Department of Biochemistry and Genetics, School of medicine, Zhejiang University, 866th Yu Hang Tang Road, 310058, Hangzhou, China.
Environ Toxicol. 2014 Feb;29(2):234-42. doi: 10.1002/tox.21751. Epub 2012 Jan 5.
Tributyltin (TBT), a highly toxic environmental contaminant, has been shown to induce caspase-3-dependent apoptosis in human amniotic cells through protein phosphatase 2A (PP2A) inhibition and consequent JNK activation. This in vivo study was undertaken to further verify the results derived from our previous in vitro study. Mice were orally dosed with 0, 10, 20, and 60 mg/kg of body weight TBT, and levels of PP2A, reactive oxygen species (ROS), mitogen-activated protein kinase (MAPK), Bax/Bcl-2, and caspase-3 were detected in the mouse livers. Apoptosis was also evaluated using the TUNEL assay. The results showed that PP2A activity was inhibited, ROS levels were elevated, and MAPKs including ERK, JNK, and p38 were activated in mouse livers treated with the highest dose of TBT. Additionally, the ratio of Bax/Bcl-2 was increased, caspase-3 was activated, and apoptosis in mouse livers could be detected in the highest dose group. Therefore, a possible signaling pathway in TBT-induced apoptosis in mouse livers involves PP2A inhibition and ROS elevation serving a pivotal function as upstream activators of MAPKs; activation of MAPKs in turn leads to an increase in the Bax/Bcl-2 ratio, ultimately leading to the activation of caspase-3. The results give a comprehensive and novel description of the mechanism of TBT-induced toxicity.
三丁基锡（TBT）是一种高度毒性的环境污染物，已被证明可通过蛋白磷酸酶 2A（PP2A）抑制和随后的 JNK 激活诱导人羊膜细胞中的 caspase-3 依赖性细胞凋亡。本体内研究旨在进一步验证我们先前的体外研究结果。将小鼠经口给予 0、10、20 和 60mg/kg 体重 TBT，检测小鼠肝脏中的 PP2A、活性氧（ROS）、丝裂原活化蛋白激酶（MAPK）、Bax/Bcl-2 和 caspase-3 的水平。还使用 TUNEL 测定法评估了细胞凋亡。结果表明，在最高剂量 TBT 处理的小鼠肝脏中，PP2A 活性受到抑制，ROS 水平升高，ERK、JNK 和 p38 等 MAPKs 被激活。此外，Bax/Bcl-2 比值增加，caspase-3 被激活，在最高剂量组的小鼠肝脏中可检测到细胞凋亡。因此，TBT 诱导的小鼠肝脏细胞凋亡的可能信号通路涉及 PP2A 抑制和 ROS 升高，作为 MAPKs 的上游激活剂发挥关键作用；MAPKs 的激活反过来导致 Bax/Bcl-2 比值增加，最终导致 caspase-3 的激活。这些结果全面而新颖地描述了 TBT 诱导毒性的机制。
