Epigenome-wide DNA methylation in leukocytes and toenail metals: The normative aging study.
DNA Methylation
Epigenome-wide association study
Joint effects
Pathway analysis
Toenail metals
Journal
Environmental research
ISSN: 1096-0953
Titre abrégé: Environ Res
Pays: Netherlands
ID NLM: 0147621
Informations de publication
Date de publication:
15 01 2023
15 01 2023
Historique:
received:
07
09
2022
revised:
27
10
2022
accepted:
10
11
2022
pmc-release:
15
01
2024
pubmed:
16
11
2022
medline:
11
1
2023
entrez:
15
11
2022
Statut:
ppublish
Résumé
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. 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. 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. 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. This study provides an approach to understanding the potential epigenetic mechanisms underlying observed relations between toenail metals and adverse health endpoints.
Sections du résumé
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.
Identifiants
pubmed: 36379232
pii: S0013-9351(22)02124-7
doi: 10.1016/j.envres.2022.114797
pmc: PMC9825663
mid: NIHMS1853015
pii:
doi:
Substances chimiques
Cadmium
00BH33GNGH
Metals
0
Arsenic
N712M78A8G
Mercury
FXS1BY2PGL
Manganese
42Z2K6ZL8P
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
114797Subventions
Organisme : NIEHS NIH HHS
ID : P30 ES000002
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES009089
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES025225
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES027747
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
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.
Références
Nat Commun. 2020 Jan 3;11(1):15
pubmed: 31900413
Int J Hyg Environ Health. 2019 Apr;222(3):556-562
pubmed: 30826206
Sci Rep. 2022 Jun 15;12(1):9938
pubmed: 35705627
Bioinformatics. 2013 Jan 15;29(2):189-96
pubmed: 23175756
N Engl J Med. 2002 Nov 28;347(22):1747-54
pubmed: 12456850
J Dermatol Sci. 2021 Nov;104(2):112-121
pubmed: 34657752
Nat Commun. 2015 Feb 02;6:6156
pubmed: 25639486
EBioMedicine. 2021 Jan;63:103151
pubmed: 33279859
Environ Res. 2006 Sep;102(1):125-39
pubmed: 16442520
BMC Bioinformatics. 2012 May 08;13:86
pubmed: 22568884
Int J Cancer. 2020 Apr 1;146(7):1862-1878
pubmed: 31696517
Mol Cancer. 2008 Jul 10;7:62
pubmed: 18616821
Nucleic Acids Res. 2016 Feb 18;44(3):e20
pubmed: 26384415
J Expo Sci Environ Epidemiol. 2019 Sep;29(5):663-673
pubmed: 30482937
Nature. 2012 Nov 1;491(7422):56-65
pubmed: 23128226
Stroke. 2009 Feb;40(2):363-8
pubmed: 19023099
Brief Bioinform. 2019 Nov 27;20(6):2224-2235
pubmed: 30239597
Environ Toxicol. 2016 Apr;31(4):452-60
pubmed: 25346352
Anticancer Res. 2018 Jan;38(1):137-145
pubmed: 29277766
J Neurodev Disord. 2014;6(1):17
pubmed: 25050139
Br J Cancer. 2012 Aug 21;107(5):895-900
pubmed: 22850555
Nat Neurosci. 2014 Jan;17(1):121-30
pubmed: 24270187
Toxicol Sci. 2007 Jan;95(1):156-62
pubmed: 17047031
Gerontologist. 1966 Dec;6(4):179-84
pubmed: 5342911
Biostatistics. 2015 Jul;16(3):493-508
pubmed: 25532525
J Chromatogr A. 2017 Jan 6;1479:145-152
pubmed: 27988079
Psychosom Med. 2023 Jan 1;85(1):89-97
pubmed: 36201768
Acta Pharmacol Sin. 2016 Mar;37(3):285-94
pubmed: 26806303
Sci Rep. 2016 May 04;6:25290
pubmed: 27142475
Environ Res. 2017 Jul;156:747-760
pubmed: 28482296
Tumour Biol. 2014 Dec;35(12):12189-200
pubmed: 25179839
Sci Total Environ. 1977 Jan;7(1):71-89
pubmed: 319530
Cancer Res. 2000 Oct 15;60(20):5612-6
pubmed: 11059748
Mol Psychiatry. 2018 Sep;23(9):1957-1967
pubmed: 29158582
Hum Mol Genet. 2012 Nov 1;21(21):4781-92
pubmed: 22843504
Am J Physiol Lung Cell Mol Physiol. 2020 Jan 1;318(1):L98-L111
pubmed: 31617731
J Clin Endocrinol Metab. 2015 Nov;100(11):E1491-501
pubmed: 26418287
J Mol Neurosci. 2020 Mar;70(3):320-327
pubmed: 31721002
Metallomics. 2012 Aug;4(8):784-93
pubmed: 22714537
J Pathol. 2010 Sep;222(1):89-98
pubmed: 20556744
Environ Health Perspect. 2013 Jun;121(6):650-6
pubmed: 23552396
Environ Sci Technol. 2018 Nov 20;52(22):13469-13480
pubmed: 30285427
Lipids Health Dis. 2016 Oct 4;15(1):171
pubmed: 27716295
BMC Genomics. 2017 Jan 3;18(1):4
pubmed: 28049437
Environ Health Perspect. 2018 Aug 8;126(8):087002
pubmed: 30102601
Toxicol Appl Pharmacol. 2009 Aug 1;238(3):209-14
pubmed: 19236887
Cells. 2019 Jun 06;8(6):
pubmed: 31174369
Int J Oncol. 2015 Jul;47(1):195-203
pubmed: 25963840
Environ Health Perspect. 2015 Jul;123(7):723-9
pubmed: 25748564
Eur Respir J. 2016 Aug;48(2):573-6
pubmed: 27174877
J Hazard Mater. 2015 Aug 30;294:109-20
pubmed: 25863025
Front Oncol. 2018 Apr 23;8:100
pubmed: 29740534
Int J Clin Exp Pathol. 2012;5(2):126-36
pubmed: 22400072
Epigenomics. 2017 Dec;9(12):1489-1502
pubmed: 29106300
Hum Genet. 2012 May;131(5):747-56
pubmed: 22143225
Sci Rep. 2016 Oct 19;6:34233
pubmed: 27756899
Aging (Albany NY). 2020 Jun 19;12(12):11942-11966
pubmed: 32561690
PLoS One. 2012;7(3):e32907
pubmed: 22479346
J Intern Med. 2013 May;273(5):466-77
pubmed: 23360507
Reprod Toxicol. 2016 Oct;65:263-271
pubmed: 27544570
Toxicol Appl Pharmacol. 2009 Aug 1;238(3):201-8
pubmed: 19409405
Clin Epigenetics. 2019 Jan 24;11(1):15
pubmed: 30678737
Int J Clin Pract. 2022 Sep 2;2022:7640227
pubmed: 36101810
Environ Health Perspect. 2016 May;124(5):594-600
pubmed: 26517380
Tumour Biol. 2017 Apr;39(4):1010428317695929
pubmed: 28378641
Clin Epigenetics. 2021 Nov 29;13(1):211
pubmed: 34844636
Nat Genet. 2017 Apr;49(4):515-526
pubmed: 28191889
J Expo Sci Environ Epidemiol. 2014 Mar-Apr;24(2):145-9
pubmed: 24368509
Am J Hum Genet. 2004 Apr;74(4):765-9
pubmed: 14997420
Environ Health Perspect. 2014 Oct;122(10):1066-74
pubmed: 24905780
J Clin Oncol. 2013 Jul 1;31(19):2388-95
pubmed: 23715562
Int J Cancer. 2019 Oct 1;145(7):1982-1990
pubmed: 30838640
J Neurosci. 2017 Sep 6;37(36):8655-8666
pubmed: 28878098
Epigenetics. 2017 Feb;12(2):139-148
pubmed: 27982729
Immun Inflamm Dis. 2022 Feb;10(2):241-254
pubmed: 34729929
Int J Mol Sci. 2018 Jun 20;19(6):
pubmed: 29925772
Biol Trace Elem Res. 2017 Oct;179(2):172-177
pubmed: 28220387
Nat Commun. 2019 Jul 12;10(1):3095
pubmed: 31300640
Oncol Lett. 2020 Jan;19(1):707-716
pubmed: 31897186
Neurotoxicology. 2019 Sep;74:230-241
pubmed: 31377220
Brain. 2022 Jun 3;145(5):1839-1853
pubmed: 34919654
Environ Health Perspect. 2012 Jan;120(1):98-104
pubmed: 21878420
Clin Epigenetics. 2018 Jun 1;10:73
pubmed: 29881472
Biochim Biophys Acta. 2013 Mar;1832(3):431-8
pubmed: 23195952
Front Public Health. 2022 Jul 07;10:818069
pubmed: 35875010
Front Genet. 2015 Mar 10;6:92
pubmed: 25806048
Am J Clin Nutr. 2009 Sep;90(3):686-94
pubmed: 19605566
Carcinogenesis. 2020 Dec 31;41(12):1724-1734
pubmed: 32255478
Biomed Pharmacother. 2022 Feb;146:112504
pubmed: 34922110
Gut. 2012 Nov;61(11):1583-8
pubmed: 22184070
J Biomed Biotechnol. 2012;2012:949048
pubmed: 22811600
J Am Heart Assoc. 2020 Sep;9(17):e017055
pubmed: 32808564
Biol Trace Elem Res. 2005 Nov;107(2):113-26
pubmed: 16217136
Clin Epigenetics. 2021 Nov 19;13(1):208
pubmed: 34798907
Cell Metab. 2022 May 3;34(5):651-653
pubmed: 35508105
Med Glas (Zenica). 2011 Feb;8(1):76-83
pubmed: 21263402
Environ Sci Technol. 2017 Nov 7;51(21):12443-12454
pubmed: 29043784
Hum Mol Genet. 2014 Jan 15;23(2):534-45
pubmed: 24014485
Front Pharmacol. 2021 Apr 13;12:643972
pubmed: 33927623
Psychol Med. 2020 Feb;50(3):384-395
pubmed: 30722798
Bioinformatics. 2021 May 5;37(5):711-713
pubmed: 32805005
Environ Res. 2020 Apr;183:109134
pubmed: 32018205
Clin Epigenetics. 2020 Oct 17;12(1):149
pubmed: 33069246
Int J Cancer. 2018 Nov 15;143(10):2488-2498
pubmed: 30183087
Environ Health. 2018 Aug 20;17(1):67
pubmed: 30126431
Biomed Pharmacother. 2018 Oct;106:672-677
pubmed: 29990857
Int Immunopharmacol. 2015 Dec;29(2):622-627
pubmed: 26428848
Environ Health Perspect. 2016 Aug;124(8):1253-60
pubmed: 26771251
Epigenetics. 2013 Feb;8(2):203-9
pubmed: 23314698
Clin Epigenetics. 2018 Sep 12;10(1):117
pubmed: 30208931
PLoS One. 2013 Sep 26;8(9):e74923
pubmed: 24086398
Environ Health Perspect. 2003 May;111(6):825-35
pubmed: 12760830
Oncol Lett. 2018 Jun;15(6):9941-9952
pubmed: 29928367
Medicine (Baltimore). 2018 Oct;97(43):e12800
pubmed: 30412069
Int J Mol Sci. 2020 Nov 16;21(22):
pubmed: 33207814
J Med Genet. 2019 May;56(5):332-339
pubmed: 30487245
Environ Health Perspect. 2017 Jun 26;125(6):067015
pubmed: 28669934
Proc Natl Acad Sci U S A. 2011 May 17;108(20):8390-5
pubmed: 21540330
Aging (Albany NY). 2019 Jun 10;11(11):3768-3784
pubmed: 31182679
J Eur Acad Dermatol Venereol. 2010 Apr;24(4):420-3
pubmed: 19744178
Environ Int. 2022 Jan;158:106955
pubmed: 34717175
Sci Rep. 2022 Jan 27;12(1):1496
pubmed: 35087173
Front Neurosci. 2021 Mar 08;15:646518
pubmed: 33762907
Int J Mol Sci. 2018 Aug 20;19(8):
pubmed: 30127261
J Natl Cancer Inst. 2020 Jan 1;112(1):87-94
pubmed: 30989176