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Phenotypic screening for developmental neurotoxicity: mechanistic data at the level of the cell
Citation:
Mundy, W. Phenotypic screening for developmental neurotoxicity: mechanistic data at the level of the cell. Developmental Neurotoxicology Society, San Antonio, TX, June 26 - 29, 2016.
Impact/Purpose:
This work describes the organizing principles by which mechanistic data at the level of the cell can be used to better incorporate mode-of-action into risk assessment decisions. It will be presented at a symposium entitled "Systematic evaluation of mechanistic data for developmental neurotoxicity outcomes".
Description:
There are large numbers of environmental chemicals with little or no available information on their toxicity, including developmental neurotoxicity. Because of the resource-intensive nature of traditional animal tests, high-throughput (HTP) methods that can rapidly evaluate chemicals for the potential to affect the developing brain are being explored. Typically, HTP screening uses biochemical and molecular assays to detect the interaction of a chemical with a known target or molecular initiating event (e.g., the mechanism of action). For developmental neurotoxicity, however, the mechanism(s) is often unknown. Thus, we have developed assays for detecting chemical effects on the key events of neurodevelopment at the cellular level (e.g., proliferation, differentiation, neurite growth, synaptogenesis, network formation). Cell-based assays provide a test system at a level of biological complexity that encompasses many potential neurotoxic mechanisms. For example, phenotypic assessment of neurite outgrowth at the cellular level can detect chemicals that target kinases, ion channels, or esterases at the molecular level. The results from cell-based assays can be placed in a conceptual framework using an Adverse Outcome Pathway (AOP) which links molecular, cellular, and organ level effects with apical measures of developmental neurotoxicity. Testing a wide range of concentrations allows for the distinction between selective effects on neurodevelopmental and non-specific changes in cell viability. It is often difficult, however, to extrapolate effective in vitro concentrations to in vivo doses. The relative value of mechanistic data at the cellular level can be considered in terms of both the biological relevance (e.g., primary cells versus cell lines, brain region, animal versus human origin) and complexity (e.g., number of cell types represented, connectivity) of the cell models used. For example, chemical effects on synaptogenesis in a complex primary neural culture would be interpreted differently than effects observed in a neural cell line. Similarly, results from human neural models can be different from those derived from rodent models, and may be more relevant to human adverse effects.