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Bases Mécanistiques Des Effets D'un Insecticide Agrovétérinaire, Le Fipronil, Et/Ou De Ses Métabolites Sur La Fonction Thyroïdienne Chez Le Rat

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Bases Mécanistiques Des Effets D'un Insecticide Agrovétérinaire, Le Fipronil, Et/Ou De Ses Métabolites Sur La Fonction Thyroïdienne Chez Le Rat REMERCIEMENTS A Mme Anne Duittoz et Mr Patrick Balaguer qui ont accepté d'être rapporteurs de cette thèse et de consacrer de leur temps à la lecture et à l'appréciation de ce manuscrit. A Mme Barbara Demeneix, Mme Larissa Takser, Mr Daniel Zalko et Mr Roger Rahmani qui ont accepté de participer à ce jury de thèse en qualité d'examinateurs. Je tiens également à remercier Mr Daniel Zalko et Mr Roger Rahmani de m'avoir ouvert les portes de leurs laboratoires. A Catherine Viguié, pour m'avoir guidée depuis le master et m'avoir fait découvrir le monde de la recherche. Je la remercie pour son investissement dans ce projet, pour ses remarques constructives et pour sa franchise qui m'ont poussée à aller toujours plus loin. Je n'oublierai pas les "abstract version 12", les "tu vas me détester mais…" ou les "c'est quand même mieux le mouton". A Pascal Martin, pour m'avoir permis de comprendre qu'il faut de tout pour faire un bon chercheur et pour m'avoir fait confiance lors de cette année passée à l'INRA. Je le remercie de sa gentillesse et de sa bonne humeur en toutes circonstances. A Mr Pierre-Louis Toutain et Mr Alain Bousquet-Mélou qui m'ont accueillie au sein de l'ancienne UMR181. Je les remercie pour leurs précieux conseils en pharmacocinétique et de m'avoir renouvelé leur confiance pour les mois à venir. A Véronique Gayrard et Nicole Picard-Hagen, pour leur grande disponibilité, pour les conseils apportés lors de mes comités de thèse, des réunions d'équipe et lors de la rédaction de cette thèse et pour avoir toujours participé à ce projet avec enthousiasme. A Karine Gauthier, Hervé Guillou et Jean-Pierre Cravedi qui ont accepté de suivre ce travail en participant à mon comité de thèse, pour leurs conseils et suggestions constructives. Et plus particulièrement à Hervé Guillou qui m'a accueillie dans son équipe et à Jean-Pierre Cravedi pour m'avoir lancé de nouveaux défis comme la thyroïdectomie sur rat congelé. A la "dream team" de l'analytique sans qui rien n'aurait été possible. Merci à Sylvie Puel et Marlène Lacroix pour toutes les méthodes de dosage qu'elles ont développées pour moi et pour m'avoir fait une place dans leur bureau pendant les longues heures de rédaction de ce manuscrit. Promis je laisse le champ libre au BPA ! A nos biostatisticiens Didier Concordet et Céline Laffont-Rousset qui ont toujours répondu favorablement à mes problèmes d'analyse de données. A Yannick Lippi pour m'avoir toujours cru quand je disais que c'était la dernière PCR, pour sa bonne humeur et son humour. 1 2 REMERCIEMENTS A Elisabeth Perdu et Isabelle Jouanin, pour leur aide précieuse et leur contribution à ce projet. Je remercie également Elisabeth Perdu pour sa disponibilité et sa gentillesse en toutes circonstances. A Georges de Sousa, pour m'avoir transmis ses connaissances dans la mise en culture des hépatocytes même par -10°C ou +35°C. A toute l'équipe zootechnique de l'Ecole Vétérinaire: Kevin Arnoux, Sylvain Bruyas, Jean-Pierre Gau, Cédric Lacassagne, Joseph Maligoy et Valentin Rodriguez, pour m'avoir accompagnée tout au long de cette thèse, et à celle de l'INRA: Colette Bétoulières, Patrice Rouby et Caroline Sommer. Caroline, je te remercie aussi pour tous ces bons moments passés à l'animalerie, pour ta joie de vivre et pour tous nos bavardages autour d'un café. A tous les anciens ou nouveaux thésards. A Alice Marmugi, Simon Ducheix et Alexandra Montagner qui m'ont adoptée lors de mon passage à l'INRA. A Julien Leghait pour son passage de témoin. A Anne-Sylvie Kesteman pour sa participation à ce projet de thèse (j'ai toujours les 8 euros de notre pari). A Julie Antic, Isabelle Bargues et Dalia Khachman, pour avoir partagé des pauses, des soirées et des rires. A Delphine Bibbal, c'est toujours un plaisir de te revoir parmi nous. A Elisabeth Jeunesse, pour tes "gâteaux sans gâteaux" et pour avoir toujours su gérer nos manips de l'extrême. A Aude Ferran pour la naissance d'une amitié qui je l'espère se prolongera au-delà de ces trois années de thèse. A Séverine Collet pour tous les bons moments passés ensemble et surtout pour tes mojitos. A quand le Chihuahua et la Porsche ? A Tanguy Corbel notre petit "Lemming" et à Maleck Vasseur notre futur véto sans qui le bureau des thésards aurait été beaucoup plus triste, bon courage les garçons pour la rédaction. A tous les membres des ex-UMR181 et ex-UR66. Parce que sans la participation de chacun de vous ce travail ne serait pas ce qu'il est. A tous ceux qui me sont proches et chers, Ludo, pour ton soutien de chaque jour et pour tout ce que tu m'apportes mes parents, mon frère et mes sœurs, pour avoir toujours été là quand j'en ai eu besoin mes deux grands-pères, cette thèse vous est dédiée mes deux grands-mères, pour vos multiples questions sur cette thèse et pour votre vitalité mes tantes, oncles, cousins et cousines, pour tout ce qui fait qu'on est une famille. 3 4 VALORISATION SCIENTIFIQUE Les travaux de cette thèse, ainsi que les travaux sur les thématiques de recherche des équipes auxquelles j'étais associée, ont fait l'objet des publications et communications suivantes. Publications Roques, B.B., Lacroix, M.Z., Puel, S., Gayrard, V., Picard-Hagen, N., Jouanin, I., Perdu, E., Martin, P.G., and Viguié, C. (2012). CYP450-dependent biotransformation of the insecticide fipronil into fipronil sulfone can mediate fipronil-induced thyroid disruption in rats. Toxicol Sci, 127(1), 29-41. Roques, B.B., Lacroix, M.Z., Puel, S., Gayrard, V., Picard-Hagen, N., Jouanin, I., Perdu, E., Martin, P.G., and Viguié, C. (Under Press). CYP450-dependent biotransformation of the insecticide fipronil into fipronil sulfone can mediate fipronil-induced thyroid disruption in rats - Erratum. Viguié, C., Collet, S., Gayrard, V., Picard-Hagen, N., Puel, S., Roques, B.B., Toutain, P.L., and Lacroix, M.Z. (Under Press). Maternal and fetal exposure to bisphenol A and modifications of thyroid function in pregnant ewes and their newborn lambs. Endocrinology. Lacroix, M.Z., Puel, S., Roques, B.B., Debrauwer, L., Viguié, C. (Under Review). Simultaneous quantification of thyroid hormones and their metabolites in rat plasma by UPLC/MS/MS: application for the evaluation of endocrine disruption. Endocrinology. Communications orales Roques, B.B., Lacroix, M.Z., Puel, S., Kesteman, A.S., Jouanin, I., Perdu, E., de Sousa, G., Rahmani, R., Gayrard, V., Picard-Hagen, N., and Viguié, C. (2011). Toxicologie comparative du fipronil et de son principal métabolite le fipronil sulfone: complémentarité des modèles animaux et cellulaires. 10èmes Journées d'animation scientifique du département santé animale (JASDSA), Fréjus, France. Roques, B.B., Lacroix, M.Z., Moussaoui, N., Leghait, J., Puel, S., Lasserre, F., Guillou, H., Viguié, C., and Martin, P.G.P. (2012). Contribution of the nuclear receptors PXR and CAR to gene expression modulations induced by fipronil in rodent liver. 12th International Congress of the European Association for Veterinary Pharmacology and Toxicology (EAVPT), Noordwijkerhout, The Netherlands. 5 VALORISATION SCIENTIFIQUE Roques, B.B., Lacroix, M.Z., Moussaoui, N., Leghait, J., Puel, S., Lasserre, F., Guillou, H., Viguié, C., and Martin, P.G.P. (2012). Contribution of the nuclear receptors PXR and CAR to gene expression modulations induced by fipronil in rodent liver. 4th Health Food Symposium, Toulouse, France. Roques, B.B., Lacroix, M.Z., Perdu, E., Polizzi, A., Lasserre, F., Puel, S., Gayrard, V., Picard-Hagen, N., Leghait, J., Martin, P.G.P., Viguié, C. (Speaker) (2012). Hepatic thyroid hormone transport and thyroid hormone metabolism interplay might be involved in fipronil-induced disruption of thyroid homeostasis. French Endocrine Disruptor Research Programme (PNRPE) - Recent advances on the environmental and health effects of endocrine disrupters, Paris, France. Communications sous forme de poster Roques, B.B., Gayrard, V., Kesteman, A.S., Lacroix, M.Z., Perdu, E., Picard-Hagen, N., Puel, S., and Viguié, C. (2010). Does the transformation of fipronil into fipronil sulfone lead to a bioactivation of fipronil potential as a thyroid disruptor ? 7th Gordon Research Conference on Environmental Endocrine Disruptors, Les Diablerets, Switzerland. Roques, B.B., Gayrard, V., Kesteman, A.S., Lacroix, M.Z., Perdu, E., Picard-Hagen, N., Puel, S., and Viguié, C. (2010). Does the transformation of fipronil into fipronil sulfone lead to a bioactivation of fipronil potential as a thyroid disruptor ? 1st European Doctoral College on Environment and Health (EDCEH), Rennes, France. Puel, S., Lacroix, M.Z., Roques, B.B., and Viguié, C. (2011). Développement d'une nouvelle méthode de dosage des hormones thyroïdiennes (HT) et métabolites par UHPLC/MS/MS. 10èmes Journées d'animation scientifique du département santé animale (JASDSA), Fréjus, France. Roques, B.B., de Sousa, G., Lacroix, M.Z., Puel, S., Rahmani, R., and Viguié, C. (2011). Development of a rat primary cultured hepatocyte model for the screening of potential thyroid disruptors acting on hepatic metabolic pathways of thyroid hormones, application to fipronil. 6th Copenhagen Workshop on Endocrine Disrupters, University Department of Growth and Reproduction, Rigshospitalet, Denmark. Lacroix, M.Z., Puel, S., Roques, B.B., Debrauwer, L., and Viguié, C. (2012). Quantification des hormones thyroïdiennes (HT) et métabolites par UPLC/MS/MS. CT4, INRA, département AlimH, Perturbateurs endocriniens et métaboliques, Dijon, France 6 TABLE DES MATIERES INTRODUCTION 25 ETUDE BIBLIOGRAPHIQUE 27 A. LES PERTURBATEURS ENDOCRINIENS 28 1. DEFINITION 28 2. INTERET DE L'ETUDE DES PERTURBATEURS THYROÏDIENS 28 B. PERTURBATEURS THYROÏDIENS ET SYNTHESE DES HORMONES THYROÏDIENNES 30 1. PERTURBATION DE LA PRODUCTION DES HORMONES THYROÏDIENNES 30 a.
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