Oxidative stress in granulosa cells contributes to poor oocyte quality and IVF-ET outcomes in women with polycystic ovary syndrome

Lai, Qiaohong; Xiang, Wenpei; Li, Qing; Zhang, Hanwang; Li, Yufeng; Zhu, Guijin; Xiong, Chengliang; Jin, Lei

doi:10.1007/s11684-017-0575-y

Cited by 135 publications

(101 citation statements)

References 34 publications

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“…Apart from direct damage inflicted on oocytes by oxidative stress, granulosa cell function may be impaired, adding indirectly to functional impairment of associated oocytes. Evidence of oxidative stress in granulosa cells recovered along with oocytes for human in vitro fertilization was more severe for oocytes that failed to become fertilized or develop to blastocyst stage (Ávila et al, 2016;Lai et al, 2018), indicating that oxidative stress, at least at the antral stage of follicular development, has a detrimental effect on the follicle and oocyte.…”

Section: Oxidative Stress Contributes To Infertilitymentioning

confidence: 99%

Symposium review: Mechanisms of disruption of fertility by infectious diseases of the reproductive tract

Gilbert

2019

Journal of Dairy Science

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Section: Oxidative Stress Contributes To Infertilitymentioning

confidence: 99%

Symposium review: Mechanisms of disruption of fertility by infectious diseases of the reproductive tract

Gilbert

2019

Journal of Dairy Science

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“…) and in the ovarian granulosa cells (Lai et al . ) of PCOS patients. In support of these clinical findings, previous studies by us and others have also reported that PCOS‐like rodents exhibit increased ovarian ROS levels and decreased ovarian and uterine superoxide dismutase (SOD) levels (Ullah et al .…”

Section: Introductionmentioning

confidence: 97%

Hyperandrogenism and insulin resistance‐induced 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

Zhang

Zhao

et al. 2019

The Journal of Physiology

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Key pointsr Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanisms remain unknown.r Herein, pregnant rats chronically treated with 5α-dihydrotestosterone (DHT) and insulin exhibited hyperandrogenism and insulin resistance, as well as increased fetal loss, and these features are strikingly similar to those observed in pregnant PCOS patients.r Fetal loss in our DHT+insulin-treated pregnant rats was associated with mitochondrial dysfunction, disturbed superoxide dismutase 1 and Keap1/Nrf2 antioxidant responses, over-production of reactive oxygen species (ROS) and impaired formation of the placenta.r Chronic treatment of pregnant rats with DHT or insulin alone indicated that DHT triggered many of the molecular pathways leading to placental abnormalities and fetal loss, whereas insulin often exerted distinct effects on placental gene expression compared to co-treatment with DHT and insulin.r Treatment of DHT+insulin-treated pregnant rats with the antioxidant N-acetylcysteine improved fetal survival but was deleterious in normal pregnant rats.r Our results provide insight into the fetal loss associated with hyperandrogenism and insulin resistance in women and suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy.Yuehui Zhang is a professor and chief physician in the . She carried out postdoctoral research training in reproductive endocrinology at the University of Gothenburg, Sweden and obstetrics and gynaecology at the University of Pennsylvania, USA. Her research aims are to uncover the cellular and molecular mechanisms in aetiologies of polycystic ovary syndrome (PCOS) and other gynaecological diseases, as well as to develop an effective treatment for PCOS patients.Abstract Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanism of PCOS-induced fetal loss during pregnancy remains obscure and specific therapies are lacking. We used pregnant rats treated with 5α-dihydrotestosterone (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-treated 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-production of reactive oxygen species (ROS) in the placenta, mitochondrial dysfunction, and disturbed superoxide dismutase 1 (SOD1) and Keap1/Nrf2 antioxidant responses constitute im...

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“…Moreover, the expression of several other negative regulators of ferroptosis such as Ho1 (heme oxygenase 1) (6) and Mt1g (metallothionein 1G) (20) are downregulated in the gravid uterus after combined maternal exposure to DHT and INS (18). Increased circulating ROS levels have been observed in both non-pregnant and pregnant rodents in which PCOS features have been induced (19, 21). Elevated ROS production and decreased anti-oxidative capacity has been observed in the ovarian granulosa cells and leukocytes of PCOS patients (21-23), and oxidative stress is proposed to contribute to miscarriage and infertility in women with PCOS (24, 25).…”

Section: Introductionmentioning

confidence: 99%

“…Increased circulating ROS levels have been observed in both non-pregnant and pregnant rodents in which PCOS features have been induced (19, 21). Elevated ROS production and decreased anti-oxidative capacity has been observed in the ovarian granulosa cells and leukocytes of PCOS patients (21-23), and oxidative stress is proposed to contribute to miscarriage and infertility in women with PCOS (24, 25). It is therefore likely that the promotion of pathologic oxidative stress and activation of ferroptosis in the gravid uterus and placenta contribute to HAIR-induced fetal loss in both animal models and humans.…”

Section: Introductionmentioning

confidence: 99%

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

Zhang

Jia

et al. 2020

Preprint

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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.

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Oxidative stress in granulosa cells contributes to poor oocyte quality and IVF-ET outcomes in women with polycystic ovary syndrome

Cited by 135 publications

References 34 publications

Symposium review: Mechanisms of disruption of fertility by infectious diseases of the reproductive tract

Symposium review: Mechanisms of disruption of fertility by infectious diseases of the reproductive tract

Hyperandrogenism and insulin resistance‐induced 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

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

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