Using Pluripotent Stem Cells and Their Progeny as an
            <i>In Vitro</i>
            Model to Assess (Developmental) Neurotoxicity

Hoelting, Lisa; Leist, Marcel; Stoppini, Luc

doi:10.1002/9783527674183.ch13

Cited by 3 publications

(2 citation statements)

References 237 publications

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“…Because of this, the availability of human iPSC and their differentiated derivatives is critical for properly understanding the human nervous system biology including neurotoxicity and development neurotoxicology (Hoelting et al, 2014; Hou et al, 2013; Maldonado-Soto et al, 2014). Our results demonstrate that it is important to test toxicity on specific cells types as significant differences in responses were seen between different neural cells (e.g., neurons versus astrocytes).…”

Section: Discussionmentioning

confidence: 99%

Comparative neurotoxicity screening in human iPSC-derived neural stem cells, neurons and astrocytes

et al. 2016

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Induced pluripotent stem cells (iPSC) and their differentiated derivatives offer a unique source of human primary cells for toxicity screens. Here, we report on the comparative cytotoxicity of 80 compounds (neurotoxicants, developmental neurotoxicants, environmental compounds) in iPSC as well as isogenic iPSC-derived neural stem cells (NSC), neurons, and astrocytes. All compounds were tested over a 24-hour period at 10 and 100 μM, in duplicate, with cytotoxicity measured using the MTT assay. Of the 80 compounds tested, 50 induced significant cytotoxicity in at least one cell type; per cell type, 32, 38, 46, and 41 induced significant cytotoxicity in iPSC, NSC, neurons, and astrocytes, respectively. Four compounds (valinomycin, 3,3′,5,5′-tetrabromobisphenol, deltamethrin, triphenyl phosphate) were cytotoxic in all four cell types. Retesting these compounds at 1, 10, and 100 μM using the same exposure protocol yielded consistent results as compared with the primary screen. Using rotenone, we extended the testing to seven additional iPSC lines of both genders; no substantial difference in the extent of cytotoxicity was detected among the cell lines. Finally, the cytotoxicity assay was simplified by measuring luciferase activity using lineage-specific luciferase reporter iPSC lines which were generated from the parental iPSC line.

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Section: Discussionmentioning

confidence: 99%

Comparative neurotoxicity screening in human iPSC-derived neural stem cells, neurons and astrocytes

et al. 2016

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“…These ‘fundamental biological/neurodevelopmental processes’ include neural cell proliferation and differentiation, neuronal and glial cell migration, axonal and dendritic outgrowth as well as synapse formation and stabilization, apoptosis and myelination (Fig. 1) (Hoelting et al, 2015; Smirnova et al, 2015; van Thriel et al, 2012). Additional overarching processes, mostly limited to pathological situations reflect different states of glial activation, often termed neuroinflammation (Falsig et al, 2004; Kuegler et al, 2010; 2012; Zerrate et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use

Aschner

Ceccatelli

Daneshian

et al. 2016

ALTEX

127

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SummaryThere is a paucity of information concerning the developmental neurotoxicity (DNT) hazard posed by industrial and environmental chemicals. New testing approaches will most likely be based on batteries of alternative and complementary (non-animal) tests. As DNT is assumed to result from the modulation of fundamental neurodevelopmental processes (such as neuronal differentiation, precursor cell migration or neuronal network formation) by chemicals, the first generation of alternative DNT tests target these processes. The advantage of such types of assays is that they capture toxicants with multiple targets and modes-of-action. Moreover, the processes modelled by the assays can be linked to toxicity endophenotypes, i.e. alterations in neural connectivity that form the basis for neurofunctional deficits in man. The authors of this review convened in a workshop to define criteria for the selection of positive/negative controls, to prepare recommendations on their use, and to initiate the setup of a directory of reference chemicals. For initial technical optimization of tests, a set of >50 endpoint-specific control compounds was identified. For further test development, an additional “test” set of 33 chemicals considered to act directly as bona fide DNT toxicants is proposed, and each chemical is annotated to the extent it fulfills these criteria. A tabular compilation of the original literature used to select the test set chemicals provides information on statistical procedures, and toxic/non-toxic doses (both for pups and dams). Suggestions are provided on how to use the >100 compounds (including negative controls) compiled here to address specificity, adversity and use of alternative test systems.

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Literature review on in vitro and alternative Developmental Neurotoxicity (DNT) testing methods

Fritsche

Alm

Baumann

et al. 2015

EFSA Supporting Publications

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The goal of this systematic review performed under a contract with EFSA was the evaluation of information on assessment methods in the field of developmental neurotoxicity (DNT). Therefore, a systematic and comprehensive literature search and collection of scientific literature and all other relevant grey literature and website information (in English) from past 20 years until mid of April 2014 on the state of the art of in vivo DNT testing methods including novel and alternative non-mammalian models, in vitro test methods, in silico methods, read across and combination of testing methods in test batteries was performed. This systematic review identified a variety of methods covering early and later stages of neurodevelopment that have the ability to predict DNT of chemicals. Few in vivo models alternative to OECD TG 426 were identified. In general, the available published in vivo data is scattered and heterogeneous, making comparisons across exposure paradigms and compounds very difficult. Thus, to make more useful evaluations, publications with more consistent experimental designs are needed, and more focused in vivo-in vitro comparisons are needed to establish useful effect biomarkers and testing models. From the alternative methods, a testing strategy covering early and later neurodevelopmental stages (from stem cell to zebrafish larvae motor behaviour) can be assembled. For gaining regulatory acceptance, definition of biological application domains of alternative methods by performing e.g. in vitro -in vivo validation is needed. Moreover, protocols for cell-based and zebrafish assays need international standardization. With such standardized protocols, the test battery needs to be tested for its sensitivity and specificity by testing concentration-responses of known DNT positive and negative compounds across the different assays. Such data might then be used either for regulatory decision-making or compound prioritization in favour of a reduction of rodent guideline in vivo testing.

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Using Pluripotent Stem Cells and Their Progeny as an In Vitro Model to Assess (Developmental) Neurotoxicity

Cited by 3 publications

References 237 publications

Comparative neurotoxicity screening in human iPSC-derived neural stem cells, neurons and astrocytes

Comparative neurotoxicity screening in human iPSC-derived neural stem cells, neurons and astrocytes

Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use

Literature review on in vitro and alternative Developmental Neurotoxicity (DNT) testing methods

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