{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T22:37:52Z","timestamp":1793227072698,"version":"4.5.0"},"reference-count":0,"publisher":"Bioscientifica","issue":"3","content-domain":{"domain":["joe.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,9]]},"abstract":"\n Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance and a high risk of miscarriage during pregnancy. Similarly, in rats, maternal exposure to 5\u03b1-dihydrotestosterone (DHT) and insulin from gestational day 7.5 to 13.5 leads to hyperandrogenism and insulin resistance and subsequently increased fetal loss. A variety of hormonal and metabolic stimuli are able to trigger different types of regulated cell death under physiological and pathological conditions. These include ferroptosis, apoptosis and necroptosis. We hypothesized that, in rats, maternal hyperandrogenism and insulin-resistance-induced fetal loss is mediated, at least in part, by changes in the ferroptosis, apoptosis and necroptosis pathways in the gravid uterus and placenta. Compared with controls, we found that co-exposure to DHT and insulin led to decreased levels of glutathione peroxidase 4 (GPX4) and glutathione, increased glutathione\u2009+\u2009glutathione disulfide and malondialdehyde, aberrant expression of ferroptosis-associated genes (\n Acsl4<\/jats:italic>\n ,\n Tfrc<\/jats:italic>\n ,\n Slc7a11<\/jats:italic>\n , and\n Gclc<\/jats:italic>\n ), increased iron deposition and activated ERK\/p38\/JNK phosphorylation in the gravid uterus. In addition, we observed shrunken mitochondria with electron-dense cristae, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of\n Dpp4<\/jats:italic>\n , a mitochondria-encoded gene responsible for ferroptosis induction in the uteri of rats co-exposed to DHT and insulin. However, in the placenta, DHT and insulin exposure only partially altered the expression of ferroptosis-related markers (e.g. region-dependent GPX4, glutathione\u2009+\u2009glutathione disulfide, malondialdehyde,\n Gls2<\/jats:italic>\n and\n Slc7a11<\/jats:italic>\n mRNAs, and phosphorylated p38 levels). Moreover, we found decreased expression of\n Dpp4<\/jats:italic>\n mRNA and increased expression of\n Cisd1<\/jats:italic>\n mRNA in placentas of rats co-exposed to DHT and insulin. Further, DHT\u2009+\u2009insulin-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal hyperandrogenism and insulin resistance causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Our data also suggest that apoptosis and necroptosis may play a role in coordinating or compensating for hyperandrogenism and insulin-resistance-induced ferroptosis when the gravid uterus and placenta are dysfunctional.\n <\/jats:p>","DOI":"10.1530\/joe-20-0155","type":"journal-article","created":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T12:44:40Z","timestamp":1593089080000},"page":"247-263","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":126,"title":["Hyperandrogenism and insulin resistance modulate gravid uterine and placental ferroptosis in PCOS-like rats"],"prefix":"10.1530","volume":"246","author":[{"given":"Yuehui","family":"Zhang","sequence":"first","affiliation":[{"name":"1Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Hu","sequence":"additional","affiliation":[{"name":"2Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"name":"3Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Jia","sequence":"additional","affiliation":[{"name":"1Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqi","family":"Liu","sequence":"additional","affiliation":[{"name":"1Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"4Department of Acupuncture and Moxibustion, Second Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Wang","sequence":"additional","affiliation":[{"name":"1Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[{"name":"2Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"name":"3Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Cui","sequence":"additional","affiliation":[{"name":"2Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"name":"5Department of Gynecology, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"2Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"},{"name":"6Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China"},{"name":"7Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Lager","sequence":"additional","affiliation":[{"name":"8Department of Women\u2019s and Children\u2019s Health, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda Nancy","family":"Sferruzzi-Perri","sequence":"additional","affiliation":[{"name":"9Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhua","family":"Han","sequence":"additional","affiliation":[{"name":"1Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songjiang","family":"Liu","sequence":"additional","affiliation":[{"name":"1Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoke","family":"Wu","sequence":"additional","affiliation":[{"name":"1Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mats","family":"Br\u00e4nnstr\u00f6m","sequence":"additional","affiliation":[{"name":"10Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linus R","family":"Shao","sequence":"additional","affiliation":[{"name":"2Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5kan","family":"Billig","sequence":"additional","affiliation":[{"name":"2Department of Physiology\/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","container-title":["Journal of Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/joe.bioscientifica.com\/view\/journals\/joe\/246\/3\/JOE-20-0155.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/joe.bioscientifica.com\/downloadpdf\/journals\/joe\/246\/3\/JOE-20-0155.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:57:12Z","timestamp":1784555832000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/joe\/article\/246\/3\/247-263\/5398"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9]]},"references-count":0,"journal-issue":{"issue":"3"},"URL":"https:\/\/doi.org\/10.1530\/joe-20-0155","relation":{},"ISSN":["0022-0795","1479-6805"],"issn-type":[{"value":"0022-0795","type":"print"},{"value":"1479-6805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9]]}}}