RT Journal Article
SR Electronic
T1 Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.30.015529
DO 10.1101/2020.03.30.015529
A1 Yuehui Zhang
A1 Min Hu
A1 Wenyan Jia
A1 Guoqi Liu
A1 Jiao Zhang
A1 Bing Wang
A1 Juan Li
A1 Peng Cui
A1 Xin Li
A1 Susanne Lager
A1 Amanda Nancy Sferruzzi-Perri
A1 Yanhua Han
A1 Songjiang Liu
A1 Xiaoke Wu
A1 Mats Brännström
A1 Linus R Shao
A1 Håkan Billig
YR 2020
UL http://biorxiv.org/content/early/2020/03/31/2020.03.30.015529.abstract
AB Ferroptosis, a form of regulated necrotic cell death, plays roles in diverse physiological processes and diseases. Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance (HAIR) and an increased risk of miscarriage and placental dysfunction during pregnancy. However, whether maternal HAIR alters mechanisms leading to ferroptosis in the gravid uterus and placenta remains unknown. Previous studies in rats showed that maternal exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces 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., region-dependent 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, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of Dpp4, a mitochondria-encoded gene responsible for ferroptosis induction. In contrast, in placentas co-exposed to DHT and INS we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA (a mitochondria-encoded iron-export factor). 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.Suppl Figures: https://doi.org/10.6084/m9.figshare.11794059.v5PCOSpolycystic ovary syndrome;HAIRhyperandrogenism and insulin resistance;DHT5α-dihydrotestosterone;INShuman recombinant insulin;Gpx4glutathione peroxidase 4;GSHglutathione (reduced state);GSSGglutathione disulfide (oxidized state);JNKc-JUN NH2-terminal kinase;MAPKmitogen-activated protein kinase;MDAmalondialdehyde;GDgestational day;TEMtransmission electron microscopy.