Glutamate excitotoxicity is involved in cell death caused by tributyltin in cultured rat cortical neurons
Glutamate excitotoxicity is involved in cell death caused by tributyltin in cultured rat cortical neurons
复制标题
DOI：
10.1093/toxsci/kfj007
复制
发表时间：
2006-01-01
影响因子：
3.8
通讯作者：
Ohta, S
中科院分区：
文献类型：
--
作者：
Nakatsu, Y;Kotake, Y;Ohta, S
三丁基锡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，三丁基锡的神经毒性在培养的大鼠皮层神经元进行了研究。三丁基锡引起显着的时间和剂量依赖性的台盼蓝染色细胞的数量增加。细胞外谷氨酸浓度的测定表明，谷氨酸释放的三丁基锡诱导。应用谷氨酸受体拮抗剂MK-801和CNQX可减轻神经毒性。这些结果表明，释放的谷氨酸和谷氨酸受体参与三丁基锡毒性。接下来，我们研究了各种因素，认为是参与谷氨酸兴奋性毒性也影响三丁基锡毒性。发现α-生育酚（一种膜渗透性抗氧化剂）、SB 202190（一种p38促分裂原活化蛋白激酶抑制剂）和U-0126（一种细胞外信号调节蛋白激酶抑制剂）可降低三丁基锡诱导的细胞死亡。MK-801和CNQX降低ERK的磷酸化，但不降低p38的磷酸化。半胱天冬酶-3抑制剂对三丁基锡毒性没有影响，三丁基锡没有改变核形态。提示三丁基锡引起的谷氨酸兴奋毒性与细胞凋亡无关。总之，我们证明，三丁基锡诱导谷氨酸释放和随后激活谷氨酸受体，导致神经元死亡。我们提出了两个独立的神经元死亡途径三丁基锡，一个是谷氨酸受体依赖性细胞死亡通过ERK磷酸化，另一个可能是谷氨酸受体不依赖性细胞死亡通过p38激活。
Tributyltin, an endocrine-disrupting chemical, has been used as a heat stabilizer, agricultural pesticide, and component of antifouling paints. In this study, the neurotoxicity of tributyltin was investigated in cultured rat cortical neurons. Tributyltin caused marked time- and dose-dependent increases in the number of trypan blue-stained cells. Measurement of extracellular glutamate concentration showed that glutamate release was induced by tributyltin. Application of the glutamate receptor antagonists MK-801 and CNQX decreased the neurotoxicity. These results suggest that released glutamate and glutamate receptors are involved in tributyltin toxicity. Next, we examined whether various factors, believed to be involved in glutamate excitotoxicity also influence tributyltin toxicity. Cell death induced by tributyltin was found to be reduced by alpha-tocopherol (a membrane-permeable antioxidant), SB202190 (a p38 mitogen-activated protein kinase inhibitor), and U-0126 (an extracellular signal-regulated protein kinase kinase inhibitor). MK-801 and CNQX decreased the phosphorylation of ERK, but not that of p38. A caspase-3 inhibitor had no effect on tributyltin toxicity, and tributyltin did not change the nuclear morphology. These results suggest that the glutamate excitotoxicity caused by tributyltin is unrelated to apoptosis. In conclusion, we demonstrated that tributyltin induced glutamate release and subsequent activation of glutamate receptors, leading to neuronal death. We propose two independent neuronal death pathways by tributyltin; one is glutamate receptor-dependent cell death via ERK phosphorylation, and the other may be glutamate receptor-independent cell death via p38 activation.