MEST mediates the impact of prenatal bisphenol A exposure on long-term body weight development.

Autor: Junge KM; 1Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany., Leppert B; 1Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany., Jahreis S; 1Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.; 2Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany., Wissenbach DK; 3Department Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.; 4Institute of Forensic Medicine, University Hospital Jena, Jena, Germany., Feltens R; 3Department Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany., Grützmann K; 1Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT) Dresden, 01307 Dresden, Germany.; 6German Cancer Consortium (DKTK), Dresden, Germany.; 7German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Thürmann L; 1Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.; Berlin Institute of Health and Charité-Universitätsmedizin Berlin, Center for Digital Health, Berlin, Germany., Bauer T; German Cancer Research Center (DKFZ), Division of Theoretical Bioinformatics, Heidelberg, Germany., Ishaque N; German Cancer Research Center (DKFZ), Division of Theoretical Bioinformatics, Heidelberg, Germany.; 15Institute of Agriculture and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany., Schick M; German Cancer Research Center (DKFZ), Genomics and Proteomics Core Facility, Heidelberg, Germany., Bewerunge-Hudler M; 7German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Röder S; 1Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany., Bauer M; 1Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany., Schulz A; 10Medical Faculty, Rudolf-Schönheimer-Institute of Biochemistry, University of Leipzig, Leipzig, Germany., Borte M; Children's Hospital, Municipal Hospital 'St. Georg', Leipzig, Germany., Landgraf K; 12LIFE-Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.; 13Hospital for Children and Adolescents-Centre for Pediatric Research, University of Leipzig, Leipzig, Germany., Körner A; 12LIFE-Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.; 13Hospital for Children and Adolescents-Centre for Pediatric Research, University of Leipzig, Leipzig, Germany., Kiess W; 12LIFE-Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.; 13Hospital for Children and Adolescents-Centre for Pediatric Research, University of Leipzig, Leipzig, Germany., von Bergen M; 3Department Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.; 14Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, University of Leipzig, Leipzig, Germany., Stangl GI; 15Institute of Agriculture and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena Leipzig, Germany., Trump S; 1Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany., Eils R; 17German Cancer Research Center (DKFZ), Heidelberg Center for Personalized Oncology, DKFZ-HIPO, Heidelberg, Germany.; Berlin Institute of Health and Charité-Universitätsmedizin Berlin, Center for Digital Health, Berlin, Germany.; 19Health Data Science Unit, Heidelberg University Hospital, Heidelberg, Germany., Polte T; 1Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.; 2Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany., Lehmann I; 1Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.; Unit for Molecular Epidemiology, Berlin Institute of Health (BIH) and Charitè - Universitätsmedizin Berlin, Berlin, Germany.
Jazyk: angličtina
Zdroj: Clinical epigenetics [Clin Epigenetics] 2018 Apr 20; Vol. 10, pp. 58. Date of Electronic Publication: 2018 Apr 20 (Print Publication: 2018).
DOI: 10.1186/s13148-018-0478-z
Abstrakt: Background: Exposure to endocrine-disrupting chemicals can alter normal physiology and increase susceptibility to non-communicable diseases like obesity. Especially the prenatal and early postnatal period is highly vulnerable to adverse effects by environmental exposure, promoting developmental reprogramming by epigenetic alterations. To obtain a deeper insight into the role of prenatal bisphenol A (BPA) exposure in children's overweight development, we combine epidemiological data with experimental models and BPA-dependent DNA methylation changes.
Methods: BPA concentrations were measured in maternal urine samples of the LINA mother-child-study obtained during pregnancy ( n  = 552), and BPA-associated changes in cord blood DNA methylation were analyzed by Illumina Infinium HumanMethylation450 BeadChip arrays ( n  = 472). Methylation changes were verified by targeted MassARRAY analyses, assessed for their functional translation by qPCR and correlated with children's body mass index (BMI) z scores at the age of 1 and 6 years. Further, female BALB/c mice were exposed to BPA from 1 week before mating until delivery, and weight development of their pups was monitored ( n  ≥ 8/group). Additionally, human adipose-derived mesenchymal stem cells were treated with BPA during the adipocyte differentiation period and assessed for exposure-related epigenetic, transcriptional and morphological changes ( n  = 4).
Results: In prenatally BPA-exposed children two CpG sites with deviating cord blood DNA-methylation profiles were identified, among them a hypo-methylated CpG in the promoter of the obesity-associated mesoderm-specific transcript ( MEST) . A mediator analysis suggested that prenatal BPA exposure was connected to cord blood MEST promoter methylation and MEST expression as well as BMI z scores in early infancy. This effect could be confirmed in mice in which prenatal BPA exposure altered Mest promoter methylation and transcription with a concomitant increase in the body weight of the juvenile offspring. An experimental model of in vitro differentiated human mesenchymal stem cells also revealed an epigenetically induced MEST expression and enhanced adipogenesis following BPA exposure.
Conclusions: Our study provides evidence that MEST mediates the impact of prenatal BPA exposure on long-term body weight development in offspring by triggering adipocyte differentiation.
Competing Interests: The human study was approved by the Ethics Committee of the University of Leipzig (file ref. # 046-2006, #206-12-02072012). Participation in the human study was voluntary and written informed consent was obtained from the parents of the participating children. The Committee on Animal Welfare of Saxony approved animal protocols used in this study.Not applicable—no individual patient data is reported.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Databáze: MEDLINE
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