DNA damage associated with assisted reproductive technologies is an important factor affecting gamete fertility and embryo development. Activation of the TGR5 receptor by tauroursodeoxycholic acid (TUDCA) has been shown to reduce endoplasmic reticulum (ER) stress in embryos; however, its effect on genome damage responses (GDR) activation to facilitate DNA damage repair has not been examined. This study aimed to investigate the effect of TUDCA on DNA damage repair and embryo development. In a porcine model of ultraviolet light (UV)-induced nuclear stress, TUDCA reduced DNA damage and ER stress in developing embryos, as measured by γH2AX and glucose-regulated protein 78 immunofluorescence, respectively. TUDCA was equally able to rescue early embryo development. No difference in total cell number, DNA damage, or percentage of apoptotic cells, measured by cleaved caspase 3 immunofluorescence, was noted in embryos that reached the blastocyst stage. Interestingly, Dicer-substrate short interfering RNA-mediated disruption of TGR5 signaling abrogated the beneficial effects of TUDCA on UV-treated embryos. Quantitative PCR analysis revealed activation of the GDR, through increased messenger RNA abundance of DNAPK, 53BP1, and DNA ligase IV, as well as the ER stress response, through increased spliced XBP1 and X-linked inhibitor of apoptosis. Results from this study demonstrated that TUDCA activates TGR5-mediated signaling to reduce DNA damage and improve embryo development after UV exposure.

中文翻译：

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牛磺去氧胆酸通过TGR5受体起作用，促进DNA损伤修复并改善早期猪胚胎发育。

与辅助生殖技术相关的DNA损伤是影响配子受精和胚胎发育的重要因素。牛磺去氧胆酸（TUDCA）激活TGR5受体可减少胚胎内质网（ER）应激。但是，尚未研究其对基因组损伤反应（GDR）活化以促进DNA损伤修复的作用。这项研究旨在调查TUDCA对DNA损伤修复和胚胎发育的影响。在由紫外线（UV）引起的核应激的猪模型中，分别通过γH2AX和葡萄糖调节的蛋白78免疫荧光测定，TUDCA减少了发育中胚胎的DNA损伤和ER应激。TUDCA同样有能力挽救早期胚胎的发育。总细胞数，DNA损伤或凋亡细胞百分比无差异，通过切割的胱天蛋白酶3免疫荧光检测到，已达到胚泡阶段的胚胎。有趣的是，切丁酶底物短干扰RNA介导的TGR5信号转导破坏了TUDCA对紫外线处理的胚胎的有益作用。定量PCR分析显示，通过增加剪接的XBP1和X连锁凋亡抑制剂，使信使RNA丰度增加的DNAPK，53BP1和DNA连接酶IV以及ER应激反应，从而激活了GDR。这项研究的结果表明，TUDCA激活TGR5介导的信号传导，以减少DNA损伤并改善紫外线照射后的胚胎发育。切丁酶底物短干扰RNA介导的TGR5信号转导破坏了TUDCA对紫外线处理的胚胎的有益作用。定量PCR分析显示，通过增加剪接的XBP1和X连锁凋亡抑制剂，使信使RNA丰度增加的DNAPK，53BP1和DNA连接酶IV以及ER应激反应，从而激活了GDR。这项研究的结果表明，TUDCA激活TGR5介导的信号传导，以减少DNA损伤并改善紫外线照射后的胚胎发育。切丁酶底物短干扰RNA介导的TGR5信号转导破坏了TUDCA对紫外线处理的胚胎的有益作用。定量PCR分析显示，通过增加剪接的XBP1和X连锁凋亡抑制剂，使信使RNA丰度增加的DNAPK，53BP1和DNA连接酶IV以及ER应激反应，从而激活了GDR。这项研究的结果表明，TUDCA激活TGR5介导的信号传导，以减少DNA损伤并改善紫外线照射后的胚胎发育。