College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu, People's Republic of China.
Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, Jiangsu, People's Republic of China.
Cell Biol Toxicol. 2023 Aug;39(4):1715-1734. doi: 10.1007/s10565-022-09776-4. Epub 2022 Nov 8.
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 (Ca) 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.
环境颗粒物 (PMs) 对人类和动物的雌性生殖健康有不良影响。硅纳米颗粒 (SNPs) 作为 PMs 的主要成分之一，可以通过促进卵巢颗粒细胞凋亡来诱导卵泡闭锁。然而，SNP 诱导凋亡的分子机制尚不清楚。本工作重点揭示内质网应激在 SNP 诱导的凋亡中的作用机制。我们的结果表明，通过气管内滴注，球形 Stöber SNPs（110nm，25.0mg/kg b.w.）诱导卵泡闭锁，促进颗粒细胞凋亡；同时，SNP 降低了体外颗粒细胞的活力并增加了其凋亡。SNP 被摄取并在内质网中积累。此外，我们的结果发现 SNP 增加了颗粒细胞细胞质中的钙离子（Ca）浓度。此外，SNP 通过增加 PERK 和 ATF6 通路相关蛋白水平和 IP3R1 依赖性钙动员来激活内质网应激，通过增加 IP3R1 水平来实现。此外，4-PBA 通过抑制内质网应激来恢复 IP3R1 依赖性钙动员并减少凋亡。ATF4-C/EBP 同源蛋白 (CHOP)-ER 氧化还原酶 1α (ERO1α) 通路通过在卵巢颗粒细胞中耗尽 ATF4、CHOP 和 ERO1α 来调节 SNP 诱导的 IP3R1 依赖性钙动员和细胞凋亡。在此，我们证明内质网应激通过激活 IP3R1 介导的钙动员与 SNP 诱导的卵巢毒性协同作用，导致细胞凋亡，其中 PERK-ATF4-CHOP-ERO1α 通路在卵巢颗粒细胞中发挥重要作用。
