Inactivation of NF-κB Signaling Facilitates the Occurrence of Premature Ovarian Failure via Accelerating Granulosa Cell Death

Abstract

Background: Premature ovarian failure (POF) is defined as deployment of amenorrhea because of the cessation of ovarian function prior to woman’s age of 40 years. The POF pathological mechanism has not yet well understood although genetic aberrations, autoimmune damage, and environmental factors have been identified. Methods: In this study, we assume that NF-κB inactivation is closely associated with the development of POF based on the data from previous literatures and CTX-induced POF mouse model. By establishing a NF-κB inactivated mouse model, using histomorphology and molecular biology methods to analyze. Findings: In the successfully established NF-κB-inactivated mouse model, we found the reduced expression of nuclear P65 and the increased expression of IκBα in ovarian granulosa cells; the reduced numbers of antral follicles; the reduction of Ki67/PCNA-labeled cell proliferation and enhanced Fas/FasL-dependent apoptosis in granulosa cells; the increase of phosphorylated H2AX-labelled DNA damage; the elevated level of FSH and declined E2 and AMH; the decreased expressions of FSHR and Cyp19a1 in granulosa cells, which was reversed in the context of blocking NF-κB signaling with Bay 11-7082. Dual-luciferase reporter assay demonstrated that p50 could stimulate the transcription of GRP78. Interpretation: Lack of NF-κB signaling normal response (i.e., inactivation of NF-κB signaling) would increase the incidence of granulosa cell death, which further causes an accelerated antral follicular atresia. Another pathway to initiate the death of granulosa cells might result from the imbalance of ER stress caused by GRP78. Funding Information: This study was supported by NSFC grants (31771331, 31971108) Declaration of Interests: The authors declare that there are no conflict of interests. Ethics Approval Statement: This study was carried out in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Jinan University.