title: Bile acids alter male fertility through G-protein-coupled bile acid receptor 1 signaling pathways in mice.
abstract: Bile acids (BAs) are signaling molecules that are involved in many physiological functions, such as glucose and energy metabolism. These effects are mediated through activation of the nuclear and membrane receptors, farnesoid X receptor (FXR-α) and TGR5 (G-protein-coupled bile acid receptor 1; GPBAR1). Although both receptors are expressed within the testes, the potential effect of BAs on testis physiology and male fertility has not been explored thus far. Here, we demonstrate that mice fed a diet supplemented with cholic acid have reduced fertility subsequent to testicular defects. Initially, germ cell sloughing and rupture of the blood-testis barrier occur and are correlated with decreased protein accumulation of connexin-43 (Cx43) and N-cadherin, whereas at later stages, apoptosis of spermatids is observed. These abnormalities are associated with increased intratesticular BA levels in general and deoxycholic acid, a TGR5 agonist, in particular. We demonstrate here that Tgr5 is expressed within the germ cell lineage, where it represses Cx43 expression through regulation of the transcriptional repressor, T-box transcription factor 2 gene. Consistent with this finding, mice deficient for Tgr5 are protected against the deleterious testicular effects of BA exposure.
  
  
  CONCLUSIONS
  These data identify the testis as a new target of BAs and emphasize TGR5 as a critical element in testicular pathophysiology. This work may open new perspectives on the potential effect of BAs on testis physiology during liver dysfunction.
authors.affiliation: INSERM U 1103, Génétique Reproduction et Développement (GReD), Aubière, France; Clermont Université, Université Blaise, Pascal, GReD, BP 80026, Aubière, France; CNRS, UMR 6293, GReD, Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Baptissart
authors.forename: Aurélie
authors.initials: A
authors.lastname: Vega
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Martinot
authors.forename: Aurélien J
authors.initials: AJ
authors.lastname: Pommier
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Marceau
authors.forename: Angélique
authors.initials: A
authors.lastname: de Haze
authors.forename: Silvère
authors.initials: S
authors.lastname: Baron
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Jean-Marc A
authors.initials: JM
authors.lastname: Lobaccaro
authors.forename: David H
authors.initials: DH
authors.lastname: Volle
mesh_terms: D000818:Animals; D019826:Cholic Acid / Q000008:administration & dosage / Q000378:metabolism*; D005298:Fertility; D007248:Infertility, Male / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D013094:Spermatozoa / Q000187:drug effects; D013737:Testis / Q000187:drug effects*; D013739:Testosterone / Q000097:blood
chemical_list: C513561:Gpbar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D013739:Testosterone; D007334:Insulin-Like Growth Factor I; D019826:Cholic Acid