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Title: Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood

Abstract

Here, lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk. The objective of this study was to determine whether maternal, postnatal, and early childhood lead exposure can alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth, and development. Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. When participants were adults, we used Sequenom EpiTYPER assays to test peripheral blood DNA to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes. Statistical analyses were conducted using linear regression. Mean blood lead concentration from birth to 78 months was associated with a significant decrease in PEG3 DMR methylation (β = –0.0014; 95% CI: –0.0023, –0.0005, p = 0.002), stronger in males (β = –0.0024; 95% CI: –0.0038, –0.0009, p = 0.003) than in females (β = –0.0009; 95% CI: –0.0020, 0.0003, p = 0.1). Elevated mean childhood blood leadmore » concentration was also associated with a significant decrease in IGF2/H19 (β = –0.0013; 95% CI: –0.0023, –0.0003, p = 0.01) DMR methylation, but primarily in females, (β = –0.0017; 95% CI: –0.0029, –0.0006, p = 0.005) rather than in males, (β = –0.0004; 95% CI: –0.0023, 0.0015, p = 0.7). Elevated blood lead concentration during the neonatal period was associated with higher PLAGL1/HYMAI DMR methylation regardless of sex (β = 0.0075; 95% CI: 0.0018, 0.0132, p = 0.01). The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months. Our findings provide evidence that early childhood lead exposure results in sexdependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19, and PLAGL1/HYMAI in adulthood.« less

Authors:
 [1];  [2];  [1];  [3];  [4];  [1];  [5];  [6];  [7];  [3];  [8]
  1. Duke Univ., Durham, NC (United States)
  2. Univ. of Cincinnati, OH (United States)
  3. North Carolina State Univ., Raleigh, NC (United States)
  4. Univ. of North Carolina, Chapel Hill, NC (United States)
  5. Univ. of Cincinnati, Cincinnati, OH (United States), College of Medicine
  6. Univ. of Cincinnati, OH (United States). College of Medicine
  7. Univ. of Cincinnati, Cincinnati, OH (United States). College of Medicine
  8. North Carolina State Univ., Raleigh, NC (United States); Duke Univ., Durham, NC (United States)
Publication Date:
Research Org.:
North Carolina State Univ., Raleigh, NC (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1395575
Grant/Contract Number:  
FG02-10ER64931; SC0003778
Resource Type:
Accepted Manuscript
Journal Name:
Environmental Health Perspectives
Additional Journal Information:
Journal Volume: 124; Journal Issue: 5; Journal ID: ISSN 0091-6765
Publisher:
National Institute of Environmental Health Sciences
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Li, Yue, Xie, Changchun, Murphy, Susan K., Skaar, David, Nye, Monica, Vidal, Adriana C., Cecil, Kim M., Dietrich, Kim N., Puga, Alvaro, Jirtle, Randy L., and Hoyo, Cathrine. Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood. United States: N. p., 2015. Web. doi:10.1289/ehp.1408577.
Li, Yue, Xie, Changchun, Murphy, Susan K., Skaar, David, Nye, Monica, Vidal, Adriana C., Cecil, Kim M., Dietrich, Kim N., Puga, Alvaro, Jirtle, Randy L., & Hoyo, Cathrine. Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood. United States. doi:10.1289/ehp.1408577.
Li, Yue, Xie, Changchun, Murphy, Susan K., Skaar, David, Nye, Monica, Vidal, Adriana C., Cecil, Kim M., Dietrich, Kim N., Puga, Alvaro, Jirtle, Randy L., and Hoyo, Cathrine. Fri . "Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood". United States. doi:10.1289/ehp.1408577. https://www.osti.gov/servlets/purl/1395575.
@article{osti_1395575,
title = {Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood},
author = {Li, Yue and Xie, Changchun and Murphy, Susan K. and Skaar, David and Nye, Monica and Vidal, Adriana C. and Cecil, Kim M. and Dietrich, Kim N. and Puga, Alvaro and Jirtle, Randy L. and Hoyo, Cathrine},
abstractNote = {Here, lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk. The objective of this study was to determine whether maternal, postnatal, and early childhood lead exposure can alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth, and development. Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. When participants were adults, we used Sequenom EpiTYPER assays to test peripheral blood DNA to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes. Statistical analyses were conducted using linear regression. Mean blood lead concentration from birth to 78 months was associated with a significant decrease in PEG3 DMR methylation (β = –0.0014; 95% CI: –0.0023, –0.0005, p = 0.002), stronger in males (β = –0.0024; 95% CI: –0.0038, –0.0009, p = 0.003) than in females (β = –0.0009; 95% CI: –0.0020, 0.0003, p = 0.1). Elevated mean childhood blood lead concentration was also associated with a significant decrease in IGF2/H19 (β = –0.0013; 95% CI: –0.0023, –0.0003, p = 0.01) DMR methylation, but primarily in females, (β = –0.0017; 95% CI: –0.0029, –0.0006, p = 0.005) rather than in males, (β = –0.0004; 95% CI: –0.0023, 0.0015, p = 0.7). Elevated blood lead concentration during the neonatal period was associated with higher PLAGL1/HYMAI DMR methylation regardless of sex (β = 0.0075; 95% CI: 0.0018, 0.0132, p = 0.01). The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months. Our findings provide evidence that early childhood lead exposure results in sexdependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19, and PLAGL1/HYMAI in adulthood.},
doi = {10.1289/ehp.1408577},
journal = {Environmental Health Perspectives},
number = 5,
volume = 124,
place = {United States},
year = {2015},
month = {6}
}

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    Works referencing / citing this record:

    Association of blood leukocyte DNA methylation at LINE-1 and growth-related candidate genes with pubertal onset and progression
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