Abstract
Ambient particulate matters (PMs) have adverse effects in human and animal female reproductive health. Silica nanoparticles (SNPs), as a major component of PMs, can induce follicular atresia via the promotion of ovarian granulosa cell apoptosis. However, the molecular mechanisms of apoptosis induced by SNPs are not very clear. This work focuses on revealing the mechanisms of ER stress on SNP-induced apoptosis. Our results showed that spherical Stöber SNPs (110 nm, 25.0 mg/kg b.w.) induced follicular atresia via the promotion of granulosa cell apoptosis by intratracheal instillation in vivo; meanwhile, SNPs decreased the viability and increase apoptosis in granulosa cells in vitro. SNPs were taken up and accumulated in the vesicles of granulosa cells. Additionally, our results found that SNPs increased calcium ion (Ca2+) concentration in granulosa cell cytoplasm. Furthermore, SNPs activated ER stress via an increase in the PERK and ATF6 pathway-related protein levels and IP3R1-dependent calcium mobilization via an increase in IP3R1 level. In addition, 4-PBA restored IP3R1-dependent calcium mobilization and decreased apoptosis via the inhibition of ER stress. The ATF4-C/EBP homologous protein (CHOP)-ER oxidoreductase 1 alpha (ERO1α) pathway regulated SNP-induced IP3R1-dependent calcium mobilization and cell apoptosis via ATF4, CHOP, and ERO1α depletion in ovarian granulosa cells. Herein, we demonstrate that ER stress cooperated in SNP-induced ovarian toxicity via activation of IP3R1-mediated calcium mobilization, leading to apoptosis, in which the PERK-ATF4-CHOP-ERO1α pathway plays an essential role in ovarian granulosa cells.
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The datasets used and/or analyzed during this study are available from the corresponding authors on reasonable request.
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Funding
This research was funded by the National Natural Science Foundation of China (31702298), the Natural Science Foundation of Jiangsu Province (BK20170498), the China Postdoctoral Science Foundation (2017M621843), the Postgraduate Research & Practice Innovation Program of Jiangsu Province (SJCX21_1643 and SJCX21_1639), High Talent Supporting Program of Yangzhou University (Dr. Fenglei Chen), the Qing Lan Project of Yangzhou University (Dr. Fenglei Chen), the United States National Institute of Environmental Health Sciences (R01ES024681), and the Priority Academic Program Development of Jiangsu Higher Education Institution (PAPD).
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F.C. wrote the main manuscript text. J.G. and Y.W. prepared Fig. S1. Z.Z. prepared Fig. 1. F.C., J.S., Y.W., and J.Z. prepared Figs. 2, 3, 4, 5, 6, 7, 8, and 9. F.C., X.X., X.Z., N.K., H.G., and J.Z. revised the manuscript. F.C. and J.S. responded the comments of the reviewers. F.C. and H.G. provided the funding. All authors reviewed the manuscript.
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All the methods in the present study were performed according to the approved guidelines. All surgery was performed under chloral hydrate, and all efforts were made to minimize suffering. All experiments were approved by the Committee on the Ethics of Animal Experiments of Yangzhou University (review number: 202103322).
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Chen, F., Sun, J., Wang, Y. et al. Silica nanoparticles induce ovarian granulosa cell apoptosis via activation of the PERK-ATF4-CHOP-ERO1α pathway-mediated IP3R1-dependent calcium mobilization. Cell Biol Toxicol 39, 1715–1734 (2023). https://doi.org/10.1007/s10565-022-09776-4
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DOI: https://doi.org/10.1007/s10565-022-09776-4