Department of Animal Science, McGill University, Quebec, Canada.
ReproPel, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil.
Biol Reprod. 2021 Jul 2;105(1):76-86. doi: 10.1093/biolre/ioab072.
Conditions of impaired energy and nutrient homeostasis, such as diabetes and obesity, are associated with infertility. Hyperglycemia increases endoplasmic reticulum stress as well as oxidative stress and reduces embryo development and quality. Oxidative stress also causes deoxyribonucleic acid damage, which impairs embryo quality and development. The natural bile acid tauroursodeoxycholic acid reduces endoplasmic reticulum stress and rescues developmentally incompetent late-cleaving embryos, as well as embryos subjected to nuclear stress, suggesting the endoplasmic reticulum stress response, or unfolded protein response, and the genome damage response are linked. Tauroursodeoxycholic acid acts via the Takeda-G-protein-receptor-5 to alleviate nuclear stress in embryos. To evaluate the role of tauroursodeoxycholic acid/Takeda-G-protein-receptor-5 signaling in embryo unfolded protein response, we used a model of glucose-induced endoplasmic reticulum stress. Embryo development was impaired by direct injection of tauroursodeoxycholic acid into parthenogenetically activated oocytes, whereas it was improved when tauroursodeoxycholic acid was added to the culture medium. Attenuation of the Takeda-G-protein-receptor-5 precluded the positive effect of tauroursodeoxycholic acid supplementation on development of parthenogenetically activated and fertilized embryos cultured under standard conditions and parthenogenetically activated embryos cultured with excess glucose. Moreover, attenuation of tauroursodeoxycholic acid/Takeda-G-protein-receptor-5 signaling induced endoplasmic reticulum stress, oxidative stress and cell survival genes, but decreased expression of pluripotency genes in parthenogenetically activated embryos cultured under excess glucose conditions. These data suggest that Takeda-G-protein-receptor-5 signaling pathways link the unfolded protein response and genome damage response. Furthermore, this study identifies Takeda-G-protein-receptor-5 signaling as a potential target for mitigating fertility issues caused by nutrient excess-associated blastomere stress and embryo death.
能量和营养稳态受损的情况，如糖尿病和肥胖，与不孕有关。高血糖会增加内质网应激以及氧化应激，从而降低胚胎发育和质量。氧化应激还会导致脱氧核糖核酸损伤，从而损害胚胎质量和发育。天然胆酸牛磺熊脱氧胆酸可减轻内质网应激并挽救发育能力差的晚期分裂胚胎和核应激胚胎，表明内质网应激反应或未折叠蛋白反应与基因组损伤反应有关。牛磺熊脱氧胆酸通过 Takeda-G 蛋白受体-5 发挥作用，以减轻胚胎中的核应激。为了评估牛磺熊脱氧胆酸/Takeda-G 蛋白受体-5 信号在胚胎未折叠蛋白反应中的作用，我们使用了葡萄糖诱导的内质网应激模型。直接将牛磺熊脱氧胆酸注射到孤雌激活卵母细胞中会损害胚胎发育，而将牛磺熊脱氧胆酸添加到培养基中则会改善胚胎发育。Takeda-G 蛋白受体-5 的衰减阻止了牛磺熊脱氧胆酸补充对标准条件下培养的孤雌激活和受精胚胎以及高葡萄糖培养的孤雌激活胚胎发育的积极影响。此外，牛磺熊脱氧胆酸/Takeda-G 蛋白受体-5 信号通路的衰减会诱导内质网应激、氧化应激和细胞存活基因，但会降低高葡萄糖条件下培养的孤雌激活胚胎中多能性基因的表达。这些数据表明，Takeda-G 蛋白受体-5 信号通路将未折叠蛋白反应和基因组损伤反应联系起来。此外，这项研究确定了 Takeda-G 蛋白受体-5 信号通路作为减轻与营养过剩相关的卵裂球应激和胚胎死亡导致的生育问题的潜在靶点。
