Concentration dependence of the mechanisms of tributyltin-induced apoptosis
Concentration dependence of the mechanisms of tributyltin-induced apoptosis
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DOI：
10.1093/toxsci/kfm039
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发表时间：
2007-06-01
影响因子：
3.8
通讯作者：
Ohta, Shigeru
中科院分区：
文献类型：
--
作者：
Nakatsu, Yusuke;Kotake, Yaichiro;Ohta, Shigeru
氯化三丁基锡（TBT）是一种干扰内分泌的化学品，已被用作热稳定剂、农业杀虫剂和油漆的成分。在这项研究中，我们研究了三丁基锡在PC 12细胞中的细胞毒性机制的浓度依赖性。暴露于500 nM和2 μ M三丁基锡的PC 12细胞增加了显示核碎裂的细胞数量，这是一种典型的凋亡特征，并激活了caspase-3。2 μ M三丁基锡处理的细胞内Ca ~（2+）浓度峰值高于500 nM三丁基锡处理的细胞。2 μ M三丁基锡引起的细胞内Ca ~（2+）增加是通过三磷酸肌醇受体和兰尼碱受体释放Ca ~（2+）介导的，而500 nM三丁基锡引起的细胞内Ca ~（2+）增加是通过电压依赖性钙通道（VDCC）介导的。接下来，我们研究了Ca 2+增加后导致细胞死亡的机制是否不同。活性氧（ROS）仅参与2 μ M三丁基锡诱导的细胞死亡，而c-jun N-末端激酶（JNK）仅介导500 nM三丁基锡诱导的毒性。因此，2 μ M三丁基锡引起的半胱天冬酶依赖性细胞凋亡介导的一个大的Ca 2+增加通过肌醇1，4，5-三磷酸受体和ryanodine受体，随后产生的ROS。由500 nM三丁基锡引起的细胞凋亡是通过VDCC介导的中度Ca 2+增加，然后是JNK的磷酸化。这些结果表明，TBT诱导的细胞凋亡是通过不同的途径依赖于TBT的浓度，我们显示了一个罕见的例子，上游的细胞凋亡机制是不同的，这取决于毒性损伤的强度。
Tributyltin chloride (TBT), an endocrine-disrupting chemical, has been used as a heat stabilizer, agricultural pesticide, and component of antifouling paints. In this study, we investigated the concentration dependence of the mechanisms of tributyltin cytotoxicity in PC12 cells. Exposure of PC12 cells to both 500nM and 2 mu M tributyltin increased the number of cells showing nuclear fragmentation, a typical apoptotic feature, and activated caspase-3. The peak Ca2+ concentration in 2 mu M tributylt-intreated cells was higher than that in 500nM tributyltin-treated cells. The intracellular Ca2+ increase induced by 2 mu M tributyltin was mediated by Ca2+, release from both inositol 1,4,5-trisphosphate receptor and ryanodine receptor, while the Ca2+ increase induced by 500nM tributyltin was mediated through the voltage-dependent calcium channel (VDCC). Next, we investigated whether the mechanisms leading to cell death after Ca2+ increase were different. Reactive oxygen species (ROS) were involved only in 2 mu M tributyltin-induced cell death, while c-jun N-terminal kinase (JNK) mediated only 500nM tributyltin-induced toxicity. Thus, caspase-dependent apoptosis caused by 2 mu M tributyltin was mediated by a large Ca2+ increase via inositol 1,4,5-trisphosphate receptor and ryanodine receptor, followed by generation of ROS. Apoptosis caused by 500nM tributyltin was mediated by a moderate Ca2+ increase through the VDCC, followed by phosphorylation of JNK. These results suggest that apoptosis by TBT is induced via distinct pathways depending on the TBT concentration, and we showed a rare example that upstream mechanisms of apoptosis are distinct depending on strength of toxic insult.