PMID- 36379232
OWN - NLM
STAT- MEDLINE
DCOM- 20230110
LR  - 20240116
IS  - 1096-0953 (Electronic)
IS  - 0013-9351 (Print)
IS  - 0013-9351 (Linking)
VI  - 217
DP  - 2023 Jan 15
TI  - Epigenome-wide DNA methylation in leukocytes and toenail metals: The normative 
      aging study.
PG  - 114797
LID - S0013-9351(22)02124-7 [pii]
LID - 10.1016/j.envres.2022.114797 [doi]
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.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Wang, Cuicui
AU  - Wang C
AD  - Department of Environmental Health, Harvard T.H. Chan School of Public Health, 
      Boston, MA 02115, USA. Electronic address: cuicuiwang@hsph.harvard.edu.
FAU - Xu, Zongli
AU  - Xu Z
AD  - Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, 
      Research Triangle Park, NC, USA.
FAU - Qiu, Xinye
AU  - Qiu X
AD  - Department of Environmental Health, Harvard T.H. Chan School of Public Health, 
      Boston, MA 02115, USA.
FAU - Wei, Yaguang
AU  - Wei Y
AD  - Department of Environmental Health, Harvard T.H. Chan School of Public Health, 
      Boston, MA 02115, USA.
FAU - Peralta, Adjani A
AU  - Peralta AA
AD  - Department of Environmental Health, Harvard T.H. Chan School of Public Health, 
      Boston, MA 02115, USA.
FAU - Yazdi, Mahdieh Danesh
AU  - Yazdi MD
AD  - Department of Environmental Health, Harvard T.H. Chan School of Public Health, 
      Boston, MA 02115, USA; Program in Public Health, Department of Family, 
      Population, and Preventive Medicine, Renaissance School of Medicine at Stony 
      Brook University, Stony Brook, NY, USA.
FAU - Jin, Tingfan
AU  - Jin T
AD  - Department of Environmental Health, Harvard T.H. Chan School of Public Health, 
      Boston, MA 02115, USA.
FAU - Li, Wenyuan
AU  - Li W
AD  - School of Public Health and Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Hangzhou, Zhejiang, China.
FAU - Just, Allan
AU  - Just A
AD  - Department of Environmental Medicine and Public Health, Icahn School of Medicine 
      at Mount Sinai, New York, NY 10029, USA.
FAU - Heiss, Jonathan
AU  - Heiss J
AD  - Department of Environmental Medicine and Public Health, Icahn School of Medicine 
      at Mount Sinai, New York, NY 10029, USA.
FAU - Hou, Lifang
AU  - Hou L
AD  - Department of Preventive Medicine, Feinberg School of Medicine, Northwestern 
      University, Chicago, IL 60611, USA.
FAU - Zheng, Yinan
AU  - Zheng Y
AD  - Department of Preventive Medicine, Feinberg School of Medicine, Northwestern 
      University, Chicago, IL 60611, USA.
FAU - Coull, Brent A
AU  - Coull BA
AD  - Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, 
      MA 02115, USA.
FAU - Kosheleva, Anna
AU  - Kosheleva A
AD  - Department of Environmental Health, Harvard T.H. Chan School of Public Health, 
      Boston, MA 02115, USA.
FAU - Sparrow, David
AU  - Sparrow D
AD  - VA Normative Aging Study, VA Boston Healthcare System, Boston, MA 02130, USA; 
      Department of Medicine, Boston University School of Medicine, Boston, MA 02118, 
      USA.
FAU - Amarasiriwardena, Chitra
AU  - Amarasiriwardena C
AD  - Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 
      USA; Department of Environmental Medicine and Public Health, Icahn School of 
      Medicine at Mount Sinai, New York, NY, USA.
FAU - Wright, Robert O
AU  - Wright RO
AD  - Department of Environmental Medicine and Public Health, Icahn School of Medicine 
      at Mount Sinai, New York, NY, USA.
FAU - Baccarelli, Andrea A
AU  - Baccarelli AA
AD  - Department of Environmental Health Sciences, Columbia Mailman School of Public 
      Health, New York, NY 10032, USA.
FAU - Schwartz, Joel D
AU  - Schwartz JD
AD  - Department of Environmental Health, Harvard T.H. Chan School of Public Health, 
      Boston, MA 02115, USA; Department of Epidemiology, Harvard T.H. Chan School of 
      Public Health, Boston, MA 02115, USA.
LA  - eng
GR  - P30 ES000002/ES/NIEHS NIH HHS/United States
GR  - P30 ES009089/ES/NIEHS NIH HHS/United States
GR  - R01 ES025225/ES/NIEHS NIH HHS/United States
GR  - R01 ES027747/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20221112
PL  - Netherlands
TA  - Environ Res
JT  - Environmental research
JID - 0147621
RN  - 00BH33GNGH (Cadmium)
RN  - 0 (Metals)
RN  - N712M78A8G (Arsenic)
RN  - FXS1BY2PGL (Mercury)
RN  - 42Z2K6ZL8P (Manganese)
SB  - IM
MH  - Male
MH  - Humans
MH  - Aged
MH  - DNA Methylation
MH  - Cadmium
MH  - Epigenome
MH  - Nails
MH  - *Cardiovascular Diseases
MH  - Bayes Theorem
MH  - Metals/toxicity
MH  - Aging
MH  - *Arsenic/toxicity
MH  - Leukocytes
MH  - *Mercury
MH  - Manganese
PMC - PMC9825663
MID - NIHMS1853015
OTO - NOTNLM
OT  - DNA Methylation
OT  - Epigenome-wide association study
OT  - Joint effects
OT  - Pathway analysis
OT  - Toenail metals
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2022/11/16 06:00
MHDA- 2023/01/11 06:00
PMCR- 2024/01/15
CRDT- 2022/11/15 19:22
PHST- 2022/09/07 00:00 [received]
PHST- 2022/10/27 00:00 [revised]
PHST- 2022/11/10 00:00 [accepted]
PHST- 2022/11/16 06:00 [pubmed]
PHST- 2023/01/11 06:00 [medline]
PHST- 2022/11/15 19:22 [entrez]
PHST- 2024/01/15 00:00 [pmc-release]
AID - S0013-9351(22)02124-7 [pii]
AID - 10.1016/j.envres.2022.114797 [doi]
PST - ppublish
SO  - Environ Res. 2023 Jan 15;217:114797. doi: 10.1016/j.envres.2022.114797. Epub 2022 
      Nov 12.