Bénazir Siddeek1,2, Nadjem Lakhdari1,2, Lilia Inoubli1,2, Rachel Paul-Bellon1,2, Véronique Isnard3, Emmanuelle Thibault4, André Bongain3, Daniel Chevallier2,5, Emanuela Repetto2,6, Michele Trabucchi2,6, Jean-François Michiels2,7, Catherine Yzydorczyk8, Umberto Simeoni8, Michel Urtizberea9, Claire Mauduit1,10,11, Mohamed Benahmed1,2,12. 1. Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 5, Nice F-06204, France. 2. Université de Nice Sophia-Antipolis, Unité de Formation et de Recherche (UFR) Médecine, Nice F-06000, France. 3. Centre Hospitalier Universitaire de Nice, Pôle de Digestif-Obstétrique, Centre de Reproduction, Nice F-06202, France. 4. Centre Hospitalier Universitaire de Nice, Pôle de Biologie, Centre de Reproduction, Nice F-06202, France. 5. Centre Hospitalier Universitaire de Nice, Pôle d'Urologie, Service d'Urologie, Nice F-06202, France. 6. Institut National de la Santé et de la Recherche Médicale, Unité 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 10, Nice F-06204, France. 7. Centre Hospitalier Universitaire de Nice, Pôle de Biologie, Service d'Anatomie et de Cytologie Pathologiques, Nice F-06202, France. 8. Division of Paediatrics & DOHaD Laboratory, CHUV & University of Lausanne, CH-1011, Switzerland. 9. BASF Agro, Ecully F-69130, France. 10. Université Lyon 1, UFR Médecine Lyon Sud, Lyon F-69921, France. 11. Hospices Civils de Lyon, Hopital Lyon Sud, Laboratoire d'Anatomie et de Cytologie Pathologiques, Pierre-Bénite F-69495, France. 12. Centre Hospitalier Universitaire de Nice, Département de Recherche Clinique et d'Innovation, Nice F-06001, France.
Abstract
AIM: 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. RESULTS: 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. CONCLUSION: miR-101-EZH2 pathway deregulation could represent a novel pathophysiological epigenetic basis for adult germ cell disease with environmental and developmental origins.
AIM: 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. RESULTS: 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. CONCLUSION:miR-101-EZH2 pathway deregulation could represent a novel pathophysiological epigenetic basis for adult germ cell disease with environmental and developmental origins.