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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Environmentally relevant developmental methylmercury exposures alter neuronal differentiation in a human-induced pluripotent stem cell model.

Authors: Prince, Lisa M; Neely, M Diana; Warren, Emily B; Thomas, Morgan G; Henley, Madeline R; Smith, Kiara K; Aschner, Michael; Bowman, Aaron B

Published In Food Chem Toxicol, (2021 Jun)

Abstract: Developmental methylmercury (MeHg) exposure selectively targets the cerebral and cerebellar cortices, as seen by disruption of cytoarchitecture and glutamatergic (GLUergic) neuron hypoplasia. To begin to understand the mechanisms of this loss of GLUergic neurons, we aimed to develop a model of developmental MeHg neurotoxicity in human-induced pluripotent stem cells differentiating into cortical GLUergic neurons. Three dosing paradigms at 0.1 μM and 1.0 μM MeHg, which span different stages of neurodevelopment and reflect toxicologically relevant accumulation levels seen in human studies and mammalian models, were established. With these exposure paradigms, no changes were seen in commonly studied endpoints of MeHg toxicity, including viability, proliferation, and glutathione levels. However, MeHg exposure induced changes in mitochondrial respiration and glycolysis and in markers of neuronal differentiation. Our novel data suggests that GLUergic neuron hypoplasia seen with MeHg toxicity may be due to the partial inhibition of neuronal differentiation, given the increased expression of the early dorsal forebrain marker FOXG1 and corresponding decrease in expression on neuronal markers MAP2 and DCX and the deep layer cortical neuronal marker TBR1. Future studies should examine the persistent and latent functional effects of this MeHg-induced disruption of neuronal differentiation as well as transcriptomic and metabolomic alterations that may mediate MeHg toxicity.

PubMed ID: 33831500 Exiting the NIEHS site

MeSH Terms: Cell Differentiation/drug effects*; Cell Proliferation/drug effects; Cell Survival/drug effects; Doublecortin Domain Proteins; Doublecortin Protein; Forkhead Transcription Factors/metabolism; Glutathione/metabolism; Humans; Induced Pluripotent Stem Cells/drug effects*; Methylmercury Compounds/toxicity*; Microtubule-Associated Proteins/metabolism; Nerve Tissue Proteins/metabolism; Neurons/drug effects*; Neuropeptides/metabolism; No-Observed-Adverse-Effect Level

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Last Reviewed: October 07, 2024