OR35-01 Colonic Mitochondrial Dysfunction and Sub-acute Gastrointestinal Inflammation in Two Hyperandrogenemic Rodent Models of PCOS

Abstract

Abstract Disclosure: N. Hoang: None. S. Rezq: None. J. Basnet: None. A.M. Huffman: None. K. Brooks: None. L.L. Yanes Cardozo: None. D.G. Romero: None. K.S. Edwards: None. Introduction: Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women during their reproductive years. Approximately 80% of PCOS women suffer from hyperandrogenemia. PCOS women often exhibited symptoms of irritable bowel syndrome (IBS) that is associated with sub-acute gastrointestinal (GI) inflammation. However, the underlying pathophysiology for the development of IBS is unknown. Mitochondrial dysfunction is associated with the development of inflammation and hyperandrogenemia can alter mitochondrial function. This study aims to investigate the mechanisms linking PCOS and mitochondrial dysfunction to the development of IBS symptoms. Methods: The hyperandrogenemic female (HAF) rodent models exhibit characteristics similar to PCOS women such as increased body weight, fat mass, and food intake. At 4 weeks of age, female rats received dihydrotestosterone (DHT, 7.5mg/90 days) pellets. At 3 weeks of age female mice were implanted with Silastic tubes filled with DHT (8mg) or vehicle. At 15 weeks of age, colon tissues were collected for histology (H&E staining) and mitochondria isolation. Intact mitochondrial respiration, mitochondrial reactive oxygen species (mtROS), and complex IV activity, a marker for oxidative phosphorylation capacity, were measured using the Oroboros O2k-FluoRespirometer. Data was normalized to mitochondrial content using citrate synthase (CS) activity. Results: Histology from the colon of HAF rats showed an increase in immune cell infiltration and structural derangement. Both HAF rodent models showed an increase in GI inflammation and alterations to colon mitochondrial function. Complex I-driven respiration showed a significant (p<0.05) decrease (60%) in both rats and mice. Both rats and mice showed a significant (p<0.05) decrease (50%) in complex II-driven respiration. Quality of mitochondria is determined by the respiratory control ratio (RCR). A significant (p<0.05) decrease in RCR was observed for both rats (40%) and mice (20%). Both rats and mice showed a 2-fold increase in mtROS (p<0.05). Complex IV activity was significantly (p<0.05) decreased in both rats (3.91±0.97 vs. 5.22±1.13 nmol e-/CS activity) and mice (0.03±0.01 vs. 0.05±0.01 nmol e-/CS activity) compared to control. Conclusions: The observed colonic inflammation and associated mitochondrial dysfunction in both rodent models of PCOS suggests that mitochondrial dysfunction is involved in the development of IBS symptoms in PCOS. This study provides a better understanding of the role of mitochondria in the development of IBS with PCOS and an avenue for the development of strategies to re-establish normal mitochondrial function. This could provide options for preventive and therapeutic interventions for IBS where there are limited treatment options in PCOS women. Supported by NIH grants: P20PGM121334 Presentation Date: Sunday, June 18, 2023