Endoplasmic reticulum (ER) stress is associated with several aging-related diseases; however, the mechanism underlying age-related deterioration of oocyte quality is unclear. Here, we used post-ovulatory, in vivo aged mouse oocytes as a model. Super-ovulated oocytes harvested from the oviduct at 14 h and 20 h post-hCG injection were designated as ‘fresh’ and ‘aged’, respectively. Embryo development following IVF was compared between fresh, aged and ER stress-induced oocytes. Expression of the ER stress marker GRP78 was examined at each stage. To evaluate the effect of salubrinal, an ER stress suppressor, on embryo development following IVF, expression levels of GRP78 and phospho-eukaryotic initiation factor 2 alpha were compared between aged and salubrinal-treated aged oocytes. Embryo transfer of salubrinal-treated aged oocytes was performed to examine the safety of salubrinal. Similar to aged oocytes, ER stress-induced oocytes showed lower fertilization rates and poor embryo development. Following IVF, expression of GRP78 decreased with embryo development. GRP78 expression was significantly higher in aged oocytes than in fresh oocytes. Salubrinal lowered GRP78 levels and improved embryo development. No adverse effect of salubrinal treatment was found on the birth weight of pups or on organogenesis in mice. The limitation of this study was that protein kinase-like ER kinase was the only ER stress pathway examined; the role of IRE1 and ATF6 pathways was not considered. Nevertheless, salubrinal can significantly improve embryo development in in vivo aged oocytes undergoing ER stress. Hence, regulation of ER stress might represent a promising therapeutic strategy to overcome poor oocyte quality.

中文翻译：

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内质网应激对卵母细胞衰老机制的影响。

内质网 (ER) 应激与多种衰老相关疾病有关；然而，与年龄相关的卵母细胞质量恶化的机制尚不清楚。在这里，我们使用了排卵后的体内老年小鼠卵母细胞作为模型。在 hCG 注射后 14 小时和 20 小时从输卵管收获的超排卵母细胞分别被指定为“新鲜”和“老化”。体外受精后的胚胎发育在新鲜、老化和 ER 应激诱导的卵母细胞之间进行了比较。在每个阶段检查内质网应激标记 GRP78 的表达。为了评估 Salubrinal（一种 ER 应激抑制剂）对 IVF 后胚胎发育的影响，比较了老年和经 Salubrinal 处理的老年卵母细胞之间 GRP78 和磷酸化真核起始因子 2 α 的表达水平。进行了salubrinal处理的老化卵母细胞的胚胎移植以检查salubrinal的安全性。与老化的卵母细胞类似，ER 应激诱导的卵母细胞受精率较低，胚胎发育不良。在试管婴儿之后，GRP78 的表达随着胚胎发育而降低。GRP78 在老化卵母细胞中的表达明显高于新鲜卵母细胞。Salubrinal 降低 GRP78 水平并改善胚胎发育。未发现 Salubrinal 治疗对幼崽的出生体重或小鼠的器官发生有不利影响。这项研究的局限性在于蛋白激酶样 ER 激酶是唯一检查的 ER 应激途径。没有考虑 IRE1 和 ATF6 通路的作用。尽管如此，salubrinal 可以显着改善胚胎发育 这项研究的局限性在于蛋白激酶样 ER 激酶是唯一检查的 ER 应激途径。没有考虑 IRE1 和 ATF6 通路的作用。尽管如此，salubrinal 可以显着改善胚胎发育 这项研究的局限性在于蛋白激酶样 ER 激酶是唯一检查的 ER 应激途径。没有考虑 IRE1 和 ATF6 通路的作用。尽管如此，salubrinal 可以显着改善胚胎发育经历内质网应激的体内老化卵母细胞。因此，调节内质网应激可能是克服卵母细胞质量差的一种有前景的治疗策略。