INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63000, Clermont-Ferrand, France.
Sci Rep. 2018 Nov 15;8(1):16875. doi: 10.1038/s41598-018-34863-0.
Besides their well-known roles in digestion and fat solubilization, bile acids (BAs) have been described as signaling molecules activating the nuclear receptor Farnesoid-X-receptor (FXRα) or the G-protein-coupled bile acid receptor-1 (GPBAR-1 or TGR5). In previous reports, we showed that BAs decrease male fertility due to abnormalities of the germ cell lineage dependent on Tgr5 signaling pathways. In the presentstudy, we tested whether BA exposure could impact germ cell DNA integrity leading to potential implications for progeny. For that purpose, adult F0 male mice were fed a diet supplemented with cholic acid (CA) or the corresponding control diet during 3.5 months prior mating. F1 progeny from CA exposed founders showed higher perinatal lethality, impaired BA homeostasis and reduced postnatal growth, as well as altered glucose metabolism in later life. The majority of these phenotypic traits were maintained up to the F2 generation. In F0 sperm cells, differential DNA methylation associated with CA exposure may contribute to the initial programming of developmental and metabolic defects observed in F1 and F2 offspring. Tgr5 knock-out mice combined with in vitro strategies defined the critical role of paternal Tgr5 dependent pathways in the multigenerational impacts of ancestral CA exposure.
除了在消化和脂肪溶解方面的众所周知的作用，胆汁酸（BAs）已被描述为激活核受体法尼醇 X 受体（FXRα）或 G 蛋白偶联胆汁酸受体-1（GPBAR-1 或 TGR5）的信号分子。在之前的报告中，我们表明 BAs 由于依赖于 Tgr5 信号通路的生殖细胞谱系异常而降低了雄性生育能力。在本研究中，我们测试了 BA 暴露是否会影响生殖细胞的 DNA 完整性，从而对后代产生潜在影响。为此，成年 F0 雄性小鼠在交配前 3.5 个月用添加胆酸（CA）的饮食或相应的对照饮食喂养。来自 CA 暴露的创始者的 F1 后代表现出更高的围产期致死率、胆汁酸稳态受损和出生后生长减少，以及生命后期葡萄糖代谢改变。这些表型特征中的大多数在 F2 代中得以维持。在 F0 精子细胞中，与 CA 暴露相关的差异 DNA 甲基化可能导致在 F1 和 F2 后代中观察到的发育和代谢缺陷的初始编程。Tgr5 敲除小鼠与体外策略相结合，定义了父系 Tgr5 依赖性途径在祖先 CA 暴露的多代影响中的关键作用。
