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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 estrogen.Circulating estradiol levels in control (Cont) females (white bars) and males (black bars) and those exposed to TP quantified through RIA (A). Immunolocalisation of ERS1 in a representative liver (B) and kidney (C) in the d90 female fetus. Inset is negative control. Renal (light bars) and hepatic (dark bars) ERS1 expression in d90 females, whose mothers were prenatally treated with control oil (Cont) or TP (D). Values represent mean ±S.E.M. ** P<0.01. Scale bars represent 100μm.
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pone.0132113.g005: Role of estrogen.Circulating estradiol levels in control (Cont) females (white bars) and males (black bars) and those exposed to TP quantified through RIA (A). Immunolocalisation of ERS1 in a representative liver (B) and kidney (C) in the d90 female fetus. Inset is negative control. Renal (light bars) and hepatic (dark bars) ERS1 expression in d90 females, whose mothers were prenatally treated with control oil (Cont) or TP (D). Values represent mean ±S.E.M. ** P<0.01. Scale bars represent 100μm.

Mentions: Fetal estradiol concentrations are increased after maternal androgenisation in the female fetus (P<0.01) but not the male fetus (Fig 5A). ESR1 could be detected at low levels in liver cells (Fig 5B) and it was specifically localised to the tubules in the fetal renal cortex (Fig 5C). ESR1 was expressed in higher levels in the female fetal kidney than the liver (P<0.05; Fig 5D) and there was no effect of prenatal androgenisation. However, gene expression for ESR1 was low and at the limits of assay detection. AR however was robustly expressed and at a greater level in the fetal kidney than the fetal liver (P<0.01; Fig 6A). In addition, as reported previously [24], maternal androgenisation increased female fetal androgen concentrations (P<0.001) while having no effect on male fetal androgens (Fig 6B). Little AR could be detected in the nuclei of hepatocytes (Fig 6C) while it was detected in the nuclei of fetal renal tubules (Fig 6D). Renal tubular cells synthesising PEPCK also expressed androgen receptors (Fig 6E). In addition after stopping maternal androgenisation female fetal testosterone concentrations normalised (Fig 6F) as did renal PEPCK expression (Fig 6G). This means that direct alterations in sex steroid action, particularly androgens, may explain both the tissue and sex specific effect of androgenisation on fetal gluconeogenesis.


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 estrogen.Circulating estradiol levels in control (Cont) females (white bars) and males (black bars) and those exposed to TP quantified through RIA (A). Immunolocalisation of ERS1 in a representative liver (B) and kidney (C) in the d90 female fetus. Inset is negative control. Renal (light bars) and hepatic (dark bars) ERS1 expression in d90 females, whose mothers were prenatally treated with control oil (Cont) or TP (D). Values represent mean ±S.E.M. ** P<0.01. Scale bars represent 100μm.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132113.g005: Role of estrogen.Circulating estradiol levels in control (Cont) females (white bars) and males (black bars) and those exposed to TP quantified through RIA (A). Immunolocalisation of ERS1 in a representative liver (B) and kidney (C) in the d90 female fetus. Inset is negative control. Renal (light bars) and hepatic (dark bars) ERS1 expression in d90 females, whose mothers were prenatally treated with control oil (Cont) or TP (D). Values represent mean ±S.E.M. ** P<0.01. Scale bars represent 100μm.
Mentions: Fetal estradiol concentrations are increased after maternal androgenisation in the female fetus (P<0.01) but not the male fetus (Fig 5A). ESR1 could be detected at low levels in liver cells (Fig 5B) and it was specifically localised to the tubules in the fetal renal cortex (Fig 5C). ESR1 was expressed in higher levels in the female fetal kidney than the liver (P<0.05; Fig 5D) and there was no effect of prenatal androgenisation. However, gene expression for ESR1 was low and at the limits of assay detection. AR however was robustly expressed and at a greater level in the fetal kidney than the fetal liver (P<0.01; Fig 6A). In addition, as reported previously [24], maternal androgenisation increased female fetal androgen concentrations (P<0.001) while having no effect on male fetal androgens (Fig 6B). Little AR could be detected in the nuclei of hepatocytes (Fig 6C) while it was detected in the nuclei of fetal renal tubules (Fig 6D). Renal tubular cells synthesising PEPCK also expressed androgen receptors (Fig 6E). In addition after stopping maternal androgenisation female fetal testosterone concentrations normalised (Fig 6F) as did renal PEPCK expression (Fig 6G). This means that direct alterations in sex steroid action, particularly androgens, may explain both the tissue and sex specific effect of androgenisation on fetal gluconeogenesis.

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