Bile acids alter male fertility through G-protein-coupled bile acid receptor 1 signaling pathways in mice

Authors

  • Marine Baptissart,

    1. INSERM U 1103, Génétique Reproduction et Développement (GReD), Aubière, France
    2. Clermont Université, Université Blaise, Pascal, GReD, Aubière, France
    3. CNRS, UMR 6293, GReD, Aubière, France
    4. Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
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  • Aurélie Vega,

    1. INSERM U 1103, Génétique Reproduction et Développement (GReD), Aubière, France
    2. Clermont Université, Université Blaise, Pascal, GReD, Aubière, France
    3. CNRS, UMR 6293, GReD, Aubière, France
    4. Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
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  • Emmanuelle Martinot,

    1. INSERM U 1103, Génétique Reproduction et Développement (GReD), Aubière, France
    2. Clermont Université, Université Blaise, Pascal, GReD, Aubière, France
    3. CNRS, UMR 6293, GReD, Aubière, France
    4. Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
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  • Aurélien J. Pommier,

    1. INSERM U 1103, Génétique Reproduction et Développement (GReD), Aubière, France
    2. Clermont Université, Université Blaise, Pascal, GReD, Aubière, France
    3. CNRS, UMR 6293, GReD, Aubière, France
    4. Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
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  • Sander M. Houten,

    1. Academic Medical Center, Laboratory Genetic Metabolic Diseases, Amsterdam, The Netherlands
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  • Geoffroy Marceau,

    1. EA 7281–Retinoids, Reproduction and Developmental Diseases, Laboratoire de Biochimie Medicale, Clermont-Ferrand, France
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  • Angélique de Haze,

    1. INSERM U 1103, Génétique Reproduction et Développement (GReD), Aubière, France
    2. Clermont Université, Université Blaise, Pascal, GReD, Aubière, France
    3. CNRS, UMR 6293, GReD, Aubière, France
    4. Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
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  • Silvère Baron,

    1. INSERM U 1103, Génétique Reproduction et Développement (GReD), Aubière, France
    2. Clermont Université, Université Blaise, Pascal, GReD, Aubière, France
    3. CNRS, UMR 6293, GReD, Aubière, France
    4. Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
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  • Kristina Schoonjans,

    1. Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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  • Jean-Marc A. Lobaccaro,

    1. INSERM U 1103, Génétique Reproduction et Développement (GReD), Aubière, France
    2. Clermont Université, Université Blaise, Pascal, GReD, Aubière, France
    3. CNRS, UMR 6293, GReD, Aubière, France
    4. Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
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  • David H. Volle

    Corresponding author
    1. INSERM U 1103, Génétique Reproduction et Développement (GReD), Aubière, France
    2. Clermont Université, Université Blaise, Pascal, GReD, Aubière, France
    3. CNRS, UMR 6293, GReD, Aubière, France
    4. Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
    • Address reprint request to: David H. Volle, Ph.D., UMR Inserm U 1103, CNRS 6293, Clermont Université, Génétique Reproduction et Développement, Université Blaise Pascal, BP 80026, F-63170 Aubière, France. E-mail: david.volle@inserm.fr; fax: +33-4-73407042.

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  • Potential conflict of interest: Nothing to report.

  • This work was funded by Inserm, CNRS, Clermont Université, Ministère de l'Enseignement Supérieur et de la Recherche (to M.B.), the Swiss National Science Foundation (to K.S.), Ligue contre le Cancer (Comité Puy de Dôme, to D.H.V.), Nouveau Chercheur Auvergne (to S.B. and no. R12087CC, to D.H.V.), and ANR Jeune Chercheur (no. 1103, to D.H.V.).

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. (Hepatology 2014;60:1054-1065)

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