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In an Ovine Model of Polycystic Ovary Syndrome (PCOS) Prenatal Androgens Suppress Female Fetal Renal Gluconeogenesis.

Connolly F, Rae MT, Späth K, Boswell L, McNeilly AS, Duncan WC - PLoS ONE (2015)

Bottom Line: PEPCK and G6PC were localised to fetal hepatocytes but maternal androgens had no effect on female or male fetuses.The tissue specific effects may be related to the increased expression of ESR1 (P<0.01) and AR (P<0.05) in the kidney when compared to the fetal liver.These data further highlight the fetal and sexual dimorphic effects of maternal androgenisation, an antecedent to adult disease and the plasticity of fetal development.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh, United Kingdom.

ABSTRACT
Increased maternal androgen exposure during pregnancy programmes a polycystic ovary syndrome (PCOS)-like condition, with metabolic dysfunction, in adult female offspring. Other in utero exposures associated with the development of insulin resistance, such as intrauterine growth restriction and exposure to prenatal glucocorticoids, are associated with altered fetal gluconeogenesis. We therefore aimed to assess the effect of maternal androgenisation on the expression of PEPCK and G6PC in the ovine fetus. Pregnant Scottish Greyface sheep were treated with twice weekly testosterone propionate (TP; 100mg) or vehicle control from day 62 to day 102 of gestation. At day 90 and day 112 fetal plasma and liver and kidney tissue was collected for analysis. PEPCK and G6PC expression were analysed by quantitative RT-PCR, immunohistochemistry and western blotting. PEPCK and G6PC were localised to fetal hepatocytes but maternal androgens had no effect on female or male fetuses. PEPCK and G6PC were also localised to the renal tubules and renal PEPCK (P<0.01) and G6PC (P = 0.057) were lower in females after prenatal androgenisation with no change in male fetuses. These tissue and sex specific observations could not be explained by alterations in fetal insulin or cortisol. The sexual dimorphism may be related to the increase in circulating estrogen (P<0.01) and testosterone (P<0.001) in females but not males. The tissue specific effects may be related to the increased expression of ESR1 (P<0.01) and AR (P<0.05) in the kidney when compared to the fetal liver. After discontinuation of maternal androgenisation female fetal kidney PEPCK expression normalised. These data further highlight the fetal and sexual dimorphic effects of maternal androgenisation, an antecedent to adult disease and the plasticity of fetal development.

No MeSH data available.


Related in: MedlinePlus

Fetal hepatic gluconeogenesis.Immunostaining of PEPCK (A) and G6PC (B) in the hepatocytes of the fetal liver (brown). Hepatic expression of PEPCK (C) and G6PC (D) quantified by qRT-PCR, in control (Cont) and prenatally androgenised females (TP; white bars) and males (black bars) at d90 of gestation. Values represent mean ±S.E.M. Scale bars represent 100μm.
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pone.0132113.g001: Fetal hepatic gluconeogenesis.Immunostaining of PEPCK (A) and G6PC (B) in the hepatocytes of the fetal liver (brown). Hepatic expression of PEPCK (C) and G6PC (D) quantified by qRT-PCR, in control (Cont) and prenatally androgenised females (TP; white bars) and males (black bars) at d90 of gestation. Values represent mean ±S.E.M. Scale bars represent 100μm.

Mentions: Key enzymes in the gluconeogenic pathway, PEPCK and G6PC, could be localised to liver hepatocytes at d90 of fetal life (Fig 1A and 1B). As these genes are important determinants of fetal glucose homeostasis, which are transcriptionally regulated, qRT-PCR was performed to identify if prenatal androgen exposure altered their expression. Neither PEPCK (Fig 1C) nor G6PC (Fig 1D) were changed in response to prenatal androgen treatment in either the male or female ovine fetus.


In an Ovine Model of Polycystic Ovary Syndrome (PCOS) Prenatal Androgens Suppress Female Fetal Renal Gluconeogenesis.

Connolly F, Rae MT, Späth K, Boswell L, McNeilly AS, Duncan WC - PLoS ONE (2015)

Fetal hepatic gluconeogenesis.Immunostaining of PEPCK (A) and G6PC (B) in the hepatocytes of the fetal liver (brown). Hepatic expression of PEPCK (C) and G6PC (D) quantified by qRT-PCR, in control (Cont) and prenatally androgenised females (TP; white bars) and males (black bars) at d90 of gestation. Values represent mean ±S.E.M. Scale bars represent 100μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492923&req=5

pone.0132113.g001: Fetal hepatic gluconeogenesis.Immunostaining of PEPCK (A) and G6PC (B) in the hepatocytes of the fetal liver (brown). Hepatic expression of PEPCK (C) and G6PC (D) quantified by qRT-PCR, in control (Cont) and prenatally androgenised females (TP; white bars) and males (black bars) at d90 of gestation. Values represent mean ±S.E.M. Scale bars represent 100μm.
Mentions: Key enzymes in the gluconeogenic pathway, PEPCK and G6PC, could be localised to liver hepatocytes at d90 of fetal life (Fig 1A and 1B). As these genes are important determinants of fetal glucose homeostasis, which are transcriptionally regulated, qRT-PCR was performed to identify if prenatal androgen exposure altered their expression. Neither PEPCK (Fig 1C) nor G6PC (Fig 1D) were changed in response to prenatal androgen treatment in either the male or female ovine fetus.

Bottom Line: PEPCK and G6PC were localised to fetal hepatocytes but maternal androgens had no effect on female or male fetuses.The tissue specific effects may be related to the increased expression of ESR1 (P<0.01) and AR (P<0.05) in the kidney when compared to the fetal liver.These data further highlight the fetal and sexual dimorphic effects of maternal androgenisation, an antecedent to adult disease and the plasticity of fetal development.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh, United Kingdom.

ABSTRACT
Increased maternal androgen exposure during pregnancy programmes a polycystic ovary syndrome (PCOS)-like condition, with metabolic dysfunction, in adult female offspring. Other in utero exposures associated with the development of insulin resistance, such as intrauterine growth restriction and exposure to prenatal glucocorticoids, are associated with altered fetal gluconeogenesis. We therefore aimed to assess the effect of maternal androgenisation on the expression of PEPCK and G6PC in the ovine fetus. Pregnant Scottish Greyface sheep were treated with twice weekly testosterone propionate (TP; 100mg) or vehicle control from day 62 to day 102 of gestation. At day 90 and day 112 fetal plasma and liver and kidney tissue was collected for analysis. PEPCK and G6PC expression were analysed by quantitative RT-PCR, immunohistochemistry and western blotting. PEPCK and G6PC were localised to fetal hepatocytes but maternal androgens had no effect on female or male fetuses. PEPCK and G6PC were also localised to the renal tubules and renal PEPCK (P<0.01) and G6PC (P = 0.057) were lower in females after prenatal androgenisation with no change in male fetuses. These tissue and sex specific observations could not be explained by alterations in fetal insulin or cortisol. The sexual dimorphism may be related to the increase in circulating estrogen (P<0.01) and testosterone (P<0.001) in females but not males. The tissue specific effects may be related to the increased expression of ESR1 (P<0.01) and AR (P<0.05) in the kidney when compared to the fetal liver. After discontinuation of maternal androgenisation female fetal kidney PEPCK expression normalised. These data further highlight the fetal and sexual dimorphic effects of maternal androgenisation, an antecedent to adult disease and the plasticity of fetal development.

No MeSH data available.


Related in: MedlinePlus