Multigenerational impacts of bile exposure are mediated by TGR5 signaling pathways

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile / metabolism*
  • Cell Lineage / drug effects
  • Cholic Acid / pharmacology
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation / drug effects
  • DNA Methylation / genetics
  • DNA Methyltransferase 3B
  • Diet
  • Gene Expression Regulation / drug effects
  • Male
  • Mice, Inbred C57BL
  • Phenotype
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction* / drug effects
  • Spermatozoa / cytology
  • Spermatozoa / drug effects
  • Spermatozoa / metabolism


  • Gpbar1 protein, mouse
  • Receptors, G-Protein-Coupled
  • DNA (Cytosine-5-)-Methyltransferases
  • Cholic Acid