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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
Authors: Georgiadis, P
Gavriil, M
Rantakokko, P
Ladoukakis, E
Botsivali, M
Kelly, RS
Bergdahl, IA
Kiviranta, H
Vermeulen, RCH
Spaeth, F
Hebbels, DGAJ
Kleinjans, JCS
De Kok, TMCM
Palli, D
Vineis, P
Kyrtopoulos, SA
EnviroGenomarkers consortium
Item Type: Journal Article
Abstract: 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.
Issue Date: 15-Feb-2019
Date of Acceptance: 28-Jan-2019
URI: http://hdl.handle.net/10044/1/67576
DOI: https://dx.doi.org/10.1016/j.envint.2019.01.068
ISSN: 0160-4120
Publisher: Elsevier
Start Page: 24
End Page: 36
Journal / Book Title: Environment International
Volume: 126
Copyright Statement: © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 513943
Keywords: B-cell lymphoma
DNA methylation
Environmental toxicology
Hazard assessment
Molecular epidemiology
Persistent organic pollutants
EnviroGenomarkers consortium
MD Multidisciplinary
Environmental Sciences
Publication Status: Published
Conference Place: Netherlands
Online Publication Date: 2019-02-15
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care



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