Previous studies have shown that dibutyltin (DBT) interferes with the function of human natural killer (NK) cells, diminishing their capacity to destroy tumor cells, in vitro. DBT is a widespread environmental contaminant and has been found in human blood. As NK cells are our primary immune defense against tumor cells, it is important to understand the mechanism by which DBT interferes with their function. The current study examines the effects of DBT exposures on key enzymes in the signaling pathway that regulates NK responsiveness to tumor cells. These include several protein tyrosine kinases (PTKs), mitogen activated protein kinases (MAPKs) and mitogen activated protein kinase kinases (MAP2Ks). The results showed that in vitro exposures of NK cells to DBT had no effect on PTKs. However, exposures to DBT for as little as 10 min were able to increase the phosphorylation (activation) of the MAPKs. The DBT-induced activations of these MAPKs, appears to be due to DBT-induced activations of the immediate upstream activators of the MAPKs, MAP2Ks. The results suggest that DBT-interference with the MAPK signaling pathway is a consequence of DBT exposures, which could account for DBT-induced decreases in NK function.

Dibutyltin (DBT) is a widespread environmental contaminant. Detectable levels have been found in human blood. Natural killer (NK) cells are able to lyse tumor cells and virally infected cells. Previous studies have shown that DBT decreases the lytic function of NK cells. In this study we assessed the effects of those concentrations of DBT that decrease NK lytic function on the status of protein tyrosine kinases (PTKs) (Syk, Zap‐70, Src and Pyk), and Mitogen‐activated protein kinases (MAPKs) (p38, p44/42, JNK). Such studies will help elucidate the mechanism by which DBT decreases NK lytic function. NK cells that were exposed to (10, 5, 2.5, 1, 0.5 μM) DBT for 10 min did not show any significant changes in the levels or activation state of Syk, Pyk, or Src. Exposure of NK cells to 10 μM DBT for 10 min resulted in a significant increase in the phosphorylation of p38 (1.8 fold) and p44/42 (1.7 fold). A 6 h exposure to 10 μM DBT caused a significant increase in phosphorylation of p44/42 but no significant change in p38, phospho‐p38, p44/42, phospho‐JNK, or JNK levels. These data indicate that in vitro exposure to DBT, caused no changes in the levels or activation state of PTKs but caused significant activation the MAPKs, p38 and p44/42 after a 10min exposure to 10 μM DBT. This activation of p44/42 maintains out to 6 h. Supported by NIH grant 2S06GM0809228.