A metabolome-wide association study of in utero metal and trace element exposures with cord blood metabolome profile: Findings from the Boston Birth Cohort

Mingyu Zhang¹, Jessie P Buckley², Liming Liang³, Xiumei Hong⁴, Guoying Wang⁴, Mei-Cheng Wang⁵, Marsha Wills-Karp⁶, Xiaobin Wang⁷, Noel T Mueller⁸

Affiliations

¹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA.
² Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁶ Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁸ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA. Electronic address: noeltmueller@jhu.edu.

PMID: 34991243
PMCID: PMC8742133
DOI: 10.1016/j.envint.2021.106976

A metabolome-wide association study of in utero metal and trace element exposures with cord blood metabolome profile: Findings from the Boston Birth Cohort

Mingyu Zhang et al. Environ Int. 2022 Jan.

. 2022 Jan:158:106976.

doi: 10.1016/j.envint.2021.106976. Epub 2021 Nov 19.

Authors

Mingyu Zhang¹, Jessie P Buckley², Liming Liang³, Xiumei Hong⁴, Guoying Wang⁴, Mei-Cheng Wang⁵, Marsha Wills-Karp⁶, Xiaobin Wang⁷, Noel T Mueller⁸

Affiliations

¹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA.
² Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁶ Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷ Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁸ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA. Electronic address: noeltmueller@jhu.edu.

PMID: 34991243
PMCID: PMC8742133
DOI: 10.1016/j.envint.2021.106976

Abstract

Background: Exposure to metals lead (Pb), mercury (Hg), and cadmium (Cd) and trace elements selenium (Se) and manganese (Mn) has been linked to the developmental origins of cardiometabolic diseases, but the mechanisms are not well-understood.

Objective: Conduct a metabolome-wide association study to understand how in utero exposure to Pb, Hg, Cd, Se, and Mn affects the metabolic programming of fetuses.

Methods: We used data from the Boston Birth Cohort, which enrolled mother-child pairs from Boston, MA. We measured metals and trace elements in maternal red blood cells (RBCs) collected 24-72 h after delivery, and metabolites in cord blood collected at birth. We used multivariable linear regression to examine associations of metals and trace elements with metabolites and Bonferroni correction to account for multiple comparisons. We assessed non-linear associations of metals and trace elements with metabolites using restricted cubic spline plots.

Results: This analysis included 670 mother-child pairs (57% non-Hispanic Black and 24% Hispanic). After Bonferroni correction, there were 25 cord metabolites associated with at least one of the metals or trace elements. Pb was negatively associated with the xenobiotic piperine, Cd was positively associated with xenobiotics cotinine and hydroxycotinine, and Hg was associated with 8 lipid metabolites (in both directions). Se and Mn shared associations with 6 metabolites (in both directions), which mostly included nucleotides and amino acids; Se was additionally associated with 7 metabolites (mostly amino acids, nucleotides, and carnitines) and Mn was additionally associated with C36:4 hydroxy phosphatidylcholine. Restricted cubic spline plots showed that most associations were linear.

Discussion: Maternal RBC metal and trace element concentrations were associated in a dose-dependent fashion with cord blood metabolites. What remains to be determined is whether these metals- and trace elements-associated changes in cord metabolites can influence a child's risk of cardiometabolic diseases.

Keywords: Cadmium; Child health; Environmental health; Heavy metals; Lead; Manganese; Mercury; Metabolome; Metabolome-wide association study; Metabolomics; Selenium; Trace elements.

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Conflict of interest statement

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.

Figures

**Fig. 1.**
Volcano plots of associations of lead (Panel A), mercury (Panel B), cadmium (Panel C), selenium (Panel D), and manganese (Panel E) with cord metabolites after Bonferroni correction for multiple comparisons among mother-child pairs in the Boston Birth Cohort (n = 670). Models adjusted for maternal age at delivery, race/ethnicity, educational level, pre-pregnancy body mass index, preeclampsia, diabetes mellitus, cigarette smoking history, and second-hand smoking exposure during pregnancy.

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A metabolome-wide association study of in utero metal and trace element exposures with cord blood metabolome profile: Findings from the Boston Birth Cohort

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A metabolome-wide association study of in utero metal and trace element exposures with cord blood metabolome profile: Findings from the Boston Birth Cohort

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Conflict of interest statement

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