Hyperandrogenism and Insulin Resistance-Induced Fetal Loss: Evidence for Placental Mitochondrial Abnormalities and Elevated ROS Production in PCOS-Like Pregnant Rats

Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanism of PCOS-induced fetal loss during pregnancy is unclear. We used pregnant rats treated with 5α-dihydrotestosterone (DHT) and insulin to investigate the effects of hyperandrogenism and insulin resistance on fetal survival and to determine the molecular link between PCOS conditions and placental dysfunction during pregnancy. We show that pregnant rats chronically treated with a combination of DHT and insulin exhibited endocrine aberrations such as hyperandrogenism and insulin resistance that mirror pregnant PCOS patients. Compared to normal pregnant rats, PCOS-like pregnant rats had greater fetal loss and subsequently decreased litter sizes. This negative effect was accompanied by impaired trophoblast differentiation, abnormal glycogen accumulation, and decreased angiogenesis in the placenta. We report that over-production of reactive oxygen species (ROS) in the placenta, mitochondrial dysfunction, and disturbed SOD1 and Keap1/Nrf2 antioxidant responses constitute important contributors to fetal loss in PCOS-like pregnant rats. Furthermore, dose-dependent treatment with the antioxidant N-acetylcysteine (NAC) improved fetal survival in PCOS-like pregnant rats dependent on Keap1/Nrf2 and NFκB signaling molecules. However, similar treatment resulted in fetal loss in normal pregnant rats, most likely due to PCOS-like endocrine abnormality induced by NAC. Our work suggests that the deleterious effects of hyperandrogenism and insulin resistance on fetal survival are related to a constellation of mitochondrial-ROS-SOD1/Nrf2 changes in the placenta. Our findings also suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy. Funding: This work was supported by the Swedish Medical Research Council (grant number 10380), the Swedish federal government under the LUA/ALF agreement (grant number ALFGBG-147791), the Jane and Dan Olsson’s Foundation, and the Adlerbert Research Foundation to HB and LRS as well as the National Natural Science Foundation of China (grant number 81774136), the Project of Young Innovation Talents in Heilongjiang Provincial University (grant number UNPYSCT-2015121), the Project of Innovation Talents (Young Reserve Talents) in Harbin city (grant number 2015RAQYJ089), and the Scientific Research Foundation of the Heilongjiang Province for Returned Chinese Scholars to YZ. ANSP is supported by a Royal Society Dorothy Hodgkin Research Fellowship. Declaration of Interest: The authors declare that no competing interests exist. Ethical Approval: The study was approved and authorized by the Animal Care and Use Committee of the Heilongjiang University of Chinese Medicine, China (HUCM 2015-0112), and followed the National Institutes of Health guidelines on the care and use of animals.