DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia
Objectives: To characterize the impact of PCB exposure on DNA methylation in peripheral blood leucocytes and to evaluate the corresponding changes in relation to possible health effects, with a focus on B-cell lymphoma. Methods: We conducted an epigenome-wide association study on 611 adults free of...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-05-01
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| Series: | Environment International |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0160412018325868 |
| _version_ | 1819074034005966848 |
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| author | Panagiotis Georgiadis Marios Gavriil Panu Rantakokko Efthymios Ladoukakis Maria Botsivali Rachel S. Kelly Ingvar A. Bergdahl Hannu Kiviranta Roel C.H. Vermeulen Florentin Spaeth Dennie G.A.J. Hebbels Jos C.S. Kleinjans Theo M.C.M. de Kok Domenico Palli Paolo Vineis Soterios A. Kyrtopoulos |
| author_facet | Panagiotis Georgiadis Marios Gavriil Panu Rantakokko Efthymios Ladoukakis Maria Botsivali Rachel S. Kelly Ingvar A. Bergdahl Hannu Kiviranta Roel C.H. Vermeulen Florentin Spaeth Dennie G.A.J. Hebbels Jos C.S. Kleinjans Theo M.C.M. de Kok Domenico Palli Paolo Vineis Soterios A. Kyrtopoulos |
| author_sort | Panagiotis Georgiadis |
| collection | DOAJ |
| description | Objectives: To characterize the impact of PCB exposure on DNA methylation in peripheral blood leucocytes and to evaluate the corresponding changes in relation to possible health effects, with a focus on B-cell lymphoma. Methods: We conducted an epigenome-wide association study on 611 adults free of diagnosed disease, living in Italy and Sweden, in whom we also measured plasma concentrations of 6 PCB congeners, DDE and hexachlorobenzene. Results: We identified 650 CpG sites whose methylation correlates strongly (FDR < 0.01) with plasma concentrations of at least one PCB congener. Stronger effects were observed in males and in Sweden. This epigenetic exposure profile shows extensive and highly statistically significant overlaps with published profiles associated with the risk of future B-cell chronic lymphocytic leukemia (CLL) as well as with clinical CLL (38 and 28 CpG sites, respectively). For all these sites, the methylation changes were in the same direction for increasing exposure and for higher disease risk or clinical disease status, suggesting an etiological link between exposure and CLL. Mediation analysis reinforced the suggestion of a causal link between exposure, changes in DNA methylation and disease.Disease connectivity analysis identified multiple additional diseases associated with differentially methylated genes, including melanoma for which an etiological link with PCB exposure is established, as well as developmental and neurological diseases for which there is corresponding epidemiological evidence. Differentially methylated genes include many homeobox genes, suggesting that PCBs target stem cells. Furthermore, numerous polycomb protein target genes were hypermethylated with increasing exposure, an effect known to constitute an early marker of carcinogenesis. Conclusions: This study provides mechanistic evidence in support of a link between exposure to PCBs and the etiology of CLL and underlines the utility of omic profiling in the evaluation of the potential toxicity of environmental chemicals. Keywords: Molecular epidemiology, Persistent organic pollutants, DNA methylation, B-cell lymphoma, Environmental toxicology, Hazard assessment |
| first_indexed | 2024-12-21T18:03:05Z |
| format | Article |
| id | doaj.art-f1d75b98ccbd47b08110b08b70283f26 |
| institution | Directory Open Access Journal |
| issn | 0160-4120 |
| language | English |
| last_indexed | 2024-12-21T18:03:05Z |
| publishDate | 2019-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Environment International |
| spelling | doaj.art-f1d75b98ccbd47b08110b08b70283f262022-12-21T18:55:01ZengElsevierEnvironment International0160-41202019-05-011262436DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemiaPanagiotis Georgiadis0Marios Gavriil1Panu Rantakokko2Efthymios Ladoukakis3Maria Botsivali4Rachel S. Kelly5Ingvar A. Bergdahl6Hannu Kiviranta7Roel C.H. Vermeulen8Florentin Spaeth9Dennie G.A.J. Hebbels10Jos C.S. Kleinjans11Theo M.C.M. de Kok12Domenico Palli13Paolo Vineis14Soterios A. Kyrtopoulos15National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, GreeceNational Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, GreeceNational Institute for Health and Welfare, Department of Health Security, Environmental Health unit, P.O. Box 95, Kuopio, FinlandNational Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, GreeceNational Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, GreeceMRC-HPA Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, UKDepartment of Biobank Research, and Occupational and Environmental Medicine, Department of Public Health and Clinical Medicine, Umeå University, SwedenMRC-HPA Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, UKInstitute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, NetherlandsDepartment of Radiation Sciences, Oncology, Umeå University, SwedenDepartment of Toxicogenomics, Maastricht University, NetherlandsDepartment of Toxicogenomics, Maastricht University, NetherlandsDepartment of Toxicogenomics, Maastricht University, NetherlandsThe Institute for Cancer Research and Prevention, Florence, ItalyMRC-HPA Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, UKNational Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece; Corresponding author at: National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece.Objectives: To characterize the impact of PCB exposure on DNA methylation in peripheral blood leucocytes and to evaluate the corresponding changes in relation to possible health effects, with a focus on B-cell lymphoma. Methods: We conducted an epigenome-wide association study on 611 adults free of diagnosed disease, living in Italy and Sweden, in whom we also measured plasma concentrations of 6 PCB congeners, DDE and hexachlorobenzene. Results: We identified 650 CpG sites whose methylation correlates strongly (FDR < 0.01) with plasma concentrations of at least one PCB congener. Stronger effects were observed in males and in Sweden. This epigenetic exposure profile shows extensive and highly statistically significant overlaps with published profiles associated with the risk of future B-cell chronic lymphocytic leukemia (CLL) as well as with clinical CLL (38 and 28 CpG sites, respectively). For all these sites, the methylation changes were in the same direction for increasing exposure and for higher disease risk or clinical disease status, suggesting an etiological link between exposure and CLL. Mediation analysis reinforced the suggestion of a causal link between exposure, changes in DNA methylation and disease.Disease connectivity analysis identified multiple additional diseases associated with differentially methylated genes, including melanoma for which an etiological link with PCB exposure is established, as well as developmental and neurological diseases for which there is corresponding epidemiological evidence. Differentially methylated genes include many homeobox genes, suggesting that PCBs target stem cells. Furthermore, numerous polycomb protein target genes were hypermethylated with increasing exposure, an effect known to constitute an early marker of carcinogenesis. Conclusions: This study provides mechanistic evidence in support of a link between exposure to PCBs and the etiology of CLL and underlines the utility of omic profiling in the evaluation of the potential toxicity of environmental chemicals. Keywords: Molecular epidemiology, Persistent organic pollutants, DNA methylation, B-cell lymphoma, Environmental toxicology, Hazard assessmenthttp://www.sciencedirect.com/science/article/pii/S0160412018325868 |
| spellingShingle | Panagiotis Georgiadis Marios Gavriil Panu Rantakokko Efthymios Ladoukakis Maria Botsivali Rachel S. Kelly Ingvar A. Bergdahl Hannu Kiviranta Roel C.H. Vermeulen Florentin Spaeth Dennie G.A.J. Hebbels Jos C.S. Kleinjans Theo M.C.M. de Kok Domenico Palli Paolo Vineis Soterios A. Kyrtopoulos DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia Environment International |
| title | DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia |
| title_full | DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia |
| title_fullStr | DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia |
| title_full_unstemmed | DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia |
| title_short | DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia |
| title_sort | dna methylation profiling implicates exposure to pcbs in the pathogenesis of b cell chronic lymphocytic leukemia |
| url | http://www.sciencedirect.com/science/article/pii/S0160412018325868 |
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