DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia. (May 2019)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Environment international. Volume 126(2019)
• Page Start: 24
• Page End: 36
• Publication Date: 2019-05
• Subjects: BCL B-cell lymphoma -- CLL B-cell chronic lymphocytic leukemia -- FDR false discovery rate -- HCB hexachlorobenzene -- MITM meet-in-the-middle -- PCBs polychlorinated biphenyls -- PcGT's polycomb group protein targets -- POPs persistent organic pollutants; Molecular epidemiology -- Persistent organic pollutants -- DNA methylation -- B-cell lymphoma -- Environmental toxicology -- Hazard assessment; Environmental protection -- Periodicals; Environmental health -- Periodicals; Environmental monitoring -- Periodicals; Environmental Monitoring -- Periodicals; Environnement -- Protection -- Périodiques; Hygiène du milieu -- Périodiques; Environnement -- Surveillance -- Périodiques; Environmental health; Environmental monitoring; Environmental protection; Periodicals; 333.705
• DOI: 10.1016/j.envint.2019.01.068
• Languages: English
• ISSNs: 0160-4120

Abstract

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. Highlights: PCB exposure causes a distinct DNA methylation profile in blood leukocytes; This profile overlaps significantly with the risk profile for future CLL; This overlap suggests a causal link between PCB exposure and CLL; The epigenetic exposure profile suggests that PCBs target stem cells;