title: Developmental epigenetic programming of adult germ cell death disease: Polycomb protein EZH2-miR-101 pathway.
abstract: The Developmental Origin of Health and Disease refers to the concept that early exposure to toxicants or nutritional imbalances during perinatal life induces changes that enhance the risk of developing noncommunicable diseases in adulthood. Patients/materials & methods: An experimental model with an adult chronic germ cell death phenotype resulting from exposure to a xenoestrogen was used.
  
  
  
  A reciprocal negative feedback loop involving decreased EZH2 protein level and increased miR-101 expression was identified. In vitro and in vivo knockdown of EZH2 induced an apoptotic process in germ cells through increased levels of apoptotic factors (BIM and BAD) and DNA repair alteration via topoisomerase 2B deregulation. The increased miR-101 levels were observed in the animal blood, meaning that miR-101 may be a part of a circulating mark of germ cell death.
  
  
  
  miR-101-EZH2 pathway deregulation could represent a novel pathophysiological epigenetic basis for adult germ cell disease with environmental and developmental origins.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice F-06204, France.|Université de Nice Sophia-Antipolis, Unité de Formation et de Recherche (UFR) Médecine, Nice F-06000, France.
authors.forename: Bénazir
authors.initials: B
authors.lastname: Siddeek
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice F-06204, France.|Université de Nice Sophia-Antipolis, Unité de Formation et de Recherche (UFR) Médecine, Nice F-06000, France.
authors.forename: Nadjem
authors.initials: N
authors.lastname: Lakhdari
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice F-06204, France.|Université de Nice Sophia-Antipolis, Unité de Formation et de Recherche (UFR) Médecine, Nice F-06000, France.
authors.forename: Lilia
authors.initials: L
authors.lastname: Inoubli
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice F-06204, France.|Université de Nice Sophia-Antipolis, Unité de Formation et de Recherche (UFR) Médecine, Nice F-06000, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Paul-Bellon
authors.affiliation: Centre Hospitalier Universitaire de Nice, Pôle de Digestif-Obstétrique, Centre de Reproduction, Nice F-06202, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Isnard
authors.affiliation: Centre Hospitalier Universitaire de Nice, Pôle de Biologie, Centre de Reproduction, Nice F-06202, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Thibault
authors.affiliation: Centre Hospitalier Universitaire de Nice, Pôle de Digestif-Obstétrique, Centre de Reproduction, Nice F-06202, France.
authors.forename: André
authors.initials: A
authors.lastname: Bongain
authors.affiliation: Université de Nice Sophia-Antipolis, Unité de Formation et de Recherche (UFR) Médecine, Nice F-06000, France.|Centre Hospitalier Universitaire de Nice, Pôle d'Urologie, Service d'Urologie, Nice F-06202, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chevallier
authors.affiliation: Université de Nice Sophia-Antipolis, Unité de Formation et de Recherche (UFR) Médecine, Nice F-06000, France.|Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 10, Nice F-06204, France.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Repetto
authors.affiliation: Université de Nice Sophia-Antipolis, Unité de Formation et de Recherche (UFR) Médecine, Nice F-06000, France.|Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 10, Nice F-06204, France.
authors.forename: Michele
authors.initials: M
authors.lastname: Trabucchi
authors.affiliation: Université de Nice Sophia-Antipolis, Unité de Formation et de Recherche (UFR) Médecine, Nice F-06000, France.|Centre Hospitalier Universitaire de Nice, Pôle de Biologie, Service d'Anatomie et de Cytologie Pathologiques, Nice F-06202, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Michiels
authors.affiliation: Division of Paediatrics & DOHaD Laboratory, CHUV & University of Lausanne, CH-1011, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Yzydorczyk
authors.affiliation: Division of Paediatrics & DOHaD Laboratory, CHUV & University of Lausanne, CH-1011, Switzerland.
authors.forename: Umberto
authors.initials: U
authors.lastname: Simeoni
authors.affiliation: BASF Agro, Ecully F-69130, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Urtizberea
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice F-06204, France.|Université Lyon 1, UFR Médecine Lyon Sud, Lyon F-69921, France.|Hospices Civils de Lyon, Hopital Lyon Sud, Laboratoire d'Anatomie et de Cytologie Pathologiques, Pierre-Bénite F-69495, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Mauduit
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice F-06204, France.|Université de Nice Sophia-Antipolis, Unité de Formation et de Recherche (UFR) Médecine, Nice F-06000, France.|Centre Hospitalier Universitaire de Nice, Département de Recherche Clinique et d'Innovation, Nice F-06001, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benahmed
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016923:Cell Death; D004249:DNA Damage; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D044127:Epigenesis, Genetic; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005854:Germ Cells / Q000378:metabolism*; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D051381:Rats; D013737:Testis / Q000187:drug effects / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C579142:MIRN101 microRNA, rat; D035683:MicroRNAs; C074283:estradiol 3-benzoate; D004958:Estradiol; C578253:EZH2 protein, rat; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: Polycomb proteins EZH2; endocrine-disrupting chemicals; epigenetic programming; male infertility; miRNAs; non-communicable diseases