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 Bendinelli; Lutzen 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

doi:10.1016/j.envint.2019.01.068

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 journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	24-36
Number of pages	13
Journal	Environment International
Volume	126
DOIs	https://doi.org/10.1016/j.envint.2019.01.068
Publication status	Published - 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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Georgiadis, P., Gavriil, M., Rantakokko, P., Ladoukakis, E., Botsivali, M., Kelly, R. S., Bergdahl, I. A., Kiviranta, H., Vermeulen, R. C. H., Spaeth, F., Hebbels, D. G. A. J., Kleinjans, J. C. S., de Kok, T. M. C. M., Palli, D., Vineis, P., Kyrtopoulos, S. A., Gottschalk, R., van Leeuwen, D., Timmermans, L., ... EnviroGenomarkers Consortium (2019). DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia. Environment International, 126, 24-36. https://doi.org/10.1016/j.envint.2019.01.068

@article{bcce5a07e0954db987ff16a3480ca4ac,

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

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 = "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",

author = "Panagiotis Georgiadis and Marios Gavriil and Panu Rantakokko and Efthymios Ladoukakis and Maria Botsivali and Kelly, {Rachel S.} and Bergdahl, {Ingvar A.} and Hannu Kiviranta and Vermeulen, {Roel C. H.} and Florentin Spaeth and Hebbels, {Dennie G. A. J.} and Kleinjans, {Jos C. S.} and {de Kok}, {Theo M. C. M.} and Domenico Palli and Paolo Vineis and Kyrtopoulos, {Soterios A.} and Ralph Gottschalk and {van Leeuwen}, Danitsja and Leen Timmermans and Benedetta Bendinelli and Lutzen Portengen and Fatemeh Saberi-Hosnijeh and Beatrice Melin and Goran Hallmans and Per Lenner and Keun, {Hector C.} and Alexandros Siskos and Athersuch, {Toby J.} and Manolis Kogevinas and Stephanou, {Euripides G.} and Antonis Myridakis and Lucia Fazzo and {De Santis}, Marco and Pietro Comba and Riikka Airaksinen and Paivi Ruokojarvi and Mark Gilthorpe and Sarah Fleming and Thomas Fleming and Yu-Kang Tu and Bo Jonsson and Thomas Lundh and Chen, {Wei J.} and Wen-Chung Lee and Hsiao, {Chuhsing Kate} and Kuo-Liong Chien and Po-Hsiu Kuo and Hung Hung and Shu-Fen Liao and {EnviroGenomarkers Consortium}",

note = "Funding Information: This work was supported by the European Union (grant 226756 ). Funding Information: The EnviroGenomarkers project and its associated studies and experimental protocols were approved by the Regional Ethical Review Board of the Ume{\aa} Division of Medical Research, for the Swedish cohort, and the Florence Health Unit Local Ethical Committee, for the Italian cohort. All participants gave written informed consent. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = may,

doi = "10.1016/j.envint.2019.01.068",

language = "English",

volume = "126",

pages = "24--36",

journal = "Environment International",

issn = "0160-4120",

publisher = "Elsevier Science",

}

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, Gottschalk, R, van Leeuwen, D, Timmermans, L, Bendinelli, B, Portengen, L, Saberi-Hosnijeh, F, Melin, B, Hallmans, G, Lenner, P, Keun, HC, Siskos, A, Athersuch, TJ, Kogevinas, M, Stephanou, EG, Myridakis, A, Fazzo, L, De Santis, M, Comba, P, Airaksinen, R, Ruokojarvi, P, Gilthorpe, M, Fleming, S, Fleming, T, Tu, Y-K, Jonsson, B, Lundh, T, Chen, WJ, Lee, W-C, Hsiao, CK, Chien, K-L, Kuo, P-H, Hung, H, Liao, S-F & EnviroGenomarkers Consortium 2019, 'DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia', Environment International, vol. 126, pp. 24-36. https://doi.org/10.1016/j.envint.2019.01.068

TY - JOUR

T1 - DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia

AU - Georgiadis, Panagiotis

AU - Gavriil, Marios

AU - Rantakokko, Panu

AU - Ladoukakis, Efthymios

AU - Botsivali, Maria

AU - Kelly, Rachel S.

AU - Bergdahl, Ingvar A.

AU - Kiviranta, Hannu

AU - Vermeulen, Roel C. H.

AU - Spaeth, Florentin

AU - Hebbels, Dennie G. A. J.

AU - Kleinjans, Jos C. S.

AU - de Kok, Theo M. C. M.

AU - Palli, Domenico

AU - Vineis, Paolo

AU - Kyrtopoulos, Soterios A.

AU - Gottschalk, Ralph

AU - van Leeuwen, Danitsja

AU - Timmermans, Leen

AU - Bendinelli, Benedetta

AU - Portengen, Lutzen

AU - Saberi-Hosnijeh, Fatemeh

AU - Melin, Beatrice

AU - Hallmans, Goran

AU - Lenner, Per

AU - Keun, Hector C.

AU - Siskos, Alexandros

AU - Athersuch, Toby J.

AU - Kogevinas, Manolis

AU - Stephanou, Euripides G.

AU - Myridakis, Antonis

AU - Fazzo, Lucia

AU - De Santis, Marco

AU - Comba, Pietro

AU - Airaksinen, Riikka

AU - Ruokojarvi, Paivi

AU - Gilthorpe, Mark

AU - Fleming, Sarah

AU - Fleming, Thomas

AU - Tu, Yu-Kang

AU - Jonsson, Bo

AU - Lundh, Thomas

AU - Chen, Wei J.

AU - Lee, Wen-Chung

AU - Hsiao, Chuhsing Kate

AU - Chien, Kuo-Liong

AU - Kuo, Po-Hsiu

AU - Hung, Hung

AU - Liao, Shu-Fen

AU - EnviroGenomarkers Consortium

N1 - Funding Information: This work was supported by the European Union (grant 226756 ). Funding Information: The EnviroGenomarkers project and its associated studies and experimental protocols were approved by the Regional Ethical Review Board of the Umeå Division of Medical Research, for the Swedish cohort, and the Florence Health Unit Local Ethical Committee, for the Italian cohort. All participants gave written informed consent. Publisher Copyright: © 2019 The Authors

PY - 2019/5

Y1 - 2019/5

N2 - 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.

AB - 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.

KW - Molecular epidemiology

KW - Persistent organic pollutants

KW - DNA methylation

KW - B-cell lymphoma

KW - Environmental toxicology

KW - Hazard assessment

KW - PERSISTENT ORGANIC POLLUTANTS

KW - POLYCHLORINATED BIPHENYL EXPOSURES

KW - POLYCOMB

KW - GENES

KW - RISK

KW - LYMPHOMA

KW - CANCER

KW - ROLES

KW - HYPERMETHYLATION

KW - HYPOMETHYLATION

U2 - 10.1016/j.envint.2019.01.068

DO - 10.1016/j.envint.2019.01.068

M3 - Article

C2 - 30776747

SN - 0160-4120

VL - 126

SP - 24

EP - 36

JO - Environment International

JF - Environment International

ER -