Tauroursodeoxycholic acid acts via TGR5 receptor to facilitate DNA damage repair and improve early porcine embryo development

Abstract

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 RNAmediated 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.

Tauroursodeoxycholic acid attenuates neuronal apoptosis via the TGR5/ SIRT3 pathway after subarachnoid hemorrhage in rats

“…TUDCA may activate TGR5-mediated signaling to reduce DNA damage and improve embryo development after ultraviolet light exposure [9]. The effects of TUDCA on insulin secretion were mimicked by the specific TGR5 agonist INT-777 [10].…”

Microbial and metabolomic mechanisms mediating the effects of dietary inulin and cellulose supplementation on porcine oocyte and uterine development

“…In this study, the secondary bile acids deoxycholic acid and taurochenodeoxycholic acid were increased in DF 1.75 gilts compared with DF 1.0 gilts. Tauroursodeoxycholic acid was shown to facilitate DNA damage repair and improve early embryo development in pigs [ 55 ] and other mammals [ 56 ]. Additionally, DF intake also altered levels of other metabolites, including spermidine [ 57 ], 4-aminobenzoic acid [ 58 ] and ibuprofen [ 59 ] that are known to influence oocyte quality or reproductive function.…”

Decabromodiphenyl ethane affects embryonic development by interfering with nuclear F‐actin in zygotes and leads to cognitive and social disorders in offspring mice

“…Because studies have reported that insufficient repair of DNA damage inhibited embryonic development. 57 Thus, DBDPE reduces PN size and increases DNA damage by interfering with nuclear F-actin assembly. Zygotic nuclear F-actin is critical for embryonic development because F-actin is assembled in the PN of mouse zygotes, and perturbation of zygotic nuclear F-actin dynamics leads to dysregulation of genes associated with genome integrity and abnormal embryonic development in mice.…”