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Etude des rôles du récepteur membranaire des acides biliaires (TGR5) dans la physiologie et la physiopathologie testiculaires

Abstract : The incidence of fertility disorders has been increasing for many years and currently affects 10 to 15 % of couples worldwide. In 30 % of male infertility cases, the causes remain unexplained. In the search for new causes, an association between liver disorders (correlated with an increase in plasma bile acid levels) and fertility disorders has been observed. A deleterious impact of bile acids, through their G-protein coupled receptor TGR5, on testicular physiology and, ultimately on fertility has been demonstrated. All these data led to the study of the roles of TGR5 on testicular physiology and pathophysiology. The role of TGR5 on germ cell lineage was studied in mouse model in response to chemotherapy treatment using busulfan, which is commonly used in the study of spermatogenesis. Our results show that the invalidation of the gene coding for TGR5 in mice minimizes the long-term deleterious effects of chemotherapy. Conversely, the activation of TGR5, induced by a cholic acid supplemented diet, in parallel with busulfan treatment, leads to a delay in the reappearance of spermatogenesis. Transcriptomic analyses have shown that the protection induced by the invalidation of the gene coding for TGR5 is associated with the overexpression of Glis2. This overexpression counteracts the effects of busulfan on the activation of the TP53 signaling pathway, associated with germ cell apoptosis. Furthermore, the involvement of TGR5 in germ cell cancers was evaluated in silico and in vitro. A deregulation of the expression profile of pluripotency genes, known to be involved in the development of testicular germ cell cancer, and a decrease in cell proliferation were observed in the absence of TGR5. These results suggest that TGR5 may be involved in the development of testicular germ cell cancer. Taken together, these findings suggest that (1) TGR5 is a major player in spermatogenesis after chemotherapy-induced testicular damage, (2) TGR5 plays a key role in testicular spermatogonial stem cell homeostasis, (3) TGR5 might be involved in testicular germ cell cancer.
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Submitted on : Thursday, November 24, 2022 - 2:42:07 PM
Last modification on : Friday, December 2, 2022 - 11:28:06 AM

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2021UCFAC108_THIROUARD.pdf
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Laura Thirouard. Etude des rôles du récepteur membranaire des acides biliaires (TGR5) dans la physiologie et la physiopathologie testiculaires. Santé. Université Clermont Auvergne, 2021. Français. ⟨NNT : 2021UCFAC108⟩. ⟨tel-03869870⟩

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