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Iron-overloaded follicular fluid increases the risk of endometriosis-related infertility by triggering granulosa cell ferroptosis and oocyte dysmaturity

ABSTRACT: To investigate the different function of endometriosis-related infertile patients follicular fluid (EMFF) and follicular fluid in control group (COFF), follicular fluid was collected and used for RNA sequencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205494 | GEO | 2022/06/15

REPOSITORIES: GEO

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Project description:Endometriosis (EMs) occurs in approximately 50% of women with infertility. The main causes of EMs-related infertility are follicle dysplasia and reduced oocyte quality. Iron overload occurs in ovarian follicular fluid (FF) of patients with EMs, and this condition is associated with oocyte maturation disorder. However, the underlying molecular mechanism remains largely unknown. In the present study, we identified the mechanism underlying ferroptosis in ovarian granulosa cells and oocyte maturation failure in EMs based on a retrospective review of in vitro fertilization/intracytoplasmic sperm injection-frozen embryo transfer outcomes in infertile patients with EMs. Mouse granulosa cells were treated with EMs-related infertile patients' follicular fluid (EMFF) in vitro. Western blot analysis, quantitative polymerase chain reaction, fluorescence staining, and transmission electron microscopy were used to assess granulosa cells ferroptosis. The effects of exosomes were examined by nanoparticle tracking analysis, RNA-seq, and Western blot analysis. Finally, the therapeutic values of vitamin E and iron chelator (deferoxamine mesylate) in vivo were evaluated in an EMs-related infertility model. Patients with ovarian EMs experienced poorer oocyte fertility than patients with non-ovarian EMs. We observed that EMFF with iron overload-induced granulosa cell ferroptosis in vitro and in vivo. Mechanically, nuclear receptor coactivator four-dependent ferritinophagy was involved in this process. Notably, granulosa cells undergoing ferroptosis further suppressed oocyte maturation by releasing exosomes from granulosa cells. In therapeutic studies, vitamin E and iron chelators effectively alleviated EMs-related infertility models. Our study indicates a novel mechanism through which EMFF with iron overload induces ferroptosis of granulosa cells and oocyte dysmaturity in EMs-related infertility, providing a potential therapeutic strategy for EMs-related infertility.

Project description:BACKGROUND: Endometriosis is a common benign gynaecological disorder. A number of studies have confirmed that the occurrence of disease in endometriosis patients is associated with metabolic changes in biological fluids and tissues. We set out to investigate the metabolic characteristics of follicular fluid in patients with ovarian endometriosis undergoing in vitro fertilization (IVF).METHODS: The current research project is an exploratory cohort study on endometriosis. A total of 19 infertile patients with ovarian endometriosis diagnosed by laparoscopy were enrolled in this study and 23 age- and BMI-matched controls (women with infertility due to male or tubal factors). All the patients underwent IVF treatment with a gonadotropin-releasing hormone antagonist protocol and completed follicular fluid (FF) collection at oocyte retrieval. The metabolomics of FF samples was analyzed by ultra high performance liquid chromatography-orbitrap exploris-mass spectrometer (UHPLC-OE-MS). The best combination of biomarkers was then selected by performing stepwise logistic regression analysis with backward elimination. RESULTS: Fifteen metabolites were identified as biomarkers associated with endometriosis. A final model containing 8-hydroxy-2-deoxyguanosine, biotin, n-acetyl-L-methionine and n-methylnicotinamide was constructed. Receiver operating characteristic analysis confirmed the value of these parameters in diagnosing endometriosis, with a sensitivity of 94.7% and a specificity of 95.7%. Analysis of fortification via the Kyoto Encyclopedia of Genes and Genome showed that 15 metabolites were enriched in 8 metabolic pathways.CONCLUSION: Metabolomics based on UHPLC-OE-MS effectively characterized the metabolomics analysis of FF in patients with ovarian endometriosis. These findings may provide a new basis for a better understanding of how diseases progress and for the discovery of new biomarkers.

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Iron-overloaded follicular fluid increases the risk of endometriosis-related infertility by triggering granulosa cell ferroptosis and oocyte dysmaturity

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