%0 Journal Article
%T Caspase-10 Is the Key Initiator Caspase Involved in Tributyltin-Mediated Apoptosis in Human Immune Cells
%A Harald F. Krug
%J Journal of Toxicology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/395482
%X Tributyltin (TBT) is one of the most toxic compounds produced by man and distributed in the environment. A multitude of toxic activities have been described, for example, immunotoxic, neurotoxic, and endocrine disruptive effects. Moreover, it has been shown for many cell types that they undergo apoptosis after treatment with TBT and the cell death of immune cells could be the molecular background of its immunotoxic effect. As low as 200£¿nM up to 1£¿¦ÌM of TBT induces all signs of apoptosis in Jurkat T cells within 1 to 24 hrs of treatment. When compared to Fas-ligand control stimulation, the same sequence of events occurs: membrane blebbing, phosphatidylserine externalisation, the activation of the ¡°death-inducing signalling complex,¡± and the following sequence of cleavage processes. In genetically modified caspase-8-deficient Jurkat cells, the apoptotic effects are only slightly reduced, whereas, in FADD-negative Jurkat cells, the TBT effect is significantly diminished. We could show that caspase-10 is recruited by the TRAIL-R2 receptor and apoptosis is totally prevented when caspase-10 is specifically inhibited in all three cell lines. 1. Introduction Tributyltin (TBT) is one of the most toxic compounds still used in antifouling paints for large commercial ships thereby distributed within the aquatic environment. Its distribution and accumulation in aquatic organisms leads to severe effects and has already reduced the number of snail species in the near of sea lanes and harbours [1]. Moreover, the trophic transfer has been demonstrated [2], and the accumulation within the food chain up to the level of marine mammals has reached concentrations that might be biological relevant [3¨C6]. The most prominent biological effect investigated so far is the so-called imposex within sea snails and dogwhelks [1, 7, 8], and this mechanism is used as biomonitoring tool for organotin compounds [9]. Despite the fact that a lot of studies have been carried out, the underlying molecular mechanism remains unclear [10, 11]. It has been proposed that the inhibition of aromatase activity alters the ratio of the hormones inducing the development of imposex, the imposition of male sex characteristics on female snails [1, 12], but other studies came to other results [11, 13]. As organotin compounds were still used and accumulate in the environment as well as in the food chain, the exposure of mammals and humans increases steadily. Moreover, it has been described earlier that organotin compounds, especially TBT, have a clear immunotoxic effect in mammals [14¨C16], and this might be
%U http://www.hindawi.com/journals/jt/2012/395482/