A 3-dimensional human embryonic stem cell (hESC)-derived model to detect developmental neurotoxicity of nanoparticles

• DOI: 10.1007/s00204-012-0984-2
• Publication Date: 2012-12-01T08:01:11Z
• Authors: Lisa Hoelting; Benjamin Scheinhardt; Olesja Bondarenko; Stefan Schildknecht; Marion Kapitza; Vivek Tanavde; Betty Tan; Qian Yi Lee; Stefan Mecking; Marcel Leist; Suzanne Kadereit
• Keywords: info:eu-repo/classification/ddc/570; Neurons; 0301 basic medicine; 0303 health sciences; Cell Survival; Health, Toxicology and Mutagenesis; Gene Expression Profiling; Cell Culture Techniques; Gene Expression Regulation, Developmental; Cell Differentiation; Cells, Immobilized; Methylmercury Compounds; Toxicology; Cell Line; 3. Good health; In Vitro Systems; 03 medical and health sciences; Polyethylene; Humans; Nanoparticles; Cells, Cultured; Embryoid Bodies; Embryonic Stem Cells

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.