Lead Induces Similar Gene Expression Changes in Brains of Gestationally Exposed Adult Mice and in Neurons Differentiated from Mouse Embryonic Stem Cells

Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati, College of Medicine, Cincinnati, Ohio, United States of America.
PLoS ONE (Impact Factor: 3.23). 11/2013; 8(11):e80558. DOI: 10.1371/journal.pone.0080558
Source: PubMed


Exposure to environmental toxicants during embryonic life causes changes in the expression of developmental genes that may last for a lifetime and adversely affect the exposed individual. Developmental exposure to lead (Pb), an ubiquitous environmental contaminant, causes deficits in cognitive functions and IQ, behavioral effects, and attention deficit hyperactivity disorder (ADHD). Long-term effects observed after early life exposure to Pb include reduction of gray matter, alteration of myelin structure, and increment of criminal behavior in adults. Despite growing research interest, the molecular mechanisms responsible for the effects of lead in the central nervous system are still largely unknown. To study the molecular changes due to Pb exposure during neurodevelopment, we exposed mice to Pb in utero and examined the expression of neural markers, neurotrophins, transcription factors and glutamate-related genes in hippocampus, cortex, and thalamus at postnatal day 60. We found that hippocampus was the area where gene expression changes due to Pb exposure were more pronounced. To recapitulate gestational Pb exposure in vitro, we differentiated mouse embryonic stem cells (ESC) into neurons and treated ESC-derived neurons with Pb for the length of the differentiation process. These neurons expressed the characteristic neuronal markers Tubb3, Syp, Gap43, Hud, Ngn1, Vglut1 (a marker of glutamatergic neurons), and all the glutamate receptor subunits, but not the glial marker Gafp. Importantly, several of the changes observed in Pb-exposed mouse brains in vivo were also observed in Pb-treated ESC-derived neurons, including those affecting expression of Ngn1, Bdnf exon IV, Grin1, Grin2D, Grik5, Gria4, and Grm6. We conclude that our ESC-derived model of toxicant exposure during neural differentiation promises to be a useful model to analyze mechanisms of neurotoxicity induced by Pb and other environmental agents.

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Available from: Alvaro Puga, May 21, 2014
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    • "Despite the growing research, the molecular mechanisms responsible for the effect of Pb in the central nervous system are still not completely clarified (Sánchez-Martín et al. 2013). It is largely accepted that neurotoxicity of lead occurs through multiple mechanisms of action. "
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    • "In addition, the axonal guidance PLXN4 (Waimey et al., 2008) and the neuronal differentiation factor NEUROG1 (Sun et al., 2001) were found to be hypermethylated and hypomethylated, respectively, in Pb-exposed differentiating hESCs. Interestingly, an increase in NEUROG1 expression was recently reported in mouse brains exposed to Pb during gestation and in neurons derived from Pb-treated mouse ESCs (Sanchez-Martin et al., 2013). Because methylation changes close to the transcription start site may impact gene expression, hypomethylation of NEUROG1 in Pbexposed differentiating cells could be in part involved in the morphological effects we observed in the generated neurons. "
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