First-degree male relatives of polycystic ovary syndrome (PCOS) sufferers can develop metabolic abnormalities evidenced by elevated circulating cholesterol and triglycerides, suggestive of a male PCOS equivalent. Similarly, male sheep overexposed to excess androgens in fetal life develop dyslipidaemia in adolescence. Dyslipidaemia, altered lipid metabolism and dysfunctional hepatic mitochondria are associated with development of non-alcoholic liver disease (NAFLD). We therefore dissected hepatic mitochondrial function and lipid metabolism in adolescent prenatally androgenized (PA) males from an ovine model of PCOS. Testosterone was directly administered to male ovine fetuses to create prenatal androgenic overexposure. Liver RNA sequencing and proteomics occurred at 6 months of age. Hepatic lipids, glycogen, ATP, reactive oxygen species (ROS), DNA damage and collagen were assessed. Adolescent PA males had increased accumulation of hepatic cholesterol and glycogen, together with perturbed glucose and fatty acid metabolism, mitochondrial dysfunction, with altered mitochondrial transport, decreased oxidative phosphorylation and ATP synthesis, and impaired mitophagy. Mitochondrial dysfunction in PA males was associated with increased hepatic ROS level and signs of early liver fibrosis, with clinical relevance to NAFLD progression. We conclude that excess in utero androgen exposure in male fetuses leads to a PCOS-like metabolic phenotype with dysregulated mitochondrial function and likely lifelong health sequelae.
Bibliographical noteAcknowledgments: The authors wish to acknowledge Joan Docherty and the staff at the Marshall Building, University of Edinburgh for their excellent animal husbandry, and Dr Sophie Shaw, Dr Alex Douglas, Dr Zeynab Heidari and Dr David Stead (University of Aberdeen) for the expertise in RNA sequencing and proteomic analysis.
Funding: This work was funded by Medical Research Council (MRC) project grant (G0901807) to WCD and MTR, and MRC project grant MR/P011535/1 (To MTR, PAF and WCD).
- Male PCOS
- prenatal programming
- mitochondrial dysfunction
- hepatic cholesterol
- oxidative phosphorylation
- liver fibrosis