ToxSci Advance Access originally published online on October 5, 2005
Toxicological Sciences 2006 89(1):235-242; doi:10.1093/toxsci/kfj007
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Glutamate Excitotoxicity Is Involved in Cell Death Caused by Tributyltin in Cultured Rat Cortical Neurons
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* Graduate School of Biomedical Sciences, Hiroshima University, 1–2–3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan; Center for Quantum Life Sciences, Hiroshima University, 1–2–3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan; Graduate School of Pharmaceutical Sciences, Kyoto University, 46–29, Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
Received August 9, 2005; accepted September 25, 2005
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 
-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.
Key Words: tributyltin-glutamate release-NMDA receptors; reactive oxygen species; mitogen-activated protein kinase; caspase.
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