Lead Exposure Disrupts Global DNA Methylation in Human Embryonic Stem Cells and Alters Their Neuronal Differentiation
Open accessAbstract
Exposure to lead (Pb) during childhood can result in learning disabilities and behavioral problems. Although described in animal models, whether Pb exposure also alters neuronal differentiation in the developing brains of exposed children is unknown. Here, we investigated the effects of physiologically relevant concentrations of Pb (from 0.4 to 1.9μM) on the capacity of human embryonic stem cells (hESCs) to progress to a neuronal fate. We found that neither acute nor chronic exposure to Pb prevented hESCs from generating neural progenitor cells (NPCs). NPCs derived from hESCs chronically exposed to 1.9μM Pb throughout the neural differentiation process generated 2.5 times more TUJ1-positive neurons than those derived from control hESCs. Pb exposure of hESCs during the stage of neural rosette formation resulted in a significant decrease in the expression levels of the neural marker genes PAX6 and MSI1. Furthermore, the resulting NPCs differentiated into neurons with shorter neurites and less branching than control neurons, as assessed by Sholl analysis. DNA methylation studies of control, acutely treated hESCs and NPCs derived from chronically exposed hESCs using the Illumina HumanMethylation450 BeadChip demonstrated that Pb exposure induced changes in the methylation status of genes involved in neurogenetic signaling pathways. In summary, our study shows that exposure to Pb subtly alters the neuronal differentiation of exposed hESCs and that these changes could be partly mediated by modifications in the DNA methylation status of genes crucial to brain development.
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The top hypomethylated genes are involved in neurological system processes, calcium ion import, and actin cytoskeleton arrangement while the top hypermethylated genes belong to families responsible for calcium ion import and development of neuronal projections.
“The top hypomethylated genes are involved in neurological system processes, calcium ion import, and actin cytoskeleton arrangement while the top hypermethylated genes belong to families responsible for calcium ion import and development of neuronal projections [ 41 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [41]
Lead exposure during neural rosette formation produces shorter neurites and reduces branching compared with controls, whereas lead exposure during later developmental stages increases the number and length of neurites.
“Lead exposure during neural rosette formation produces shorter neurites and reduces branching compared with controls, whereas lead exposure during later developmental stages increases the number and length of neurites [ 41 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [41]
In cultured human embryonic stem cells, physiologically relevant concentrations of lead (0.4-1.9 μM) cause dose-dependent changes in DNA methylation of 1275 genes during neural progenitor differentiation, with the majority displaying DNA hypomethylation.
“In cultured human embryonic stem cells, physiologically relevant concentrations of lead (0.4–1.9 µM) cause dose-dependent changes in DNA methylation of 1275 genes during neural progenitor differentiation, with the majority displaying DNA hypomethylation [ 41 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [41]
Lead-induced changes in DNA methylation are stage specific, with the greatest number of changes observed in differentiating human embryonic stem cells relative to undifferentiated human embryonic stem cells or neural progenitor cells.
“Lead-induced changes in DNA methylation are stage specific, with the greatest number of changes observed in differentiating human embryonic stem cells relative to undifferentiated human embryonic stem cells or neural progenitor cells [ 41 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [41]
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Krencik, R., & Zhang, S.-C. (2006) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2006.10.002 · Cited by 21 · see citing works
Moderate lead exposure elicits neurotrophic effects in cerebral cortical precursor cells in culture
Davidovics, Z. H., & DiCicco-Bloom, E. M. (2005) · Journal of Neuroscience Research · doi:10.1002/jnr.20539 · Cited by 19 · see citing works
Gundacker, C., Scheinast, M., Damjanovic, L., et al. (2011) · Amino Acids · doi:10.1007/s00726-011-1154-1 · Cited by 17 · see citing works
Chang, E.-A., Beyhan, Z., Yoo, M.-S., Siripattarapravat, K., Ko, T., Lookingland, K. J., Madhukar, B. V., & Cibelli, J. B. (2009) · The International Journal of Developmental Biology · doi:10.1387/ijdb.092851ec · Cited by 15 · see citing works
Baek, D. H., Park, S. H., Park, J. H., et al. (2011) · International Journal of Toxicology · doi:10.1177/1091581811416522 · Cited by 10 · see citing works
Panel Advises Tougher Limits on Lead Exposure
Kuehn, B. M. (2012) · JAMA · doi:10.1001/jama.2012.50 · Cited by 10 · see citing works
Alicea, B., Murthy, S., Keaton, S. A., Cobbett, P. J., Cibelli, J. B., & Suhr, S. T. (2013) · Stem Cells and Development · doi:10.1089/scd.2013.0040 · Cited by 6 · see citing works
Low-Level Lead Exposure and Contingency-Based Responding in Preschoolers: An Exploratory Study
Nelson, M. M., & Espy, K. A. (2009) · Developmental Neuropsychology · doi:10.1080/87565640902964565 · Cited by 3 · see citing works
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Keil, K. P., & Lein, P. J. (2016) · Environmental Epigenetics · doi:10.1093/eep/dvv012 · Cited by 167 · see citing works
Exposure of metal toxicity in Alzheimer’s disease: An extensive review
Islam, F., Shohag, S., Akhter, S., Islam, M. R., Sultana, S., Mitra, S., Chandran, D., Khandaker, M. U., Ashraf, G. M., Idris, A. M., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.903099 · Cited by 83 · see citing works
Dendritic spine actin cytoskeleton in autism spectrum disorder
Joensuu, M., Lanoue, V., & Hotulainen, P. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.08.023 · Cited by 65 · see citing works
Sex- and tissue-specific methylome changes in brains of mice perinatally exposed to lead
Sánchez-Martín, F. J., Lindquist, D. M., Landero-Figueroa, J., Zhang, X., Chen, J., Cecil, K. M., Medvedovic, M., & Puga, A. (2015) · NeuroToxicology · doi:10.1016/j.neuro.2014.12.004 · Cited by 43 · see citing works
- Authors
- Senut, M.-C., Sen, A., Cingolani, P., Shaik, A., Land, S. J., & Ruden, D. M.
- Affiliations
- Wayne State University (US)
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-02-14
- Volume
- 139
- Issue
- 1
- Pages
- 142-161
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- PMC
- PMC4023291
- OpenAlex
- W2120806558
- Cited by
- 135
- References
- 95
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 8 · 2023: 11 · 2022: 11 · 2021: 11 · 2020: 11 · 2019: 12 · 2018: 10 · 2017: 10 · 2016: 17 · 2015: 10 · 2014: 4
- FWCI
- 8.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Michigan State University
- National Cancer Institute (P30CA022453)
- National Institute of Environmental Health Sciences (ES012933, P30ES020957, R01ES012933, R21ES021983)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- lead exposure, DNA methylation, human embryonic stem cells, neuronal differentiation, neural progenitor cells, brain development, Pax6, MSI1, neurite branching
- MeSH terms
- Base Sequence, Cell Differentiation, Humans, Lead, Neurons, DNA Primers, DNA Methylation, Embryonic Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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