Abstract
Oxidative stress (OS), a common intracellular phenomenon induced by excess reactive oxygen species (ROS) generation, has been shown to be associated with mammalian ovarian follicular development blockage and granulosa cell (GC) impairment. However, the mechanism involved in these effects remains unknown, and the effect of OS on the transcriptome profiles in porcine GCs has not been fully characterized. In this study, we found that hydrogen peroxide-mediated oxidative stress induced porcine GC apoptosis and impaired cell viability. Moreover, RNA-seq analysis showed that oxidative stress induced dramatic changes in gene expression in porcine GCs. A total of 2025 differentially expressed genes (DEGs) were identified, including 1940 DEmRNAs and 55 DEmiRNAs. Functional annotation showed that the DEGs were mainly associated with cell states and function regulation. In addition, multiple hub genes (FOXO1, SOD2, BMP2, DICER1, BCL2L11, FZD4, ssc-miR-424, and ssc-miR-27b) were identified by constructing protein-protein interaction and DEmiRNA-DEmRNA regulatory networks. Furthermore, a gene-pathway-function coregulatory network was established and demonstrated that these hub genes were enriched in FoxO, TGF-β, Wnt, PIK3-Akt, MAPK, and cAMP signaling pathways, which play important roles in regulating cell apoptosis, cell proliferation, stress responses, and hormone secretion. The current research provides a comprehensive perspective of the effects of oxidative stress on porcine GCs and also identifies potential therapeutic targets for oxidative stress-induced female infertility.
Highlights
In mammalian ovaries, less than 1 percent of the follicles are mature and capable of ovulation, whereas the majority of the follicles undergo atresia and degeneration during folliculogenesis and follicular development [1]
Recent reports have suggested that follicular atresia is mainly attributed to the apoptosis of granulosa cell (GC) [4] and nonapoptotic forms of programmed cell death [5], which are mediated by a complex regulatory network that consists of multiple factors, including environmental factors [6], homeostasis [7], steroid hormones [8], cytokine [9], and epigenetic regulators [10]
Accumulating evidence shows that the reactive oxygen species- (ROS-) induced oxidative stress plays an important role in regulating the state and function of granulosa cells and even causes several anovulatory disorders [11, 12]
Summary
Less than 1 percent of the follicles are mature and capable of ovulation, whereas the majority of the follicles undergo atresia and degeneration during folliculogenesis and follicular development [1]. Accumulating evidence shows that the reactive oxygen species- (ROS-) induced oxidative stress plays an important role in regulating the state and function of granulosa cells and even causes several anovulatory disorders [11, 12]. It has been reported that excessive ROS levels are generated and accumulated in cells undergoing dramatic changes or processes that have a high aerobic energy metabolism requirement, such as autophagy, endoplasmic reticulum stress, carcinogenesis, and reproduction impairment [18,19,20]. Metabolic rates accelerate to meet the increased demand for nutrients and energy, which inevitably generates excessive ROS and further induces oxidative stress in follicles [21]
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