCK1) was twofold higher in the anemic group ( P < 0.05). Arterial plasma glucagon concentrations were 70% higher in anemic fetuses compared with controls ( P < 0.05), and they were positively associated with hepatic PCK1 mRNA expression ( P < 0.05). Arterial plasma cortisol concentrations increased 90% in the anemic fetuses ( P < 0.05), but fetal cortisol concentrations were not correlated with hepatic PCK1 mRNA expression. Hepatic glycogen content was 30% lower in anemic vs. control fetuses ( P < 0.05) and was inversely correlated with fetal arterial plasma glucagon concentrations. In isolated primary fetal sheep hepatocytes, incubation in low oxygen (3%) increased PCK1 mRNA threefold compared with incubation in normal oxygen (21%). Together, these results demonstrate that glucagon and PCK1 may potentiate fetal HGP during chronic fetal anemic hypoxemia.

Prolactin and the expression of suppressor of cytokine signaling-3 in the sheep adrenal gland before birth

2006 ◽  
Vol 291 (5) ◽  
pp. R1399-R1405 ◽  
Author(s):  
S. Gentili ◽  
J. S. Schwartz ◽  
M. J. Waters ◽  
I. C. McMillen
Keyword(s):  
Adrenal Gland ◽  
Mrna Expression ◽  
Tissue Growth ◽  
Late Gestation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Subsequent Increase ◽  
Fetal Sheep

The fetal pituitary-adrenal axis plays a key role in the fetal response to intrauterine stress and in the timing of parturition. The fetal sheep adrenal gland is relatively refractory to stimulation in midgestation (90–120 days) before the prepartum activation, which occurs around 135 days gestation (term = 147 ± 3 days). The mechanisms underlying the switch from adrenal quiescence to activation are unclear. Therefore, we have investigated the expression of suppressor of cytokine signaling-3 (SOCS-3), a putative inhibitor of tissue growth in the fetal sheep adrenal between 50 and 145 days gestation and in the adrenal of the growth-restricted fetal sheep in late gestation. SOCS-3 is activated by a range of cytokines, including prolactin (PRL), and we have, therefore, determined whether PRL administered in vivo or in vitro stimulates SOCS-3 mRNA expression in the fetal adrenal in late gestation. There was a decrease ( P < 0.005) in SOCS-3 expression in the fetal adrenal between 54 and 133 days and between 141 and 144 days gestation. Infusion of the dopaminergic agonist, bromocriptine, which suppressed fetal PRL concentrations but did not decrease adrenal SOCS-3 mRNA expression. PRL administration, however, significantly increased adrenal SOCS-3 mRNA expression ( P < 0.05). Similarly, there was an increase ( P < 0.05) in SOCS-3 mRNA expression in adrenocortical cells in vitro after exposure to PRL (50 ng/ml). Placental and fetal growth restriction had no effect on SOCS-3 expression in the adrenal during late gestation. In summary, the decrease in the expression of the inhibitor SOCS-3 after 133 days gestation may be permissive for a subsequent increase in fetal adrenal growth before birth. We conclude that factors other than PRL act to maintain adrenal SOCS-3 mRNA expression before 133 days gestation but that acute elevations of PRL can act to upregulate adrenal SOCS-3 expression in the sheep fetus during late gestation.

scholarly journals Chronic Fetal Leucine Infusion Does Not Potentiate Glucose-Stimulated Insulin Secretion or Affect Pancreatic Islet Development in Late-Gestation Growth-Restricted Fetal Sheep

2020 ◽  
Author(s):  
Brit H Boehmer ◽  
Stephanie R Wesolowski ◽  
Laura D Brown ◽  
Paul J Rozance
Keyword(s):  
Endothelial Cells ◽  
Insulin Secretion ◽  
Mrna Expression ◽  
Pancreatic Islet ◽  
Late Gestation ◽  
Β Cells ◽  
Fetal Sheep ◽  
Islet Size ◽  
Intrauterine Fetal Growth Restriction ◽  
Glucose Stimulated Insulin Secretion

ABSTRACT Background Growth-restricted fetuses have attenuated glucose-stimulated insulin secretion (GSIS), smaller pancreatic islets, less pancreatic β-cells, and less pancreatic vascularization compared with normally growing fetuses. Infusion of leucine into normal late-gestation fetal sheep potentiates GSIS, as well as increases pancreatic islet size, the proportion of the pancreas and islet comprising β-cells, and pancreatic and islet vascularity. In addition, leucine stimulates hepatocyte growth factor (HGF ) mRNA expression in islet endothelial cells isolated from normal fetal sheep. Objective We hypothesized that a 9-d leucine infusion would potentiate GSIS and increase pancreatic islet size, β-cells, and vascularity in intrauterine fetal growth restriction (IUGR) fetal sheep. We also hypothesized that leucine would stimulate HGF mRNA in islet endothelial cells isolated from IUGR fetal sheep. Methods Late-gestation Columbia-Rambouillet IUGR fetal sheep (singleton or twin) underwent surgeries to place vascular sampling and infusion catheters. Fetuses were randomly allocated to receive a 9-d leucine infusion to achieve a 50–100% increase in leucine concentrations or a control saline infusion. GSIS was measured and pancreas tissue was processed for histologic analysis. Pancreatic islet endothelial cells were isolated from IUGR fetal sheep and incubated with supplemental leucine. Data were analyzed by mixed-models ANOVA; Student, Mann-Whitney, or a paired t test; or a test of equality of proportions. Results Chronic leucine infusion in IUGR fetuses did not affect GSIS, islet size, the proportion of the pancreas comprising β-cells, or pancreatic or pancreatic islet vascularity. In isolated islet endothelial cells from IUGR fetuses, HGF mRNA expression was not affected by supplemental leucine. Conclusions IUGR fetal sheep islets are not responsive to a 9-d leucine infusion with respect to insulin secretion or any histologic features measured. This is in contrast to the response in normally growing fetuses. These results are important when considering nutritional strategies to prevent the adverse islet and β-cell consequences in IUGR fetuses.

010. PERICONCEPTIONAL UNDERNUTRITION: LIFE-LONG EFFECTS FOR THE OFFSPRING

2010 ◽  
Vol 22 (9) ◽  
pp. 6
Author(s):  
F. H. Bloomfield ◽  
M. H. Oliver ◽  
A. L. Jaquiery ◽  
C. Hernandez ◽  
J. R. G. Challis ◽  
...  
Keyword(s):  
Maternal Nutrition ◽  
Late Gestation ◽  
Critical Window ◽  
Maternal Undernutrition ◽  
Maternal Nutritional Status ◽  
Child Bearing ◽  
Offspring Sex ◽  
Periconceptional Period ◽  
Altered Response ◽  
Poor Nutrition

Poor nutrition in women of child-bearing age is common, even in Western countries. It has been estimated that approximately 30% of women of child-bearing age in affluent cities such as Sydney and Southampton are either actively dieting or have a nutritional intake that does not meet daily recommended requirements for all nutrients. We have investigated the effect of reduced maternal nutrition before and around the time of conception on fetal growth and development, and have followed offspring through to adulthood. In this paradigm, ewes were fed to lose 10–15% of their body weight and then to gain weight according to conceptus mass. Control ewes were well fed throughout. Different timing and duration of undernutrition in the periconceptional period were utilised to investigate the most critical window for fetal development. Periconceptional undernutrition resulted in accelerated development of the fetal hypothalamic-pituitary-adrenal (HPA) and glucose-insulin axes in late gestation, and preterm birth. Offspring of periconceptionally undernourished ewes demonstrated altered laterality and an altered response to isolation stress; HPA axis function was also suppressed. As offspring aged, glucose tolerance decreased and became significantly impaired by young adulthood compared with control offspring. The effects of maternal undernutrition on offspring were modified by offspring sex and also by being one of a twin pair. Interestingly, our data also demonstrate that conception as a twin, regardless of maternal nutritional status, also affects all these outcomes but in a different way to maternal undernutrition. Preliminary data suggest that epigenetic changes in feeding centres of the hypothalamus may play a role in the mechanism behind some of these effects. These studies suggest that even moderate maternal undernutrition in very early pregnancy has life-long effects. Should this also be true in humans, then health care messages for women may need to be targeted prior to pregnancy.

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