Organotin compounds are known to cause thymic
atrophy and an accompanying deficiency of cell-mediated immunity. The study reported here focused on cell death in the thymus as a contributing factor in the induction of thymic
atrophy following exposure to
dibutyltin (DBTC) and
tributyltin (TBTC). In an in vivo study, a reversible thymic
atrophy was induced in rats by a single intraperitoneal administration (2.0 mg/kg) of DBTC or TBTC; the magnitude of this effect over a 4-d post-treatment period differed between the two agents. In in vitro studies, T-lymphocytes were isolated from thymuses of naïve rats and then exposed to 1 microM DBTC or TBTC for varying periods of time. Analysis by flow cytometry showed that DBTC induced primarily
necrosis, while TBTC induced apoptosis, of the cells. Activities of
caspase-8, -9, and -3 were also measured; TBTC exposure caused marked increases in the activities, while DBTC exposure did not cause any significant change. TBTC exposure also appeared to induce expression of CAD (which fragments
DNA), but had minimal effect on levels of the
CAD inhibitor, ICAD. In contrast, DBTC exposure resulted in a larger level of ICAD expression.
WST-8 and
JC-1 assays were used to evaluate mitochondrial function, since a strong activation of
caspase-9 by TBTC suggested mitochondrial involvement. The involvement of
caspase in the activation was examined using
cytochrome c expression;
cytochrome expression and the loss of mitochondrial function occurred within 10 min of TBTC exposure. DBTC exposure affected the mitochondria less. These results indicated that effects on mitochondria likely played an important role in the induction of apoptosis by TBTC. The results of this study show that DBTC and TBTC induce
necrosis and apoptosis of T-lymphocytes, respectively, by apparently indicating different mechanisms of cell death. It follows that these increases in cell death induced by these
organotin compounds likely contributed to the thymic
atrophy observed in the rats here.