Abstract
Epigenetic changes in response to external stimuli are fast emerging as common underlying causes for the pre-disposition to adult disease. Prenatal androgenization is one such model that results in reproductive and metabolic features that are present in conditions such as polycystic ovary syndrome (PCOS). We examined the effect of prenatal androgens on liver function and metabolism of adult sheep. As non-alcoholic fatty liver disease is increased in PCOS we hypothesized that this, and other important liver pathways including metabolic function, insulin–like growth factor (IGF) and steroid receptivity, would be affected. Pregnant ewes received vehicle control (C; n = 5) or testosterone propionate (TP; n = 9) twice weekly (100 mg; i.m) from d62–102 (gestation 147 days). In a novel treatment paradigm, a second cohort received a direct C (n = 4) or TP (20 mg; n = 7) fetal injection at d62 and d82. In adults, maternal TP exposure resulted in increased insulin secretion to glucose load (P<0.05) and the histological presence of fatty liver (P<0.05) independent of central obesity. Additionally, hepatic androgen receptor (AR; P<0.05), glucocorticoid receptor (GR; P<0.05), UDP- glucose ceramide glucosyltransferase (UGCG; P<0.05) and IGF1 (P<0.01) expression were upregulated. The direct fetal intervention (C and TP) led to early fatty liver changes in all animals without differential changes in insulin secretion. Furthermore, hepatic phosphoenolpyruvate carboxykinase (PEPCK) was up-regulated in the fetal controls (P<0.05) and this was opposed by fetal TP (P<0.05). Hepatic estrogen receptor (ERα; P<0.05) and mitogen activated protein kinase kinase 4 (MAP2K4; P<0.05) were increased following fetal TP exposure. Adult liver metabolism and signaling can be altered by early exposure to sex steroids implicating epigenetic regulation of metabolic disturbances that are common in PCOS.
Highlights
An abnormal or altered fetal environment is emerging as a likely etiological factor for a host of adult diseases [1,2]
We investigated whether prenatal androgenization affected adult liver function by examining the molecular expression of: 4) hepatic steroid receptors, 5) the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and other genes involved in metabolic function, and 6) growth factor secretion by analyzing hepatic expression of insulin-like growth factor 1 (IGF1)
These early signs of liver damage were not detectable at a clinical level as there was no change in serum determinants of liver function including circulating aspartate transaminase (AST; Fig. 1C), alanine transaminase (ALT; C = 19.462.8 U/l Vs testosterone propionate (TP) = 16.661.1 U/l), alkaline phosphatase (ALP; C = 179.8623.9 U/l Vs TP = 200.1629.4 U/l) and gamma glutamyltransferase (GGT; Fig. 1D) concentrations
Summary
An abnormal or altered fetal environment is emerging as a likely etiological factor for a host of adult diseases [1,2]. The maternal environment can influence epigenetic processes in the placenta and fetus that program lasting developmental changes associated with cardiovascular disease, hypertension, obesity, type II diabetes, endocrine disruption and reproductive anomalies [2,3,4], all of which are prevalent in Westernized societies. Midgestation androgen exposure in sheep leads to polyfollicular ovaries, increased luteinizing hormone (LH), dysregulation of neuroendocrine feedback and disrupted estrous cycles in adult offspring [11,12,13]. Metabolic parameters such as hyperinsulinemia and insulin resistance are reported [14,15]
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