DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia

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*, Ralph Gottschalk, Danitsja van Leeuwen, Leen Timmermans, Benedetta BendinelliLutzen Portengen, Fatemeh Saberi-Hosnijeh, Beatrice Melin, Goran Hallmans, Per Lenner, Hector C. Keun, Alexandros Siskos, Toby J. Athersuch, Manolis Kogevinas, Euripides G. Stephanou, Antonis Myridakis, Lucia Fazzo, Marco De Santis, Pietro Comba, Riikka Airaksinen, Paivi Ruokojarvi, Mark Gilthorpe, Sarah Fleming, Thomas Fleming, Yu-Kang Tu, Bo Jonsson, Thomas Lundh, Wei J. Chen, Wen-Chung Lee, Chuhsing Kate Hsiao, Kuo-Liong Chien, Po-Hsiu Kuo, Hung Hung, Shu-Fen Liao, EnviroGenomarkers Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

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.

Original languageEnglish
Pages (from-to)24-36
Number of pages13
JournalEnvironment International
Volume126
DOIs
Publication statusPublished - May 2019

Keywords

  • Molecular epidemiology
  • Persistent organic pollutants
  • DNA methylation
  • B-cell lymphoma
  • Environmental toxicology
  • Hazard assessment
  • PERSISTENT ORGANIC POLLUTANTS
  • POLYCHLORINATED BIPHENYL EXPOSURES
  • POLYCOMB
  • GENES
  • RISK
  • LYMPHOMA
  • CANCER
  • ROLES
  • HYPERMETHYLATION
  • HYPOMETHYLATION

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