Journal
ARCHIVES OF TOXICOLOGY
Volume 87, Issue 4, Pages 721-733Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-012-0984-2
Keywords
Human embryonic stem cells; Neurospheres; Developmental neurotoxicity (DNT); Polyethylene nanoparticles; Methylmercury
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Funding
- Doerenkamp-Zbinden Foundation
- EU-FP7 ESNATS project
- Konstanz Research School Chemical Biology
- Agency for Science and Technology Research
- [SF0690063s08]
- [ETF8561]
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Nanoparticles (NPs) have been shown to accumulate in organs, cross the blood-brain barrier and placenta, and have the potential to elicit developmental neurotoxicity (DNT). Here, we developed a human embryonic stem cell (hESC)-derived 3-dimensional (3-D) in vitro model that allows for testing of potential developmental neurotoxicants. Early central nervous system PAX6(+) precursor cells were generated from hESCs and differentiated further within 3-D structures. The 3-D model was characterized for neural marker expression revealing robust differentiation toward neuronal precursor cells, and gene expression profiling suggested a predominantly forebrain-like development. Altered neural gene expression due to exposure to non-cytotoxic concentrations of the known developmental neurotoxicant, methylmercury, indicated that the 3-D model could detect DNT. To test for specific toxicity of NPs, chemically inert polyethylene NPs (PE-NPs) were chosen. They penetrated deep into the 3-D structures and impacted gene expression at non-cytotoxic concentrations. NOTCH pathway genes such as HES5 and NOTCH1 were reduced in expression, as well as downstream neuronal precursor genes such as NEUROD1 and ASCL1. FOXG1, a patterning marker, was also reduced. As loss of function of these genes results in severe nervous system impairments in mice, our data suggest that the 3-D hESC-derived model could be used to test for Nano-DNT.
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