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ToxSci Advance Access published online on October 5, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj007
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received August 9, 2005
Accepted September 25, 2005

Neurotoxicology

Glutamate Excitotoxicity is Involved in Cell Death Caused by Tributyltin in Cultured Rat Cortical Neurons

Yusuke Nakatsu 1, Yaichiro Kotake 2*, Kazuya Komasaka 1, Hiroko Hakozaki 1, Ryota Taguchi 3, Toshiaki Kume 3, Akinori Akaike 3, and Shigeru Ohta 1

1 Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
2 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
3 Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29, Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan

* To whom correspondence should be addressed.
Yaichiro Kotake, E-mail: yaichiro{at}hiroshima-u.ac.jp


  Abstract

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 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.

Keywords: Tributyltin; Glutamate Release; NMDA receptors; Reactive Oxygen Species; Mitogen activated protein kinase; Caspase.
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Y. Nakatsu, Y. Kotake, and S. Ohta
Concentration Dependence of the Mechanisms of Tributyltin-Induced Apoptosis
Toxicol. Sci., June 1, 2007; 97(2): 438 - 447.
[Abstract] [Full Text] [PDF]


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