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Trimethyltin as a Model to Explore Mechanisms of Selective Neuronal Death, Glial Reactivity, and Repair

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Handbook of Neurotoxicity

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Abstract

Animal models recapitulating aspects of human disease have been extensively employed to experimentally explore underlying cellular, organ, or systemic pathological mechanisms. The power of any model lies in understanding the specificity of the pathology and the underlying initiating mechanism of action including the fact that organ dysfunction is not a cell autonomous event but involves cell-cell interactions. Compounds like kainic acid and glutamate that induce excitotoxicity and ischemia/hypoxia resulting from a loss of oxygen represent defined mechanisms of neurotoxicity; however, with human exposures to environmental compounds or pharmacological agents or in disease processes, the mechanisms of toxicity are not as well defined. This opens up a role for other less defined models. One such exposure model for neurotoxicity is the tri-organotin compound, trimethyltin. Interesting aspects of this compound are the similarity of the pattern of neuropathology across species, the relatively similar exposure levels for damage, the absence of infiltrating blood-borne cells, and the cascade of effects characterizing the injury and repair process. This chapter will provide details on the utility of the trimethyltin model to examine neuronal specificity of the pathology, the associated heterogeneity of the microglia response, the recruitment of repair and cell replacement processes. In addition, the available data regarding events that coincide with the initiation of the injury response and the possible utility of the model for developing systemic biomarkers of nervous system damage will be discussed.

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Abbreviations

ATP:

Adenosine triphosphate

BrdU:

Bromodeoxyuridine

GFAP:

Glial fibrillary acidic protein

IL:

Interleukin

P2X2:

Purinergic ionotropic receptor 2

ROS:

Reactive oxygen species

SGZ:

Subgranular zone

SVZ:

Subventricular zone

TMT:

Trimethyltin

TNF:

Tumor necrosis factor

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

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  1. Neurotoxicology Group, Mechanistic Toxicology Branch, Division of National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

    G. Jean Harry

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    Richard M. Kostrzewa

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Harry, G.J. (2021). Trimethyltin as a Model to Explore Mechanisms of Selective Neuronal Death, Glial Reactivity, and Repair. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_233-1

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