title: In an Ovine Model of Polycystic Ovary Syndrome (PCOS) Prenatal Androgens Suppress Female Fetal Renal Gluconeogenesis.
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.
authors.affiliation: MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: Connolly
authors.affiliation: School of Health, Life and Social Sciences, Edinburgh Napier University, Edinburgh, United Kingdom.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rae
authors.affiliation: MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Katharina
authors.initials: K
authors.lastname: Späth
authors.affiliation: MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Boswell
authors.affiliation: MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Alan S
authors.initials: AS
authors.lastname: McNeilly
authors.affiliation: MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: W Colin
authors.initials: WC
authors.lastname: Duncan
mesh_terms: D000728:Androgens / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects*; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000196:embryology* / Q000473:pathology; D008297:Male; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000096:biosynthesis; D011085:Polycystic Ovary Syndrome / Q000139:chemically induced / Q000196:embryology* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D012756:Sheep; D043343:Testosterone Propionate / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D000728:Androgens; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D043343:Testosterone Propionate