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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

Role of cortisol.Serum cortisol levels in d90 females measured by RIA in controls (Cont) and fetuses collected after TP treatment (A). Renal (light bars) GR (B), HSD11B1 (C) and HSD11B2 (D) and hepatic (dark bars) GR (B) and HSD11B1 (C) transcript abundance, quantified by qRT-PCR in the d90 female fetus. HSD11B2 was not expressed in the fetal liver. Values represent mean ±S.E.M. *** P<0.001.
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pone.0132113.g004: Role of cortisol.Serum cortisol levels in d90 females measured by RIA in controls (Cont) and fetuses collected after TP treatment (A). Renal (light bars) GR (B), HSD11B1 (C) and HSD11B2 (D) and hepatic (dark bars) GR (B) and HSD11B1 (C) transcript abundance, quantified by qRT-PCR in the d90 female fetus. HSD11B2 was not expressed in the fetal liver. Values represent mean ±S.E.M. *** P<0.001.

Mentions: Cortisol is major positive regulator of gluconeogenesis. Circulating cortisol was not changed in female fetuses as a result of androgen exposure (Fig 4A). The glucocorticoid receptor was not altered in response to prenatal androgen treatment, nor did it have a tissue specific pattern of expression (Fig 4B). The peripheral cortisol generating enzyme HSD11B1 was highly expressed in the liver compared to the kidney (P<0.001) and there was no change in response to androgenisation (Fig 4C). HSD11B2 was not expressed in the liver and renal expression was also unaffected by TP treatment in d90 females (Fig 4D). This is not consistent with cortisol being involved in the differential regulation of gluconeogenesis after maternal androgenisation.


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)

Role of cortisol.Serum cortisol levels in d90 females measured by RIA in controls (Cont) and fetuses collected after TP treatment (A). Renal (light bars) GR (B), HSD11B1 (C) and HSD11B2 (D) and hepatic (dark bars) GR (B) and HSD11B1 (C) transcript abundance, quantified by qRT-PCR in the d90 female fetus. HSD11B2 was not expressed in the fetal liver. Values represent mean ±S.E.M. *** P<0.001.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132113.g004: Role of cortisol.Serum cortisol levels in d90 females measured by RIA in controls (Cont) and fetuses collected after TP treatment (A). Renal (light bars) GR (B), HSD11B1 (C) and HSD11B2 (D) and hepatic (dark bars) GR (B) and HSD11B1 (C) transcript abundance, quantified by qRT-PCR in the d90 female fetus. HSD11B2 was not expressed in the fetal liver. Values represent mean ±S.E.M. *** P<0.001.
Mentions: Cortisol is major positive regulator of gluconeogenesis. Circulating cortisol was not changed in female fetuses as a result of androgen exposure (Fig 4A). The glucocorticoid receptor was not altered in response to prenatal androgen treatment, nor did it have a tissue specific pattern of expression (Fig 4B). The peripheral cortisol generating enzyme HSD11B1 was highly expressed in the liver compared to the kidney (P<0.001) and there was no change in response to androgenisation (Fig 4C). HSD11B2 was not expressed in the liver and renal expression was also unaffected by TP treatment in d90 females (Fig 4D). This is not consistent with cortisol being involved in the differential regulation of gluconeogenesis after maternal androgenisation.

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