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Environ Int. 2019 Feb 15;126:24-36. doi: 10.1016/j.envint.2019.01.068. [Epub ahead of print]

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

Author information

1
National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece.
2
National Institute for Health and Welfare, Department of Health Security, Environmental Health unit, P.O. Box 95, Kuopio, Finland.
3
MRC-HPA Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, UK.
4
Department of Biobank Research, and Occupational and Environmental Medicine, Department of Public Health and Clinical Medicine, Umeå University, Sweden.
5
Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, Netherlands.
6
Department of Radiation Sciences, Oncology, Umeå University, Sweden.
7
Department of Toxicogenomics, Maastricht University, Netherlands.
8
The Institute for Cancer Research and Prevention, Florence, Italy.
9
National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece. Electronic address: skyrt@eie.gr.

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.

KEYWORDS:

B-cell lymphoma; DNA methylation; Environmental toxicology; Hazard assessment; Molecular epidemiology; Persistent organic pollutants

PMID:
30776747
DOI:
10.1016/j.envint.2019.01.068
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