Epigenome-wide DNA methylation in leukocytes and toenail metals: The normative aging study

Cuicui Wang; Zongli Xu; Xinye Qiu; Yaguang Wei; Adjani A Peralta; Mahdieh Danesh Yazdi; Tingfan Jin; Wenyuan Li; Allan Just; Jonathan Heiss; Lifang Hou; Yinan Zheng; Brent A Coull; Anna Kosheleva; David Sparrow; Chitra Amarasiriwardena; Robert O Wright; Andrea A Baccarelli; Joel D Schwartz

doi:10.1016/j.envres.2022.114797

Epigenome-wide DNA methylation in leukocytes and toenail metals: The normative aging study

Environ Res. 2023 Jan 15:217:114797. doi: 10.1016/j.envres.2022.114797. Epub 2022 Nov 12.

Authors

Cuicui Wang¹, Zongli Xu², Xinye Qiu³, Yaguang Wei³, Adjani A Peralta³, Mahdieh Danesh Yazdi⁴, Tingfan Jin³, Wenyuan Li⁵, Allan Just⁶, Jonathan Heiss⁶, Lifang Hou⁷, Yinan Zheng⁷, Brent A Coull⁸, Anna Kosheleva³, David Sparrow⁹, Chitra Amarasiriwardena¹⁰, Robert O Wright¹¹, Andrea A Baccarelli¹², Joel D Schwartz¹³

Affiliations

¹ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: cuicuiwang@hsph.harvard.edu.
² Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
³ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁴ 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.
⁵ School of Public Health and Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
⁶ Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁸ Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
⁹ VA Normative Aging Study, VA Boston Healthcare System, Boston, MA 02130, USA; Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
¹⁰ 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.
¹¹ Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Environmental Health Sciences, Columbia Mailman School of Public Health, New York, NY 10032, USA.
¹³ 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.

Abstract

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.

Keywords: DNA Methylation; Epigenome-wide association study; Joint effects; Pathway analysis; Toenail metals.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Aged
Aging
Arsenic* / toxicity
Bayes Theorem
Cadmium
Cardiovascular Diseases*
DNA Methylation
Epigenome
Humans
Leukocytes
Male
Manganese
Mercury*
Metals / toxicity
Nails

Substances

Cadmium
Metals
Arsenic
Mercury
Manganese

Abstract

Publication types

MeSH terms

Substances

Grants and funding