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Hyperandrogenism and insulin resistance modulate gravid uterine and placental ferroptosis in PCOS-like rats.

Journal article
Authors Yuehui Zhang
Min Hu
Wenyan Jia
Guoqi Liu
Jiao Zhang
Bing Wang
Juan Li
Peng Cui
Xin Li
Susanne Lager
Amanda N Sferruzzi-Perri
Yanhua Han
Songjiang Liu
Xiaoke Wu
Mats Brännström
Linus Ruijin Shao
Håkan Billig
Published in The Journal of endocrinology
Volume 246
Issue 3
Pages 247-63
ISSN 1479-6805
Publication year 2020
Published at Institute of Neuroscience and Physiology, Department of Physiology
Institute of Clinical Sciences, Department of Obstetrics and Gynecology
Pages 247-63
Language en
Keywords ferroptosis, Gpx4, mitochondria, gravid uterus, placenta, PCOS
Subject categories Obstetrics, Gynecology and Reproductive Medicine, Endocrinology and Diabetes, Physiology, Cell and Molecular Biology


Previous studies in rats showed that maternal exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces hyperandrogenism and insulin resistance (HAIR) and subsequently leads to placental insufficiency and fetal loss. We therefore hypothesized that maternal HAIR triggers ferroptosis in the uterus and placenta in association with fetal loss in pregnant rats. Compared with controls, we found that co-exposure to DHT and INS led to decreased levels of Gpx4 and glutathione (GSH), increased GSH+glutathione disulfide (GSSG) and malondialdehyde (MDA), aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition, and activated ERK/p38/JNK phosphorylation in the gravid uterus. However, in the placenta, DHT and INS exposure only partially altered the expression of ferroptosis-related markers (e.g., Gpx4, GSH+GSSG, MDA, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). In the uteri co-exposed to DHT and INS, we also observed shrunken mitochondria with electron-dense cristae, and increased Dpp4 mRNA expression. In contrast, in placentas co-exposed to DHT and INS we found decreased Dpp4 mRNA expression and increased Cisd1 mRNA expression. Further, DHT+INS-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal HAIR 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. Furthermore, our data suggest other cell death pathways may play a role in coordinating or compensating for HAIR-induced ferroptosis when the gravid uterus and placenta are dysfunctional.

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