Evolution of the Intracellular Changes in Neurons Caused by Trimethyltin

Abstract

Rats have been given a single dose of trimethyltin (10 mg/kg) and the intracellular events have been followed particularly in hippocampus, cerebral cortex, cerebellum and spinal ganglion cells. The earliest change visible occurs 12 h after this dose and is found to be dense membrane-bound bodies, probably derived from branching tubulo-vesicular smooth endoplasmic reticulum formations. These occur in close connection with rought endoplasmic reticulum and polyribosomes and appear also to have some association with the Golgi complex. At 24 h there is a general vacuolation of Golgi cisterns and SER membranes, and the membrane-bound dense body formation is greatly increased. SER abnormalities are particularly conspicuous in Purkinje cells. In spinal ganglion cells, while vacuolation of Golgi cisterns is intense, dense bodies are inconspicuous and are replaced by increased autophagosomes, often of great complexity. By 48 h vacuolation of Golgi cisterns has waned, but accumulation of dense bodies and secondary lysosomes has steadily increased. In spinal ganglion cells autophagosomes only are increased as the Golgi vacuolation declines. At later times steady increases of lysosomal dense bodies is seen generally accompanied in hippocampal pyramidal cells and dentate fascia cells by abundant cell death. The suggestion is put forward that the Golgi complex may be the seat of the critical metabolic lesion and disturbances to protein transfer and protein synthesis follow. No explanation for the selective loss of hippocampal h1-5 (CA1-CA4 except Sommer's sector) pyramidal cells and of small dentate fascia neurons can be derived from these conclusions.

The Toxicity and Neuropathology of Dimethylethyltin and Methyldiethyltin in Rats

“…In the neuronal necrosis an excitotoxic mechanism of action as suggested by Cremer (1981) may play a role, supported by the finding of an early phase of increased hippocampal excitability preceding neuronal destruction (Ray, 1981). Such an action is consistent with the suggestion (Brown et al 1984b) that neuronal necrosis may be associated with the chloride carrying capacity of these compounds given the fundamental role of chloride ions in controlling neuronal excitability. From the available evidence it appears that for an alkyltin to be neurotoxic the compound must contain three short-chain alkyl groups.…”

Hypoxia‐like transcriptional activation in TMT‐induced degeneration: microarray expression analysis on PC12 cells

“…The evolution of the morphological changes occurring in TMT-intoxicated cells implies early modifications of the Golgi apparatus and the ER, leading to the formation of vacuoles and membranebound dense bodies. This process evolves to the formation of autophagolysosomes and ultimately leads to cell death (Bouldin et al 1981;Brown et al 1984;Chang et al 1984;Kreyberg et al 1992). …”

Neurotoxic Effects of Trimethyltin

“…Other areas of the nervous system may be affected as well, such as the neocortex, basal ganglia, cerebellum, brain stem, spinal cord, dorsal root ganglia, olfactory cortex, retina, and the inner ear (Brown eta!. 1979;Bouldin et al 1981;Brown et al 1984a). The major pathologic finding is neuronal necrosis.…”

“…64). They are formed at the expense of the rough endoplasmic reticulum and appear to arise either from the rough endoplasmic reticulum devoid of ribosomes or, more probably, from the smooth endoplasmic reticulum (Brown et al 1984a). In some neurons, dilation of the cisternae of the endoplasmic reticulum and of the Golgi complex is apparent (Fig.…”

“…Although the loss of Nissl substance is indicative of a (direct or indirect) disturbance in protein synthesis (Brown et al 1979;Chang and Oyer 1983), specific experiments have demonstrated only a s light inhibition of protein synthetic process by trimethyltin. Possibly, the changes in the Golgi complex disturb subsequent processing of synthesized protein (Brown et al 1984a). …”