Developmental Epigenetic Programming of Adult Germ Cell Death Disease: Polycomb Protein EZH2–miR-101 Pathway

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.

Keywords::

• endocrine-disrupting chemicals
• epigenetic programming
• male infertility
• miRNAs
• non-communicable diseases
• Polycomb proteins EZH2

Supplementary data

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Acknowledgements

The authors acknowledge the Centre Méditerranéen de Médecine Moléculaire (C3M) Imaging Core Facility (Microscopy and Imaging platform Côte d’Azur, MICA) and the C3M animal room facility.

Financial & competing interests disclosure

This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM U1065), University Nice-Sophia-Antipolis, Association Nationale de la Recherche et de la Technologie (ANRT) and BASF Agro (CIFRE doctoral grant to N Lakhdari), The Long-Range Research Initiative Programme of the European Chemical Industry Council (CEFIC-LRI and BASF Agro (fellowships to B Siddeek), Agence Nationale de la Recherche (ANR, Grant ANR-06-SEST-13), Programme National de Recherche en Alimentation (PNRA, Grant ANR-07-PNRA-016), Programme National de Recherche sur les Perturbateurs Endocriniens (PNRPE, Grant PNRPE-2009-12), Nord Pas-de-Calais region (SER-2007) and Ministère l’Écologie, du Développement durable, des Transports et du Logement (MEDDTL, Grant 11-MRES-PNRPE-1-CVS-027 2011). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

NPG language editing was utilized in the production of this manuscript and was funded by INSERM.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM U1065), University Nice-Sophia-Antipolis, Association Nationale de la Recherche et de la Technologie (ANRT) and BASF Agro (CIFRE doctoral grant to N Lakhdari), The Long-Range Research Initiative Programme of the European Chemical Industry Council (CEFIC-LRI and BASF Agro (fellowships to B Siddeek), Agence Nationale de la Recherche (ANR, Grant ANR-06-SEST-13), Programme National de Recherche en Alimentation (PNRA, Grant ANR-07-PNRA-016), Programme National de Recherche sur les Perturbateurs Endocriniens (PNRPE, Grant PNRPE-2009-12), Nord Pas-de-Calais region (SER-2007) and Ministère l’Écologie, du Développement durable, des Transports et du Logement (MEDDTL, Grant 11-MRES-PNRPE-1-CVS-027 2011). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NPG language editing was utilized in the production of this manuscript and was funded by INSERM.