The Drawbacks of Paternal Obesity on Sperm Biology, Preimplantation Embryo Morphokinetics, and Its Transgenerational Impacts Georges Raad
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The drawbacks of paternal obesity on sperm biology, preimplantation embryo morphokinetics, and its transgenerational impacts Georges Raad To cite this version: Georges Raad. The drawbacks of paternal obesity on sperm biology, preimplantation embryo mor- phokinetics, and its transgenerational impacts. Agricultural sciences. Université Côte d’Azur, 2016. English. NNT : 2016AZUR4143. tel-01492786 HAL Id: tel-01492786 https://tel.archives-ouvertes.fr/tel-01492786 Submitted on 20 Mar 2017 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. Université de Nice-Sophia Antipolis Ecole doctorale SVS ED85 Sciences-Vie-Santé THESE DE DOCTORAT Pour obtenir le grade de Docteur en biologie de l‘université de Nice-Sophia Antipolis Spécialité: Recherche clinique et thérapeutique Soutenue par: Georges RAAD The drawbacks of paternal obesity on the sperm biology, the preimplantation embryo morphokinetics, and its transgenerational impacts Directrice de thèse : Valérie GRANDJEAN Co-directrice de thèse : Mira HAZZOURI Soutenue le 14 Décembre 2016 Jury : Rapporteurs : Sophie ROUSSEAUX Roger MIEUSSET 1 Table of Contents THESIS ABSTRACT ................................................................................................................6 RESUME ...................................................................................................................................8 LIST OF FIGURES ................................................................................................................ 10 LIST OF TABLES .................................................................................................................. 13 CHAPTER1 THE DRAWBACKS OF OBESITY ON THE GLOMERULOPATHY, TESTICULAR HOMEOSTASIS AND SPERM EPIGENOME .......................................... 14 I- THE BODY WEIGHT HOMEOSTASIS .................................................................................... 14 A- The human body homeostasis...................................................................................... 14 B- The body weight management ..................................................................................... 18 B. 1 The metabolic energy network ............................................................................. 18 B.1.1 The digestive system: intake, processing and distribution of foodstuffs ............. 18 B.1.2 Cells and molecules implicated in glucose homeostasis and energy management 19 a) Energy storing cells ...................................................................................... 20 a. 1 The white adipose tissue ........................................................................... 20 a. 2 The liver ................................................................................................... 22 b) Energy consuming cells ................................................................................ 23 B. 2 The control of food intake .................................................................................... 24 II- WEIGHT IMBALANCE: OBESITY COMPLICATIONS ............................................................... 25 A- The drawbacks of obesity on kidney homeostasis ........................................................ 28 A. 1 Kidney physiology .................................................................................................. 28 A. 1.1 Obesity-related glomerulopathy (ORG) ................................................................ 31 A. 1.1.a The effect of obesity on the glomerular histology .......................................... 31 A. 1.1.b Decline in renal function and obesity ............................................................ 31 a) Renal hemodynamics........................................................................................ 31 b) Hyperglycemia and hyperlipidemia: ................................................................. 33 B- The drawbacks of obesity on testicular homeostasis .................................................... 34 B. 1 Male reproductive system anatomy .......................................................................... 34 B.1.1 The effects of obesity on testicular anatomy, sexual function and seminal plasma biochemistry ................................................................................................................... 36 B. 2 Testicular histology and physiology ......................................................................... 37 B.2.1 The interstitial compartment................................................................................. 38 a) Blood vessels ....................................................................................................... 38 b) Leydig cells ......................................................................................................... 38 b.1 Overview ...................................................................................................... 38 b.2 Steroidogenesis ............................................................................................. 39 b.3 The effect of obesity on Leydig cell physiology and androgen homeostasis... 40 2 c) Immune cells ....................................................................................................... 41 c.1 Phagocytosis, proliferation and physiology of Leydig cells ............................... 41 c.2 Immunoregulation and inflammation ................................................................ 42 c.3 The effect of obesity on testicular immune cells ............................................... 42 B.2.2 Tubular compartment ........................................................................................... 43 a) Peritubular cells ................................................................................................... 44 b) Sertoli cells .......................................................................................................... 45 b. 1 Overview ...................................................................................................... 45 b. 2 Cytological features ...................................................................................... 45 b. 3 Sertoli cell functions ..................................................................................... 45 b. 4 The effects of obesity on Sertoli cell functions .............................................. 49 c) Germ cells............................................................................................................ 52 c. 1 Spermatogonia .............................................................................................. 52 c. 2 The meiotic cells ........................................................................................... 54 c. 3 The spermiogenesis ....................................................................................... 55 c. 4 The impact of male obesity on sperm parameters and embryo development .. 58 III- EPIGENETIC INHERITANCE OF PATERNAL ACQUIRED OBESITY ............................................ 60 A- Epigenetic control of gene expression during spermatogenesis and early embryogenesis 60 A. 1 DNA methylation ................................................................................................. 60 A. 1.1 DNA methylation reprogramming in mouse germ cells and pre-implantation embryos 62 A. 1.2 The drawbacks of abnormal DNA methylation profile in gametes ................. 63 A. 2 DNA hydroxymethylation and DNA demethylation ............................................. 65 A. 2.1 5-hmC dynamics during mouse spermatogenesis and embryo development .. 67 A. 3 Chromatin modifications ...................................................................................... 69 A. 3.1 Chromatin structure in somatic cells ............................................................. 69 A. 3.2 Chromatin remodelling during spermatogenesis ............................................ 72 a) Spermatogonia ................................................................................................. 72 b) Meiotic cells ..................................................................................................... 73 c) Spermatids and spermiogenesis ........................................................................ 74 c. 1 The incorporation of histones variants into the chromatin ............................. 74 c. 2 Histones hyperacetylation............................................................................. 74 c. 3 Replacement of histones by transition proteins ............................................. 75 c. 4 Replacement of TP by protamine.................................................................. 75 d) Sperm chromatin .............................................................................................. 76 d.1 Nucleoprotamine-bound sperm chromatin ..................................................... 77 d.2 Nucleosome-bound sperm chromatin ............................................................ 77 d.3 Matrix attachment regions (MARs) ..............................................................