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We used pregnant rats treated with 5\u03b1\u2010dihydrotestosterone (DHT) and insulin to investigate the impact of hyperandrogenism and insulin resistance on fetal survival and to determine the molecular link between PCOS conditions and placental dysfunction during pregnancy. Our study shows that pregnant rats chronically treated with a combination of DHT and insulin exhibited endocrine aberrations such as hyperandrogenism and insulin resistance that are strikingly similar to those in pregnant PCOS patients. Of pathophysiological significance, DHT+insulin\u2010treated pregnant rats had greater fetal loss and subsequently decreased litter sizes compared to normal pregnant rats. This negative effect was accompanied by impaired trophoblast differentiation, increased glycogen accumulation, and decreased angiogenesis in the placenta. Mechanistically, we report that over\u2010production of reactive oxygen species (ROS) in the placenta, mitochondrial dysfunction, and disturbed superoxide dismutase 1 (SOD1) and Keap1\/Nrf2 antioxidant responses constitute important contributors to fetal loss in DHT+insulin\u2010treated pregnant rats. Many of the molecular pathways leading to placental abnormalities and fetal loss in DHT+insulin treatment were also seen in pregnant rats treated with DHT alone, whereas pregnant rats treated with insulin alone often exerted distinct effects on placental gene expression compared to insulin treatment in combination with DHT. We also found that treatment with the antioxidant N<\/jats:italic>\u2010acetylcysteine (NAC) improved fetal survival in DHT+insulin\u2010treated pregnant rats, an effect related to changes in Keap1\/Nrf2 and nuclear factor\u2010\u03baB signalling. However, NAC administration resulted in fetal loss in normal pregnant rats, most likely due to PCOS\u2010like endocrine abnormality induced by the treatment. Our results suggest that the deleterious effects of hyperandrogenism and insulin resistance on fetal survival are related to a constellation of mitochondria\u2013ROS\u2013SOD1\/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.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp277879","type":"journal-article","created":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T15:34:00Z","timestamp":1560785640000},"page":"3927-3950","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["Hyperandrogenism and insulin resistance\u2010induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome"],"prefix":"10.1113","volume":"597","author":[{"given":"Yuehui","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine 150040 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