Raffray, Mark; (1995) Apoptosis as a mechanism in tri-n-butyltin mediated thymocyte cytotoxicity. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Tri-n-butyltin (TBT), an important environmental pollutant, is immunotoxic when administered to experimental animals. Thymic atrophy due to the depletion of cortical thymocytes has been shown to be central to this effect although the mechanism involved is currently undefined. The mode of cell death known as apoptosis has a key role in a number of physiological processes, including the regulation of the developing thymic T lymphocyte repertoire, but can also be triggered in pathological states including toxic injury. This study investigated the effects of bis(tri-n-butyltin) oxide (TBTO) on rat thymocytes and compared these findings to observations with other lymphotoxic model compounds. Exposure of thymocytes in vitro to low concentrations of TBTO resulted in delayed cell killing which bore many of the morphological and biochemical characteristics of apoptosis. Stereotypical internucleosomal DNA cleavage preceded viability loss and both these processes were inhibited by intracellular Ca2+ chelators, zinc, and agents expected to interfere with protein-DNA interactions. At tributyltin treatment levels less than an order of magnitude higher, cytolethahty by necrosis supervened. In contrast to thymocyte apoptosis caused by most other stimuli including glucocorticoids, that mediated by TBTO apparently did not require de novo protein synthesis. Thymocytes exposed to TBTO remained able to instigate apoptotic death although their ATP levels were severely depressed, indicating that the process was not dependent on fully conserved cellular energetics function. In common with the microtubule assembly inhibitor nocodazole, tributyltin was very effective in disrupting the cellular microtubule cytoskeleton. Though there was evidence that this effect may have been causal to nocodazole-mediated thymocyte apoptosis, a similar relationship was not apparent for TBTO. Apoptosis caused by TBTO was associated with nuclear hypodiploidy, but no overt disturbance of thymocyte cell cycle parameters occurred. In vivo studies indicated that thymocyte apoptosis contributed significantly to the cortical thymocyte deletion underlying the thymic involution provoked by administration of TBTO to immature rats.

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