抄録
Background: Tributyltin (TBT), an organotin compound and an endocrine disrupting chemical, has been widely used in agriculture and industry. TBT pollution, for the last four decades, has tremendously pervaded causing to the dramatic exposure and health risk in human. Organotins have been found to possess the diabetogenic action. The detailed effect and mechanism of TBT on pancreatic beta-cell growth and glucose metabolism still remain to be clarified. We investigated the effects of low-dose TBT exposure on cell viability and cellular signaling molecules in cultured beta-cells and glucose metabolism in mice.
Methods: The cytotoxic effects and associated signaling molecules of submicromolar TBT were determined in pancreatic beta-cell-derived RIN-m5F cells. The changes of blood glucose, plasma insulin, and glucose tolerance were detected in mice by oral administration of TBT (0.25 mg/kg) for 4 weeks in the presence or absence of antioxidant N-acetylcysteine (NAC).
Results: TBT at the concentrations of 0.5 and 1 microM significantly induced beta-cell cytotoxicity and apoptosis (P < 0.05, n=5; Figure 1A and D), which were accompanied by the poly(ADP-ribose) polymerase (PARP) cleavage and phosphorylations of mitogen-activated protein kinases (MAPKs)- JNK, p38, and ERK1/2 in a time-dependent manner. TBT (0.2-1 microM; Figure 1C) could also increase reactive oxygen species (ROS) production (P < 0.05, n=4; Figure 1B). TBT-induced beta-cell cytotoxicity and apoptosis were significantly prevented by NAC and JNK inhibitor SP600125, but not ERK1/2 inhibitor PD98059 and p38 inhibitor SB203580 (P < 0.05, n=4; Figure 1D). Both NAC and SP600125 could also inhibit the PARP cleavage and JNK phosphorylation and reduced cell viability in TBT-treated beta-cells (P < 0.05, n=4). Moreover, exposure of mice to TBT for 4 weeks revealed a decrease in plasma insulin and the increases in blood glucose and plasma malondialdehyde, which could be significantly reversed by NAC treatment (P < 0.05, n=10). After removing the TBT exposure for 2 weeks, the decreased plasma insulin levels and elevated blood glucose levels were significantly reversed (P < 0.05, n=5; Figure 1E).
Conclusions: These results suggest that low-dose TBT exposure is capable of inducing pancreatic beta-cell apoptosis and interfering with glucose homeostasis via an oxidative stress-related pathway.
