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

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  • 1 Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
  • 2 Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  • 3 Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
  • 4 Department of Acupuncture and Moxibustion, Second Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
  • 5 Department of Gynecology, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
  • 6 Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
  • 7 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
  • 8 Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
  • 9 Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
  • 10 Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Correspondence should be addressed to L R Shao: ruijin.shao@fysiologi.gu.se

*(Y Zhang and M Hu contributed equally to this work)

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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 5α-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 + glutathione disulfide and malondialdehyde, aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), 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 Dpp4, 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 + glutathione disulfide, malondialdehyde, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). Moreover, we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA in placentas of rats co-exposed to DHT and insulin. Further, DHT + insulin-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.

Supplementary Materials

    • Supplementary Materials and Methods
    • Supplemental Figure 1. Analyses of body weight variations in pregnant rats exposed to DHT and/or insulin. Values are expressed as means ± SEM. Group differences across GDs in overall maternal body weight were evaluated using repeated measures ANOVA, with different treatments (Control, DHT+INS, DHT, INS) as the between-subjects factor and gestation days (GD 0.5-14.5) as the within-subjects factor. GD, gestational day. DHT, 5α-dihydrotestosterone; INS, insulin.
    • Supplemental Figure 2. Tissue expression of Gpx4 protein in the adult rats. Protein samples (left) were isolated from selective tissues (testis, epididymis, and ovary; n = 6/tissue). The level of Gpx4 protein expression was determined by Western blot analysis (right). Each lane corresponds to the different rat samples. Relative mobilities of molecular mass standards (MW) is shown (in kilodaltons) on the left.
    • Supplemental Figure 3. Tissue expression of Gpx4 protein in the adult rat uterus. The level and localization of uterine Gpx4 protein expression in the diestrus stage in rats were determined by Western blot (A) and immunohistochemical analyses (B). In the Western blot analysis, each lane corresponds to the different rat samples. Relative mobilities of molecular mass standards (MW) are shown (in kilodaltons) on the left. Immunohistochemical images are representative of 3−5 tissue replicates per group. Detailed views of the boxed areas are shown in the inset (B). L, lumen; Le, luminal epithelial cells; Ge, glandular epithelial cells; Str, stromal cells; Myo, myometrium. Scale bars (100 μm) are indicated in the photomicrographs.
    • Supplemental Figure 4. Iron deposition in the uterine sections from pregnant rats at GD 6 (A, A1-2) and pregnant rats exposed to vehicle and DHT+INS at GD 14.5 (B, B1-4). The sections were stained by DAB-enhanced Perls’ staining for iron accumulation. Images are representative of 5−8 tissue replicates per group. Yellow arrowheads indicate punctate cytoplasmic, and granular iron-positive staining. MD, mesometrial decidua; AD, antimesometrial decidua; Myo, myometrium. Scale bars (100 μm) are indicated in the photomicrographs. DHT, 5α-dihydrotestosterone; INS, insulin.
    • Supplemental Figure 5. Mitochondrial ultrastructural defects in mesometrial decidua, and basal and labyrinth zones in pregnant rats exposed to DHT and/or insulin at GD 14.5. Scale bars (2 μm) are indicated in the photomicrographs. DHT, 5α-dihydrotestosterone; INS, insulin.

 

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