Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Georgiadis, Panagiotis, Gavriil, Marios, Rantakokko, Panu, Ladoukakis, Efthymios, Botsivali, Maria, Kelly, Rachel S., Bergdahl, Ingvar A., Kiviranta, Hannu, Vermeulen, Roel C.H., Spaeth, Florentin, Hebbels, Dennie G.A.J., Kleinjans, Jos C.S., de Kok, Theo M.C.M., Palli, Domenico, Vineis, Paolo, Kyrtopoulos, Soterios A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063446/
https://www.ncbi.nlm.nih.gov/pubmed/30776747
http://dx.doi.org/10.1016/j.envint.2019.01.068
_version_ 1783504704990347264
author Georgiadis, Panagiotis
Gavriil, Marios
Rantakokko, Panu
Ladoukakis, Efthymios
Botsivali, Maria
Kelly, Rachel S.
Bergdahl, Ingvar A.
Kiviranta, Hannu
Vermeulen, Roel C.H.
Spaeth, Florentin
Hebbels, Dennie G.A.J.
Kleinjans, Jos C.S.
de Kok, Theo M.C.M.
Palli, Domenico
Vineis, Paolo
Kyrtopoulos, Soterios A.
author_facet Georgiadis, Panagiotis
Gavriil, Marios
Rantakokko, Panu
Ladoukakis, Efthymios
Botsivali, Maria
Kelly, Rachel S.
Bergdahl, Ingvar A.
Kiviranta, Hannu
Vermeulen, Roel C.H.
Spaeth, Florentin
Hebbels, Dennie G.A.J.
Kleinjans, Jos C.S.
de Kok, Theo M.C.M.
Palli, Domenico
Vineis, Paolo
Kyrtopoulos, Soterios A.
author_sort Georgiadis, Panagiotis
collection PubMed
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.
format Online
Article
Text
id pubmed-7063446
institution National Center for Biotechnology Information
language English
publishDate 2019
record_format MEDLINE/PubMed
spelling pubmed-70634462020-03-10 DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia() Georgiadis, Panagiotis Gavriil, Marios Rantakokko, Panu Ladoukakis, Efthymios Botsivali, Maria Kelly, Rachel S. Bergdahl, Ingvar A. Kiviranta, Hannu Vermeulen, Roel C.H. Spaeth, Florentin Hebbels, Dennie G.A.J. Kleinjans, Jos C.S. de Kok, Theo M.C.M. Palli, Domenico Vineis, Paolo Kyrtopoulos, Soterios A. Environ Int Article 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. 2019-02-15 2019-05 /pmc/articles/PMC7063446/ /pubmed/30776747 http://dx.doi.org/10.1016/j.envint.2019.01.068 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Georgiadis, Panagiotis
Gavriil, Marios
Rantakokko, Panu
Ladoukakis, Efthymios
Botsivali, Maria
Kelly, Rachel S.
Bergdahl, Ingvar A.
Kiviranta, Hannu
Vermeulen, Roel C.H.
Spaeth, Florentin
Hebbels, Dennie G.A.J.
Kleinjans, Jos C.S.
de Kok, Theo M.C.M.
Palli, Domenico
Vineis, Paolo
Kyrtopoulos, Soterios A.
DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia()
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()
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063446/
https://www.ncbi.nlm.nih.gov/pubmed/30776747
http://dx.doi.org/10.1016/j.envint.2019.01.068
work_keys_str_mv AT georgiadispanagiotis dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT gavriilmarios dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT rantakokkopanu dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT ladoukakisefthymios dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT botsivalimaria dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT kellyrachels dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT bergdahlingvara dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT kivirantahannu dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT vermeulenroelch dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT spaethflorentin dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT hebbelsdenniegaj dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT kleinjansjoscs dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT dekoktheomcm dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT pallidomenico dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT vineispaolo dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia
AT kyrtopoulossoteriosa dnamethylationprofilingimplicatesexposuretopcbsinthepathogenesisofbcellchroniclymphocyticleukemia