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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Lead exposure disrupts global DNA methylation in human embryonic stem cells and alters their neuronal differentiation.

Authors: Senut, Marie-Claude; Sen, Arko; Cingolani, Pablo; Shaik, Asra; Land, Susan J; Ruden, Douglas M

Published In Toxicol Sci, (2014 May)

Abstract: 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.

PubMed ID: 24519525 Exiting the NIEHS site

MeSH Terms: Base Sequence; Cell Differentiation/drug effects*; DNA Methylation/drug effects*; DNA Primers; Embryonic Stem Cells/cytology; Embryonic Stem Cells/drug effects*; Humans; Lead/toxicity*; Neurons/cytology; Neurons/drug effects*

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