Explorer The Pancreas Is Altered by In Utero Androgen Exposure : Implications for Clinical Conditions Such as Polycystic Ovary Syndrome ( PCOS )

Using an ovine model of polycystic ovary syndrome (PCOS), (pregnant ewes injected with testosterone propionate (TP) (100 mg twice weekly) from day (d)62 to d102 of d147 gestation (maternal injection – MI-TP)), we previously reported female offspring with normal glucose tolerance but hyperinsulinemia. We therefore examined insulin signalling and pancreatic morphology in these offspring using quantitative (Q) RT-PCR and western blotting. In addition the fetal pancreatic responses to MI-TP, and androgenic and estrogenic contributions to such responses (direct fetal injection (FI) of TP (20 mg) or diethylstilbestrol (DES) (20 mg) at d62 and d82 gestation) were assessed at d90 gestation. Fetal plasma was assayed for insulin, testosterone and estradiol, pancreatic tissue was cultured, and expression of key b-cell developmental genes was assessed by QRT-PCR. In female d62MI-TP offspring insulin signalling was unaltered but there was a pancreatic phenotype with increased numbers of b-cells (P,0.05). The fetal pancreas expressed androgen receptors in islets and genes involved in b-cell development and function (PDX1, IGF1R, INSR and INS) were up-regulated in female fetuses after d62MI-TP treatment (P,0.05–0.01). In addition the d62MI-TP pancreas showed increased insulin secretion under euglycaemic conditions (P,0.05) in vitro. The same effects were not seen in the male fetal pancreas or when MI-TP was started at d30, before the male programming window. As d62MI-TP increased both fetal plasma testosterone (P,0.05) and estradiol concentrations (P,0.05) we assessed the relative contribution of androgens and estrogens. FI-TP (commencing d62) (not FIDES treatment) caused elevated basal insulin secretion in vitro and the genes altered by d62MI-TP treatment were similarly altered by FI-TP but not FI-DES. In conclusion, androgen over-exposure alters fetal pancreatic development and b-cell numbers in offspring. These data suggest that that there may be a primary pancreatic phenotype in models of PCOS, and that there may be a distinct male and female pancreas. Citation: Rae M, Grace C, Hogg K, Wilson LM, McHaffie SL, et al. (2013) The Pancreas Is Altered by In Utero Androgen Exposure: Implications for Clinical Conditions Such as Polycystic Ovary Syndrome (PCOS). PLoS ONE 8(2): e56263. doi:10.1371/journal.pone. 0056263 Editor: Stephen Franks, Imperial College London, United Kingdom Received October 25, 2012; Accepted January 7, 2013; Published February 15, 2013 Copyright: 2013 Rae et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by Medical Research Council (MRC) project grant (G0500717) to CD and ASM and MRC project grant (G0901807) to CD, MTR and ASM. KH has a University of Edinburgh CMVM studentship. CD is supported by a Scottish Senior Clinical Fellowship from the SFC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: m.rae@napier.ac. uk