TY - JOUR
T1 - Epigenome-wide DNA methylation in leukocytes and toenail metals
T2 - The normative aging study
AU - Wang, Cuicui
AU - Xu, Zongli
AU - Qiu, Xinye
AU - Wei, Yaguang
AU - Peralta, Adjani A.
AU - Yazdi, Mahdieh Danesh
AU - Jin, Tingfan
AU - Li, Wenyuan
AU - Just, Allan
AU - Heiss, Jonathan
AU - Hou, Lifang
AU - Zheng, Yinan
AU - Coull, Brent A.
AU - Kosheleva, Anna
AU - Sparrow, David
AU - Amarasiriwardena, Chitra
AU - Wright, Robert O.
AU - Baccarelli, Andrea A.
AU - Schwartz, Joel D.
N1 - Funding Information:
This work was supported by the National Institute of Environmental Health Sciences ( R01ES027747 , R01ES025225 , P30ES009089 ), and HSPH- NIEHS Center for Environmental Health ( ES000002 ). Further, Neither the National Institute of Environmental Health Sciences nor the U.S. EPA endorses the purchase of any commercial products or services mentioned in the publication.
Funding Information:
This work was supported by the National Institute of Environmental Health Sciences (R01ES027747, R01ES025225, P30ES009089), and HSPH-NIEHS Center for Environmental Health (ES000002). Further, Neither the National Institute of Environmental Health Sciences nor the U.S. EPA endorses the purchase of any commercial products or services mentioned in the publication.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2023/1/15
Y1 - 2023/1/15
N2 - Background: Environmental metal exposures have been associated with multiple deleterious health endpoints. DNA methylation (DNAm) may provide insight into the mechanisms underlying these relationships. Toenail metals are non-invasive biomarkers, reflecting a medium-term time exposure window. Objectives: This study examined variation in leukocyte DNAm and toenail arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg) among elderly men in the Normative Aging Study, a longitudinal cohort. Methods: We repeatedly collected samples of blood and toenail clippings. We measured DNAm in leukocytes with the Illumina HumanMethylation450 K BeadChip. We first performed median regression to evaluate the effects of each individual toenail metal on DNAm at three levels: individual cytosine-phosphate-guanine (CpG) sites, regions, and pathways. Then, we applied a Bayesian kernel machine regression (BKMR) to assess the joint and individual effects of metal mixtures on DNAm. Significant CpGs were identified using a multiple testing correction based on the independent degrees of freedom approach for correlated outcomes. The approach considers the effective degrees of freedom in the DNAm data using the principal components that explain >95% variation of the data. Results: We included 564 subjects (754 visits) between 1999 and 2013. The numbers of significantly differentially methylated CpG sites, regions, and pathways varied by metals. For example, we found six significant pathways for As, three for Cd, and one for Mn. The As-associated pathways were associated with cancer (e.g., skin cancer) and cardiovascular disease, whereas the Cd-associated pathways were related to lung cancer. Metal mixtures were also associated with 47 significant CpG sites, as well as pathways, mainly related to cancer and cardiovascular disease. Conclusions: This study provides an approach to understanding the potential epigenetic mechanisms underlying observed relations between toenail metals and adverse health endpoints.
AB - Background: Environmental metal exposures have been associated with multiple deleterious health endpoints. DNA methylation (DNAm) may provide insight into the mechanisms underlying these relationships. Toenail metals are non-invasive biomarkers, reflecting a medium-term time exposure window. Objectives: This study examined variation in leukocyte DNAm and toenail arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg) among elderly men in the Normative Aging Study, a longitudinal cohort. Methods: We repeatedly collected samples of blood and toenail clippings. We measured DNAm in leukocytes with the Illumina HumanMethylation450 K BeadChip. We first performed median regression to evaluate the effects of each individual toenail metal on DNAm at three levels: individual cytosine-phosphate-guanine (CpG) sites, regions, and pathways. Then, we applied a Bayesian kernel machine regression (BKMR) to assess the joint and individual effects of metal mixtures on DNAm. Significant CpGs were identified using a multiple testing correction based on the independent degrees of freedom approach for correlated outcomes. The approach considers the effective degrees of freedom in the DNAm data using the principal components that explain >95% variation of the data. Results: We included 564 subjects (754 visits) between 1999 and 2013. The numbers of significantly differentially methylated CpG sites, regions, and pathways varied by metals. For example, we found six significant pathways for As, three for Cd, and one for Mn. The As-associated pathways were associated with cancer (e.g., skin cancer) and cardiovascular disease, whereas the Cd-associated pathways were related to lung cancer. Metal mixtures were also associated with 47 significant CpG sites, as well as pathways, mainly related to cancer and cardiovascular disease. Conclusions: This study provides an approach to understanding the potential epigenetic mechanisms underlying observed relations between toenail metals and adverse health endpoints.
KW - DNA Methylation
KW - Epigenome-wide association study
KW - Joint effects
KW - Pathway analysis
KW - Toenail metals
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U2 - 10.1016/j.envres.2022.114797
DO - 10.1016/j.envres.2022.114797
M3 - Article
C2 - 36379232
AN - SCOPUS:85142759917
SN - 0013-9351
VL - 217
JO - Environmental Research
JF - Environmental Research
M1 - 114797
ER -
