lancet-header
Preprints with The Lancet is part of SSRN´s First Look, a place where journals and other research experts identify content of interest prior to publication. These preprint papers are not peer-reviewed and are posted here as part of a 12-month trial. Authors have either opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet, or submitted directly via SSRN. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. These papers should not be used for clinical decision making or reporting of research to a lay audience without indicating that this is preliminary research that has not been peer-reviewed. For more information see the Comment published in The Lancet, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com

Blood DNA Methylation Biomarkers of Cumulative Lead Exposure in Adults

26 Pages Posted: 2 Mar 2019

See all articles by Elena Colicino

Elena Colicino

Mount Sinai Health System - Icahn School of Medicine

Allan Just

Mount Sinai Health System - Icahn School of Medicine

Marianthi-Anna Kioumourtzoglou

Columbia University - Mailman School of Public Health

Pantel Vokonas

Government of the United States of America, Department of Veterans Affairs (VA), VA Boston Healthcare System

Andres Cardenas

University of California, Berkeley - School of Public Health

David Sparrow

Government of the United States of America, Department of Veterans Affairs (VA), VA Boston Healthcare System

Marc Weisskopf

Harvard University - T.H. Chan School of Public Health

Linda H. Nie

Purdue University - School of Health Sciences

Howard Hu

University of Washington - School of Public Health

Joel D. Schwartz

Harvard University - Department of Environmental Health

Robert O. Wright

Mount Sinai Health System - Icahn School of Medicine

Andrea A. Baccarelli

Columbia University - Mailman School of Public Health

More...

Abstract

Background: Lead is a ubiquitous toxicant following three compartment kinetics with the longest half-life found in bones. Patella and tibia lead levels — validated measures of cumulative lead exposure — require specialized X-ray-fluorescence-spectroscopy available only in a few centers worldwide. We developed minimally-invasive biomarkers reflecting individual cumulative lead exposure using blood DNA methylation profiles — obtainable via Illumina450K or IlluminaEPIC beadchip assays.

Methods: We developed and tested two methylation-based biomarkers using Illumina450K data from 348 Normative Aging Study (NAS) elderly men. We selected methylation sites with strong associations with bone lead levels via robust regressions analysis and constructed the final biomarkers using elastic nets. All results were validated in a NAS subset.

Findings: Participants were 73 years old on average (standard deviation, SD=6), with moderate lead levels of (mean±SD patella:27±18µg/g; tibia:21±13µg/g). Methylation-based biomarkers for lead in patella and tibia included 59 and 138 DNA methylation sites, respectively. Estimated lead levels were significantly correlated with actual measured values, (r=0·62 patella, r=0·59 tibia) and had low mean square error (MSE) (MSE=0·68 patella, MSE=0·53 tibia). Means and distributions of the estimated and actual lead levels were not significantly different across the two bones (p>0·05). Methylation-based biomarkers discriminated participants highly exposed (>median) to lead with a specificity of 74% and 73% for patella and tibia lead levels, respectively, with 70% sensitivity.

Interpretation: DNA methylation-based lead biomarkers are novel tools that can be used to reconstruct decades' worth of individual cumulative lead exposure using only blood DNA methylation profiles and may help identify the consequences of cumulative lead exposure sequences of cumulative lead exposure.

Funding Statement: EC and ROW were supported by the National Institute of Environmental Health Sciences (NIEHS) (grant: P30ES023515); ACJ was supported by NIEHS (grant: R00ES023450); MAK was supported by NIEHS (grants: R01ES028805 and P30 ES009089); MW was supported by NIEHS (grant: P30ES000002); JS was supported by NIEHS (grants: R01ES015172, P30ES000002, and R01ES027747); HH was supported by NIH (grants: R01ES021446, and R01ES005257); AAB was supported by NIEHS (grants: P30ES009089, R01ES021733, R01ES025225, and R01ES027747). The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, Massachusetts.

Declaration of Interests: All authors declare no conflict of interest.

Ethics Approval Statement: Approval from the Institutional Review Boards at the Veterans Affairs Boston Healthcare System, Brigham and Women’s Hospital, and the Harvard T.H. Chan School of Public Health was obtained prior to study commencement. All subjects provided written informed consent before participating.

Keywords: lead, DNA methylation, exposure reconstruction, cumulative exposure, machine learning

Suggested Citation

Colicino, Elena and Just, Allan and Kioumourtzoglou, Marianthi-Anna and Vokonas, Pantel and Cardenas, Andres and Sparrow, David and Weisskopf, Marc and Nie, Linda H. and Hu, Howard and Schwartz, Joel D. and Wright, Robert O. and Baccarelli, Andrea A., Blood DNA Methylation Biomarkers of Cumulative Lead Exposure in Adults (February 27, 2019). Available at SSRN: https://ssrn.com/abstract=3343644

Elena Colicino (Contact Author)

Mount Sinai Health System - Icahn School of Medicine ( email )

One Gustave L. Levy Place
New York, NY 10029-6574
United States

Allan Just

Mount Sinai Health System - Icahn School of Medicine ( email )

One Gustave L. Levy Place
New York, NY 10029-6574
United States

Marianthi-Anna Kioumourtzoglou

Columbia University - Mailman School of Public Health ( email )

600 West 168th St., 6th Floor
New York, NY 10032
United States

Pantel Vokonas

Government of the United States of America, Department of Veterans Affairs (VA), VA Boston Healthcare System ( email )

150 S Huntington Ave.
Boston, MA 02130
United States

Andres Cardenas

University of California, Berkeley - School of Public Health ( email )

50 University Hall #7360
Berkeley, CA 94720-7360
United States

David Sparrow

Government of the United States of America, Department of Veterans Affairs (VA), VA Boston Healthcare System ( email )

150 S Huntington Ave.
Boston, MA 02130
United States

Marc Weisskopf

Harvard University - T.H. Chan School of Public Health ( email )

665 Huntington Ave
Boston, MA
United States

Linda H. Nie

Purdue University - School of Health Sciences ( email )

West Lafayette, IN 47907
United States

Howard Hu

University of Washington - School of Public Health ( email )

Seattle, WA
United States

Joel D. Schwartz

Harvard University - Department of Environmental Health

401 Park Dr
Boston, MA 02215
United States

Robert O. Wright

Mount Sinai Health System - Icahn School of Medicine ( email )

One Gustave L. Levy Place
New York, NY 10029-6574
United States

Andrea A. Baccarelli

Columbia University - Mailman School of Public Health ( email )

600 West 168th St., 6th Floor
New York, NY 10032
United States

Click here to go to TheLancet.com

Go to TheLancet.com

Paper statistics

Abstract Views
115
Downloads
23