Molecular mechanisms of tributyltin-induced cellular damage : possible involvement of the immediate early genes

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Effects of tributyltin chloride (TBT) and other organotin compounds on mitogen-activated protein kinases (MAPKs) were examined in CCRF-CEM human T cell line. The levels of phosphorylated form of extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK increased in a dose-dependent manner. The phosphorylation was observed after 15 min and lasted for 4 h following TBT exposure. On the other hand, no clear changes were found in the total protein levels of ERK, JNK and p38 MAPK.The potential of MAPKs phosphorylation was TBT > dibutyltin dichloride > monobutyltin trichloride. When compared to other triorganotin compounds such as trimethyltin chloride, triphenyltin chloride and triethyltin bromide, TBT exposure induced the most marked phosphorylation of MAPKs. Chelation of intracellular Ca^<2+> with BAPTA/AM suppressed TBT-induced MAPKs phosphorylation and subsequent apoptosis. These results showed that tributyltin is a potent activator of ERK, JNK and p38 MAPK pathways, and intracellular Ca^<2+> plays an important role for MAPKs phosphorylation. Phosphorylation of MAPKs and subsequent expression of the immediate early genes may be responsible for TBT-induced cellular damage. The exposure to cadmium or inorganic mercury also induced the phosphorylation of MAPKs in CCRF-CEM cells. ERK was found to be involved in cadmium-induced apoptotic cell death in this T cell line. LL-Z1640-2, a macrocyclic nonaketide, was a potent inhibitor of metals-induced MAPKs activation in CCRF-CEM cells.TBT and other metals have been known to induce the expression of c-fos gene in the various cell types. The c-Fos-deficient fibroblasts were more severely affected than wild-type cells following the exposure to TBT and other metals, suggesting that c-fos may play a protective role against the cytotoxic effects of metals at least in fibroblasts.