title: A 3-dimensional human embryonic stem cell (hESC)-derived model to detect developmental neurotoxicity of nanoparticles.
abstract: 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.
authors.affiliation: Department of Biology, University of Konstanz, Universitaetsstrasse 10, 78457 Konstanz, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Hoelting
authors.forename: Benjamin
authors.initials: B
authors.lastname: Scheinhardt
authors.forename: Olesja
authors.initials: O
authors.lastname: Bondarenko
authors.forename: Stefan
authors.initials: S
authors.lastname: Schildknecht
authors.forename: Marion
authors.initials: M
authors.lastname: Kapitza
authors.forename: Vivek
authors.initials: V
authors.lastname: Tanavde
authors.forename: Betty
authors.initials: B
authors.lastname: Tan
authors.forename: Qian Yi
authors.initials: QY
authors.lastname: Lee
authors.forename: Stefan
authors.initials: S
authors.lastname: Mecking
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kadereit
mesh_terms: D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018914:Cells, Immobilized / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058732:Embryoid Bodies / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006801:Humans; D008767:Methylmercury Compounds / Q000633:toxicity; D053758:Nanoparticles / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D020959:Polyethylene / Q000633:toxicity*
chemical_list: D008767:Methylmercury Compounds; D020959:Polyethylene