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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 renal gluconeogenesis.Immunolocalisation of PEPCK (A) and G6PC (B) in the fetal kidney showing specific staining (brown) in the proximal tubules. Renal expression of PEPCK (C) and G6PC (D) quantified by qRT-PCR, of d90 females (white bars) and males (black bars) in both controls (Cont) and fetuses after maternal androgen exposure (TP). Representative western blot analysis of renal PEPCK in control (Cont) and prenatally TP exposed females and ACTB loading control (E). Values represent mean ±S.E.M. ** P<0.01. Scale bars represent 100μm.
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pone.0132113.g002: Fetal renal gluconeogenesis.Immunolocalisation of PEPCK (A) and G6PC (B) in the fetal kidney showing specific staining (brown) in the proximal tubules. Renal expression of PEPCK (C) and G6PC (D) quantified by qRT-PCR, of d90 females (white bars) and males (black bars) in both controls (Cont) and fetuses after maternal androgen exposure (TP). Representative western blot analysis of renal PEPCK in control (Cont) and prenatally TP exposed females and ACTB loading control (E). Values represent mean ±S.E.M. ** P<0.01. Scale bars represent 100μm.

Mentions: As the kidney is the other main source of fetal gluconeogenic activity we investigated renal expression of PEPCK and G6PC. Both PEPCK (Fig 2A) and G6PC (Fig 2B) were localised to the proximal tubules in the outer cortex of the fetal kidney at d90 of fetal life. Renal expression of PEPCK was significantly reduced (P<0.05; Fig 2C) and G6PC expression showed a trend toward reduction (P = 0.056; Fig 2D) after prenatal androgenisation. This was however was only apparent in female fetuses and no such trend was noted in males (Fig 2C and 2D). This altered renal PEPCK expression was mirrored by protein expression (Fig 2E), as assessed by Western blotting. Therefore, prenatal treatment with TP induces a tissue and sex specific alteration of gluconeogenic enzyme expression in the 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 renal gluconeogenesis.Immunolocalisation of PEPCK (A) and G6PC (B) in the fetal kidney showing specific staining (brown) in the proximal tubules. Renal expression of PEPCK (C) and G6PC (D) quantified by qRT-PCR, of d90 females (white bars) and males (black bars) in both controls (Cont) and fetuses after maternal androgen exposure (TP). Representative western blot analysis of renal PEPCK in control (Cont) and prenatally TP exposed females and ACTB loading control (E). Values represent mean ±S.E.M. ** P<0.01. Scale bars represent 100μm.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132113.g002: Fetal renal gluconeogenesis.Immunolocalisation of PEPCK (A) and G6PC (B) in the fetal kidney showing specific staining (brown) in the proximal tubules. Renal expression of PEPCK (C) and G6PC (D) quantified by qRT-PCR, of d90 females (white bars) and males (black bars) in both controls (Cont) and fetuses after maternal androgen exposure (TP). Representative western blot analysis of renal PEPCK in control (Cont) and prenatally TP exposed females and ACTB loading control (E). Values represent mean ±S.E.M. ** P<0.01. Scale bars represent 100μm.
Mentions: As the kidney is the other main source of fetal gluconeogenic activity we investigated renal expression of PEPCK and G6PC. Both PEPCK (Fig 2A) and G6PC (Fig 2B) were localised to the proximal tubules in the outer cortex of the fetal kidney at d90 of fetal life. Renal expression of PEPCK was significantly reduced (P<0.05; Fig 2C) and G6PC expression showed a trend toward reduction (P = 0.056; Fig 2D) after prenatal androgenisation. This was however was only apparent in female fetuses and no such trend was noted in males (Fig 2C and 2D). This altered renal PEPCK expression was mirrored by protein expression (Fig 2E), as assessed by Western blotting. Therefore, prenatal treatment with TP induces a tissue and sex specific alteration of gluconeogenic enzyme expression in the 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