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Identification Et Classification De Composés Reprotoxiques Par Des Approches De Toxicogénomique Prédictive Thomas Darde

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Identification Et Classification De Composés Reprotoxiques Par Des Approches De Toxicogénomique Prédictive Thomas Darde Identification et classification de composés reprotoxiques par des approches de toxicogénomique prédictive Thomas Darde To cite this version: Thomas Darde. Identification et classification de composés reprotoxiques par des approches detox- icogénomique prédictive. Médecine humaine et pathologie. Université Rennes 1, 2017. Français. NNT : 2017REN1B022. tel-01751766 HAL Id: tel-01751766 https://tel.archives-ouvertes.fr/tel-01751766 Submitted on 29 Mar 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ANNÉE 2017 THÈSE / UNIVERSITÉ DE RENNES 1 sous le sceau de l’Université Bretagne Loire pour le grade de DOCTEUR DE L’UNIVERSITÉ DE RENNES 1 Mention : Biologie et Sciences de la Santé École doctorale Biologie-Santé présentée par Thomas DARDE Préparée à l’IRSET Inserm U1085 Équipe « Physiology and physiopathology of the urogenital tract » UFR Sciences de le Vie et de l’Environnement Identification et Thèse dirigée par : classification de Frédéric CHALMEL Chargé de recherche - Inserm U 1085 IRSET composés Antoine ROLLAND reprotoxiques par Maître de conférence - Inserm U 1085 IRSET des approches de et soutenue à Rennes le 3 octobre 2017 toxicogénomique devant le jury composé de : Karine AUDOUZE Maitre de conférences – Université Paris Diderot prédictive Rapporteur Odile LECOMPTE Maitre de conférences – iCube Rapporteur Farzad PAKDEL Directeur de recherche – Inserm U1085 IRSET Président du jury Serge NEF Professeur - University of Geneva Medical School Examinateur Christian DELAMARCHE Professeur – Université Rennes 1 Examinateur Frédéric CHALMEL Chargé de recherche – Inserm U1085 IRSET Directeur de thèse i Table des matières Table des matières ....................................................................................................................... ii Liste des tableaux ....................................................................................................................... vi Liste des figures ....................................................................................................................... viii Liste des abréviations .................................................................................................................. x Remerciements ......................................................................................................................... xiv Préambule ................................................................................................................................... 1 1. Introduction ......................................................................................................................... 3 1.1. Le système endocrinien et ses hormones .................................................................... 3 1.1.1. Qu’est-ce que le système endocrinien ? .............................................................. 3 1.1.2. Présentation des différents types d’hormones ..................................................... 5 1.1.3. Le mécanisme d’action des hormones ................................................................ 7 1.1.4. La régulation du système endocrinien ................................................................ 9 1.1.5. Les glandes endocrines et leurs hormones ........................................................ 11 1.2. Le testicule ................................................................................................................ 19 1.2.1. Généralités sur l’anatomie du testicule adulte .................................................. 19 1.2.2. Fonction exocrine du testicule .......................................................................... 20 1.2.3. Fonction endocrine du testicule ........................................................................ 25 1.2.4. Mécanismes de régulation de la stéroïdogenèse ............................................... 28 1.3. Les perturbateurs endocriniens ................................................................................. 31 1.3.1. Histoire de la perturbation endocrinienne ......................................................... 31 1.3.2. Un souci de définition ....................................................................................... 34 1.3.3. Mécanisme(s) d’action d’un perturbateur endocrinien ..................................... 35 1.3.4. Effets des perturbateurs endocriniens sur l’Homme ......................................... 36 1.3.5. Présentation de perturbateurs endocriniens connus .......................................... 46 1.4. Évaluation des risques ............................................................................................... 53 1.4.1. La règlementation européenne .......................................................................... 53 1.4.2. Règlementation non adaptée aux PEs? ............................................................. 56 ii 1.4.3. Outils de détection de toxicités ......................................................................... 58 1.4.4. Tests spécifiques de détection des perturbateurs endocriniens ......................... 61 1.5. La toxicologie prédictive .......................................................................................... 67 1.5.1. Outils de toxicologie prédictive ........................................................................ 67 1.5.2. Méthodes de prédiction ..................................................................................... 73 2. Objectifs de ma thèse ........................................................................................................ 91 3. Matériels et méthodes ....................................................................................................... 93 3.1. Ressources informatiques et environnement de travail ............................................ 93 3.1.1. Langages de programmation ............................................................................. 93 3.1.2. Environnement web .......................................................................................... 96 3.2. Outils et ressources bio-informatiques .................................................................... 101 3.2.1. Suites logicielles ............................................................................................. 101 3.2.2. Navigateurs de génome ................................................................................... 101 3.2.3. Galaxy ............................................................................................................. 102 3.2.4. Vocabulaires contrôlés et ontologies .............................................................. 104 3.2.5. Bases de données ............................................................................................ 105 3.2.6. Description des différents types de fichiers .................................................... 107 3.3. Estimateurs mathématiques .................................................................................... 111 3.3.1. Estimateurs de distances ................................................................................. 111 3.3.2. Évaluation d’un modèle statistique de classification ...................................... 113 3.4. Méthodes statistiques .............................................................................................. 117 3.4.1. Analyse en composantes principales .............................................................. 117 3.4.2. Enrichissement – Loi hypergéométrique ........................................................ 122 3.4.3. Méthodes de prédiction de classe ................................................................... 123 3.5. Méthodes appliquées dans le cadre du projet ChemPSy ........................................ 127 3.5.1. Méthodes appliquées sur les données de la CTD ............................................ 127 3.5.2. Méthodes appliquées sur les données issues de GEO ..................................... 129 4. Résultats et discussion .................................................................................................... 137 4.1. ChemPSy : un système de priorisation pour les substances chimiques .................. 137 4.1.1. Résultats obtenus à partir de la CTD .............................................................. 137 iii 4.1.2. Résultats obtenus à partir de GEO .................................................................. 140 4.1.3. Conclusion et perspectives du projet ChemPSy ............................................. 159 4.2. TOXsIgN : un espace de dépôt pour les signatures toxicogénomique ................... 163 4.2.1. Manuscrit en préparation ................................................................................ 165 4.2.2. Résultats et discussion .................................................................................... 191 4.2.3. Conclusion et perspectives .............................................................................. 196 4.3. The ReproGenomics Viewer (RGV) : un navigateur de génome pour les données de reprogénomique .................................................................................................................
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