Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure

Moss, Timothy J.; Sloboda, Deborah M.; Gurrin, Lyle; Harding, Richard; Challis, John; Newnham, John P.

doi:10.1152/ajpregu.2001.281.3.r960

Cited by 164 publications

(190 citation statements)

References 26 publications

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“…We have also shown that maternal betamethasone administration resulted in significantly elevated cortisol responses to a corticotrophinreleasing hormone+vasopressin challenge in offspring at 1 year of postnatal age (Sloboda et al 2002). These same animals exhibited significantly elevated postnatal insulin responses to a glucose load at 6 months and 1 year of age, as well as significantly higher basal glucose and glucose responses at 1 year of postnatal age (Moss et al 2001). It is not known whether hepatic function in these offspring was altered, although it is possible that alterations in hepatic gluconeogenesis may contribute to these effects.…”

Section: Introductionsupporting

confidence: 51%

“…It is possible that betamethasone treatment prematurely developed sympathetic suppression of insulin secretion, since previous studies have shown that glucocorticoids have a maturational effect on the sympathetic response at birth (Segar et al 1998(Segar et al , 2001(Segar et al , 2002. We have previously shown, however, that offspring treated with prenatal glucocorticoids exhibit exaggerated insulin responses to a glucose bolus at 1 year of postnatal age, rather than inhibited insulin secretion (Moss et al 2001). Furthermore, since cord insulin levels were not different at 146 days of gestation, any possible effect on the sympathetic regulation of insulin secretion due to betamethasone treatment in this study must have been transient.…”

Section: Discussionmentioning

confidence: 84%

“…All animals received an intramuscular injection of 150 mg medroxyprogesterone acetate (Depo Provera; Upjohn, Rydalmere, NSW, Australia) at 98 days of gestation, as reported previously (Moss et al 2001). This procedure has been previously shown to reduce the incidence of prenatal losses due to maternal betamethasone administration (Sloboda et al 2000(Sloboda et al , 2002.…”

Section: Experimental Protocolsmentioning

confidence: 99%

“…Epidemiological studies have shown that low birth weight is related to elevated levels of fasting plasma cortisol levels, elevated systolic blood pressure, plasma glucose and triglyceride levels and insulin resistance in adult men (Phillips et al 1998). In experimental models, prenatal exposure to synthetic glucocorticoids results in decreased birth weight (Jobe et al 1998, Sloboda et al 2000 as well as elevations in fetal and postnatal HPA activity in sheep (Sloboda et al 2000(Sloboda et al , 2001 and in primates (Uno et al 1994). The role of the HPA axis in programming future metabolic function is also pertinent to the safety of clinical prenatal glucocorticoid treatment, since glucocorticoids are administered to women at risk of preterm birth to enhance lung function in current clinical practice (Liggins & Howie 1972).…”

Section: Introductionmentioning

confidence: 99%

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Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Sloboda¹,

Newnham²,

Challis³

2002

Journal of Endocrinology

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Prenatal glucocorticoid exposure has been associated with a reduction in birth weight and postnatal alterations in glucose homeostasis and hypothalamic-pituitary-adrenal (HPA) axis function. The mechanisms underlying these responses are unknown, although changes in fetal hepatic development may play an important role. The fetal liver produces key regulators of fuel metabolism and of the developing HPA axis that are altered by glucocorticoids. The local availability of glucocorticoids is regulated, in part, by corticosteroid-binding protein (CBG), glucocorticoid receptors (GR) and by the enzyme 11 -hydroxysteroid dehydrogenase (11 HSD), but the effects of maternal glucocorticoid administration on the expression of these genes in the fetal liver are unknown. 11 HSD1 is the predominant form of this enzyme present in the liver and is responsible for the conversion of cortisone to cortisol. To determine if prenatal glucocorticoid exposure alters fetal hepatic regulation of CBG, 11 HSD1 and GRs, we treated pregnant ewes with betamethasone (0·5 mg/kg) intramuscularly at 104, 111 and 118 days of gestation (term 150 days). Animals were killed at 125 or 146 days of gestation. Maternal betamethasone administration did not alter mean cord plasma glucose but significantly decreased cord plasma insulin levels (P<0·05) at 125 days of gestation. At 146 days of gestation, cord plasma glucose levels were significantly increased without alterations in insulin levels following maternal betamethasone treatment (P<0·05). Maternal betamethasone administration resulted in a significant increase in fetal hepatic 11 HSD1 mRNA and protein levels at 125 days of gestation (P<0·05). CBG mRNA levels were significantly elevated over control at 125 days although levels of CBG protein were not significantly different. GR protein levels were not statistically different at either 125 or 146 days of gestation following glucocorticoid administration. These data suggest that prenatal betamethasone exposure in the ovine fetus results in alterations in cord glucose and insulin levels as well as alterations in hepatic 11 HSD1 mRNA and protein expression. These changes in 11 HSD1 increase the potential to generate local cortisol from circulating cortisone. We speculate that this could affect expression of glucocorticoid-dependent hepatic enzymes involved with the regulation of glucose production and HPA responsiveness.

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Section: Introductionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 84%

Section: Experimental Protocolsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Sloboda¹,

Newnham²,

Challis³

2002

Journal of Endocrinology

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“…Numerous reviews have concluded that there are no adverse consequences of a single course of glucocorticoid treatment on the preterm infant (NIH Consensus Conference 1995, Roberts & Dalziel 2006), but no published studies of which we are aware have investigated possible effects on maternal lactation. We previously observed a high rate of neonatal mortality after repeated treatment of pregnant sheep with betamethasone and subsequent delivery at term, which was attributed to a reduction in milk production (Moss et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Disrupted secretory activation of the mammary gland after antenatal glucocorticoid treatment in sheep

Henderson¹,

Hartmann²,

Moss³

et al. 2008

Reproduction

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Antenatal glucocorticoids are administered to women at risk of preterm delivery to prevent neonatal respiratory morbidity. The effects of exogenous glucocorticoids on the development of lactation are unknown. This study investigated the effects of a single dose of antenatal glucocorticoids on secretory activation in sheep before and after parturition. Pregnant ewes (NZ36) were randomised to receive either medroxyprogesterone acetate (MPA) at 118 days of pregnancy and betamethasone at 125 days (BETA group), MPA at 118 days and saline at 125 days (MPA group) or saline at 118 and 125 days (SALINE group). The concentration of lactose, progesterone, cortisol and prolactin in maternal plasma was measured during pregnancy. After term parturition, the concentration of lactose in milk and maternal plasma was measured daily for 5 days. Lambs were weighed at birth and at 5 days of age; milk volume was measured on day 5. The concentration of lactose in maternal plasma increased significantly after betamethasone administration, corresponding to a fall in plasma progesterone. No changes in lactose were observed in MPA or SALINE ewes. Transient decreases in cortisol and increases in prolactin were observed in the BETA group, but not in either the MPA or SALINE group. After parturition, BETA ewes experienced reduced milk yield and lamb weight gain, and delayed increases in milk lactose levels compared with MPA and saline controls. This study demonstrated that, in sheep, antenatal glucocorticoid administration disrupted secretory activation, causing precocious mammary secretion before parturition and compromising postpartum milk production and lamb growth.

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Long‐term Effects of Prenatal Stress and Glucocorticoid Exposure

Painter

Roseboom

Rooij

2012

Birth Defects Research Pt C

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There is a growing body of evidence suggesting that events during prenatal life can have long-lasting effects on development and adult health. Stress during pregnancy is common and has been linked to increased incidence of a range of affective and behavioral outcomes in the offspring in later life and also some somatic outcomes. Glucocorticoids, and their actions on the fetus, which are regulated by placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), are hypothesized to mediate these effects. Animal studies have demonstrated long-term effects of stress and glucocorticoid administration on behavioral outcomes, as well as increased blood pressure, altered hypothalamic pituitary adrenal axis (HPA) function, and decreased glucose tolerance and brain size. In humans, licorice, which inhibits placental 11β-HSD2 when consumed during pregnancy, has been shown to increase the risk of behavioral problems linked to altered HPA activity. Synthetic glucocorticoids administered during pregnancy to improve fetal lung maturity in threatened preterm birth have been shown to reduce birth weight and head circumference, but have not been linked to gross changes in long-term health to date. It is important to consider the long-term consequences of stress, and medication that mimics stress, during pregnancy.

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Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure

Cited by 164 publications

References 26 publications

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Disrupted secretory activation of the mammary gland after antenatal glucocorticoid treatment in sheep

Long‐term Effects of Prenatal Stress and Glucocorticoid Exposure

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