National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece.
National Institute for Health and Welfare, Department of Health Security, Environmental Health unit, P.O. Box 95, Kuopio, Finland.
Environ Int. 2019 May;126:24-36. doi: 10.1016/j.envint.2019.01.068. Epub 2019 Feb 15.
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.
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.
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.
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.
描述 PCB 暴露对周围血白细胞 DNA 甲基化的影响，并评估其与可能的健康影响相关的变化，重点关注 B 细胞淋巴瘤。
我们对 611 名意大利和瑞典无诊断疾病的成年人进行了全基因组关联研究，在这些成年人中，我们还测量了 6 种 PCB 同系物、DDE 和六氯苯的血浆浓度。
我们鉴定了 650 个 CpG 位点，其甲基化与至少一种 PCB 同系物的血浆浓度密切相关（FDR<0.01）。在男性和瑞典，观察到更强的影响。这种表观遗传暴露谱与发表的与未来 B 细胞慢性淋巴细胞白血病（CLL）风险以及临床 CLL 相关的暴露谱（分别为 38 和 28 个 CpG 位点）广泛且具有高度统计学意义的重叠。对于所有这些位点，随着暴露增加和疾病风险或临床疾病状态升高，甲基化变化的方向相同，表明暴露与 CLL 之间存在病因联系。中介分析加强了暴露、DNA 甲基化变化和疾病之间存在因果关系的建议。疾病连接性分析确定了与差异甲基化基因相关的多个其他疾病，包括与 PCB 暴露有明确病因联系的黑色素瘤，以及存在相应流行病学证据的发育和神经疾病。差异甲基化基因包括许多同源盒基因，表明 PCB 靶向于干细胞。此外，随着暴露的增加，许多多梳蛋白靶基因被超甲基化，这种效应被认为是致癌作用的早期标志物。
本研究提供了支持 PCB 暴露与 CLL 病因之间联系的机制证据，并强调了组学分析在评估环境化学物质潜在毒性方面的实用性。
