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In Vitro Model Systems in Neurotoxicity Assessment

Reyaz Waris Ansari, Govind Singh, Aditya B. Pant

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Nervous system, a complex organ system in terms of both structure and function, is unique in that way that the neurons are not capable of regeneration after lethal damage, thus rendering the nervous system particularly vulnerable to any toxic insult. Any adverse effect on the chemistry, structure and function of the nervous system during development or at maturity, induced by chemical/ its metabolites or physical influences is considered as neurotoxicity. The word adverse can be defined as any treatment-related change, which interferes with normal function and compromises adaptation to the environment" like the morphologic changes such as neuronopathy, axonopathy, or myelinopathy, even if the changes were mild or transitory. However, neurochemical effects in the absence of structural damage are still debatable, whether they should be considered as adverse effects or not. The increasing numbers of chemicals with newer formulations are introduced in our environment workplace without adequate risk assessment many of them still awaits a proper evaluation with regard to their neurotoxic potential. A low-level prolonged exposure to many of them leads to neurological deficits that generally manifest in the later part of life with the advancement of the disease. Laboratory animals, usually rodents, are most frequently used as model systems to assess the neurotoxic endpoints like, mortality, tumor development in selected organs, neurobehavioral changes i.e. learning, locomotary behaviour, aggressive nature and biochemical neuronal injury markers, etc. But such kinds of studies are time-consuming expensive. Further, subtle effects, i.e. slightly diminished learning abilities or immune responses, may be difficult to detect. Finally, there is an ethical financial presser too, to reduce the number of animals used in toxicity testing, particularly if discomfort is involved. Therefore, government, industries, academic institutions regulatory agencies have sought alternative in vitro methods of screening of substances for toxicity, since these in vitro systems are reliable, rapid and reproducible with reduced cost. In vitro cell system got popularized as first tier system for screening at cellular molecular level with regard to their neurotoxic potential mechanism of action, before being subjected to conventional animal toxicity testing. We have focused this article on the use of in vitro systems in neurotoxicity studies and their potential role in a general strategy for neurotoxicology. The advantages and limitations of in vitro approaches for mechanistic studies and for screening of neurotoxicants are discussed.

Most in vitro systems for neurotoxicity make use of mammalian cells. In decreasing order of complexity, these models include organotypic explants, brain slices, reaggregate cultures, primary cell preparations, and established cell lines. It should be noted that with the exception of cell lines all other models involve the use of cells or tissues directly derived from animals. Thus, while the number of animals may be reduced (as in vitro systems allow the testing of multiple concentrations of chemicals and other experimental manipulations in tissue derived from a single animal), other problems inherent to the use of primary cell or tissue cultures still necessitate the use of a substantial number of animals. From the point of view of reducing the number of animals, established cell lines are certainly the system of choice. A benefit of using organotypic explants, brain slices, or reaggregate cultures is that the cytoarchitecture of the nervous system, the neural circuitry of a specific brain area, or other biochemical processes (e.g., myelination), are preserved. Systems using primary cultures, on the other hand, do not offer the retention of neuronal circuitry but allow the study of the effects of toxicants on separate cell types (e.g., neurons,)