Polycystic ovarian syndrome is accompanied by repression of gene signatures associated with biosynthesis and metabolism of steroids, cholesterol and lipids

Dessie Salilew-Wondim, Qi Wang, Dawit Tesfaye, Karl Schellander, Michael Hoelker, Md Munir Hossain, Benjamin K Tsang

Polycystic ovarian syndrome (PCOS) is a spectrum of heterogeneous disorders of reproduction and metabolism in women with potential systemic sequel such as diabetes and obesity. Although, PCOS is believed to be caused by genetic abnormalities, the genetic background that can be associated with PCOS phenotypes remains unclear due to the complexity of the trait. In this study, we used a rat model which exhibits reproductive and metabolic abnormalities similar to the human PCOS to unravel the molecular mechanisms underlining this complex syndrome. Female Sprague-Dawley rats were randomly assigned to DHT and control (CTL) groups. Rats in the DHT group were implanted with a silicone capsule continuous-releasing 83 μg 5α-dihydrotestosterone (DHT) per day for 12 weeks to mimic the hyperandrogenic state in women with PCOS. The animals were euthanized at 15 weeks of age and the pairs of ovaries were excised and the ovarian cortex tissues were used for gene expression analysis. Total RNA was from the ovarian cortex was amplified, labeled and hybridized to the Affymetrix GeneChip® Rat Genome 230 2.0 Array. A linear model system for microarray data analysis was used to identify genes affected in DHT treated rat ovaries and the molecular pathway of those genes were analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis tool. A total of 573 gene transcripts, including CPA1, CDH1, INSL3, AMH, ALDH1B1, INHBA, CYP17A1, RBP4, GAS6, GAS7 and GATA4, were activated while 430 others including HSD17B7, HSD3B6, STAR, HMGCS1, HMGCR, CYP51, CYP11A1 and CYP19A1 were repressed in DHT-treated ovaries. Functional annotation of the dysregulated genes revealed that biosynthesis and metabolism of steroids, cholesterol and lipids to be the most top functions enriched by the repressed genes. However, cell differentiation/proliferation, transcriptional regulation, neurogenesis, cell adhesion and blood vessel development processes were enriched by activated genes. The dysregulation of genes associated with biosynthesis and metabolism of steroids, cholesterol and lipids, cell differentiation/proliferation in DHT- treated ovaries could be a molecular clue for abnormal steroidogenesis, estrous cycle irregularity, abnormal folliculogenesis, anovulation and lipid metabolism in PCOS patients.