Dataset Information

Neonatal Lead (Pb) Exposure and DNA Methylation Profiles in Dried Bloodspots.

ABSTRACT: Lead (Pb) exposure remains a major concern in the United States (US) and around the world, even following the removal of Pb from gasoline and other products. Environmental Pb exposures from aging infrastructure and housing stock are of particular concern to pregnant women, children, and other vulnerable populations. Exposures during sensitive periods of development are known to influence epigenetic modifications which are thought to be one mechanism of the Developmental Origins of Health and Disease (DOHaD) paradigm. To gain insights into early life Pb exposure-induced health risks, we leveraged neonatal dried bloodspots in a cohort of children from Michigan, US to examine associations between blood Pb levels and concomitant DNA methylation profiles (n = 96). DNA methylation analysis was conducted via the Infinium MethylationEPIC array and Pb levels were assessed via high resolution inductively coupled plasma mass spectrometry (HR-ICP-MS). While at-birth Pb exposure levels were relatively low (average 0.78 µg/dL, maximum of 5.27 ug/dL), we identified associations between DNA methylation and Pb at 33 CpG sites, with the majority (82%) exhibiting reduced methylation with increasing Pb exposure (q < 0.2). Biological pathways related to development and neurological function were enriched amongst top differentially methylated genes by p-value. In addition to increases/decreases in methylation, we also demonstrate that Pb exposure is related to increased variability in DNA methylation at 16 CpG sites. More work is needed to assess the accuracy and precision of metals assessment using bloodspots, but this study highlights the utility of this unique resource to enhance environmental epigenetics research around the world.

SUBMITTER: Montrose L

PROVIDER: S-EPMC7559513 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Neonatal Lead (Pb) Exposure and DNA Methylation Profiles in Dried Bloodspots.

Montrose Luke L Goodrich Jaclyn M JM Morishita Masako M Kochmanski Joseph J Klaver Zachary Z Cavalcante Raymond R Lumeng Julie C JC Peterson Karen E KE Dolinoy Dana C DC

International journal of environmental research and public health 20200917 18

Lead (Pb) exposure remains a major concern in the United States (US) and around the world, even following the removal of Pb from gasoline and other products. Environmental Pb exposures from aging infrastructure and housing stock are of particular concern to pregnant women, children, and other vulnerable populations. Exposures during sensitive periods of development are known to influence epigenetic modifications which are thought to be one mechanism of the Developmental Origins of Health and Dis ...[more]

PMID: 32957503

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Project description:Lead (Pb) exposure is often determined through the analysis of whole blood though venipuncture poses ethical, economic, and logistical barriers. Dried Blood Spots (DBS) may help overcome such barriers though past studies measuring Pb in DBS have been challenged with quality control, small sample volumes, and other issues. Total Reflection X-Ray Fluorescence (TXRF) may help address some of these challenges but has yet to be used to measure Pb in DBS. As such, the aim of the current study was to develop, validate, and apply a method to analyze Pb in DBS samples using TXRF for use in human biomonitoring studies. First, we developed a novel method (tested a range of parameters), and then used blood reference materials to validate the method against performance criteria listed in ICH Q2A and Q2B and the European Bioanalysis Forum. Finally, we applied the method to two populations who exemplify divergent conditions (41 university members with relatively low Pb exposures sampled in a clinical environment; 40 electronic waste workers with relatively high Pb exposures sampled in a contaminated field setting). The limits of detection and quantification of the method were 0.28 and 0.69 μg/dL, respectively. The overall precision and accuracy of the method were 15% and 111%, respectively. The mean (±SD) DBS Pb levels by TXRF in the university members and e-waste workers were 0.78 (±0.46) and 3.78 (±3.01) μg/dL, respectively, and these were not different from Pb measures in venous whole blood using ICP-MS. Bland-Altman plot analyses indicated good agreement between DBS Pb measures by TXRF versus whole blood Pb measures by ICP-MS in both groups. By combining data from the two population groups, there was no significant constant bias (intercept of 0.02 μg/dL) or proportional bias (slope was -0.02) between the two measures, and the lower and upper LoA were -0.86 and 0.91 μg/dL, respectively, with a LoA range of 1.77 μg/dL. These results demonstrate that TXRF-based analysis of Pb content in DBS is a good alternative to the gold standard (i.e., ICP-MS analysis of whole blood), and helps overcome some of the challenges associated with current methods.

Project description:BackgroundGestational lead (Pb) exposure can adversely affect offspring health through multiple mechanisms, including epigenomic alterations via DNA methylation (5mC) and hydroxymethylation (5hmC), an intermediate in oxidative demethylation. Most current methods do not distinguish between 5mC and 5hmC, limiting insights into their individual roles.ObjectiveOur study sought to identify the association of trimester-specific (T1, T2, T3) prenatal Pb exposure with 5mC and 5hmC levels at multiple cytosine-phosphate-guanine sites within gene regions previously associated with prenatal Pb (HCN2, NINJ2, RAB5A, TPPP) in whole blood leukocytes of children ages 11-18 years of age.MethodsParticipants from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were selected (n=144) for pyrosequencing analysis following oxidative or standard sodium bisulfite treatment. This workflow directly quantifies total methylation (5mC+5hmC) and 5mC only; 5hmC is estimated by subtraction.ResultsParticipants were 51% male, and mean maternal blood lead levels (BLL) were 6.43±5.16μg/dL in Trimester 1 (T1), 5.66±5.21μg/dL in Trimester 2 (T2), and 5.86±4.34μg/dL in Trimester 3 (T3). In addition, 5hmC levels were calculated for HCN2 (mean±standard deviation(SD), 2.08±4.18%), NINJ2 (G/C: 2.01±5.95; GG: 0.90±3.97), RAB5A (0.66±0.80%), and TPPP (1.11±6.67%). Furthermore, 5mC levels were measured in HCN2 (81.3±9.63%), NINJ2 (heterozygotes: 38.6±7.39%; GG homozygotes: 67.3±9.83%), RAB5A (1.41±1.21%), and TPPP (92.5±8.03%). Several significant associations between BLLs and 5mC/5hmC were identified: T1 BLLs with 5mC in HCN2 (β=-0.37, p=0.03) and 5hmC in NINJ2 (β=0.49, p=0.003); T2 BLLs with 5mC in HCN2 (β=0.37, p=0.03) and 5hmC in NINJ2 (β=0.27, p=0.008); and T3 BLLs with 5mC in HCN2 (β=0.50, p=0.01) and NINJ2 (β=-0.35, p=0.004) and 5hmC in NINJ2 (β=0.45, p<0.001). NINJ2 5mC was negatively correlated with gene expression (Pearson r=-0.5, p-value=0.005), whereas 5hmC was positively correlated (r=0.4, p-value=0.04).DiscussionThese findings suggest there is variable 5hmC in human whole blood and that prenatal Pb exposure is associated with gene-specific 5mC and 5hmC levels at adolescence, providing evidence to consider 5hmC as a regulatory mechanism that is responsive to environmental exposures. https://doi.org/10.1289/EHP8507.

Dataset Information

Neonatal Lead (Pb) Exposure and DNA Methylation Profiles in Dried Bloodspots.

Publications

Neonatal Lead (Pb) Exposure and DNA Methylation Profiles in Dried Bloodspots.

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