A Human Stem Cell-Based Model for Identifying Adverse Effects of Organic and Inorganic Chemicals on the Developing Nervous System

Abstract

The aim of our study was to investigate whether a human neural stem cell line derived from umbilical cord blood (HUCB-NSC) can serve as a reliable test model for developmental neurotoxicity (DNT). We assessed the sensitivity of HUCB-NSCs at different developmental stages to a panel of neurotoxic (sodium tellurite, methylmercury chloride, cadmium chloride, chlorpyrifos, and L-glutamate) and non-neurotoxic (acetaminophen, theophylline, and D-glutamate) compounds. In addition, we investigated the effect of some compounds on key neurodevelopmental processes like cell proliferation, apoptotic cell death, and neuronal and glial differentiation. Less differentiated HUCB-NSCs were generally more sensitive to neurotoxicants, with the notable exception of L-glutamate, which showed a higher toxicity to later stages. The relative potencies of the compounds were: cadmium chloride > methylmercury chloride ) chlorpyrifos ) L-glutamate. Fifty nanomolar methylmercury chloride (MeHgCl) inhibited proliferation and induced apoptosis in early-stage cells. At the differentiated stage, 1 lM MeHgCl induced selective loss of S100b-expressing astrocytic cells. One millimolar L-glutamate did not influence the early stages of HUCB-NSC development, but it affected late stages of neuronal differentiation. A valuable system for in vitro DNT assessment should be able to discriminate between neurotoxic and non-neurotoxic compounds and show different susceptibilities to chemicals according to developmental stage and cell lineage. Although not exhaustive, this work shows that the HUCB-NSC model fulfils these criteria and may serve as a human in vitro model for DNT priority setting. STEM

Advancing the science of developmental neurotoxicity (DNT): testing for better safety evaluation

“…Some of the major hurdles associated with in vitro screening are minimized when testing with an intact organism. Because the zebrafish liver mahave been further developed and characterized, especially for their DNt testing applicability ((i): Sun et al, 2005;Jurga et al, 2006;Buzanska et al, 2009;Zychowicz et al, 2011;(ii) : Moors et al, 2007: Moors et al, , 2009Schreiber et al, 2010;Gassmann et al, 2010;tegenge et al, 2010;Fritsche et al, 2011). Human embryonic stem cells were recently differentiated in vitro for the purpose of DNt testing.…”

Current standing and future prospects for the technologies proposed to transform toxicity testing in the 21st century

“…Current in vivo-based test guidelines for developmental neurotoxicity are too timely and costly to test large numbers of chemicals. To develop a more efficient paradigm, embryonic and adult stem cells are extensively used to evaluate the adverse effects of chemicals on processes of neurodevelopment (Kuegler et al, 2010;Moors et al, 2009;Buzanska et al, 2009). A recent high content screening study measuring viability, proliferation, migration, and differentiation of neural progenitor cells showed promising results in prediction of in vivo developmental neurotoxicity (Breier et al, 2010).…”

Cellular models for disease exploring and drug screening

“…Patient-specific multipotent cells, including cord blood origin stem cells (Theoharides et al, 2006) and adult stem cells (Jakel et al, 2004;Dan and Yeoh, 2008;Buzanska et al, 2009), are better disease model candidates compared with primary or immortalized cells. Disease-specific cells can facilitate the study of disease-related genes and provide a platform to investigate the relationship between differentiation and pathogenesis.…”