Breakthrough of Mechanism for Neurotoxicity of MeHg - Oxidative Stress Produced in Mitochondria

Research Project

Project/Area Number	12680548
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Single-year Grants
Section	一般
Research Field	環境影響評価(含放射線生物学)
Research Institution	Kumamoto University
Principal Investigator	HIRAYAMA Kimiko Kumamoto University College of Medical science, Professor, 医療技術短期大学部, 教授 (70040235)
Co-Investigator(Kenkyū-buntansha)	MORI Nobuko Kumamoto University College of Medical science, Assistant, 医療技術短期大学部, 助手 (80274728)
Project Period (FY)	2000 – 2002
Project Status	Completed (Fiscal Year 2002)
Budget Amount *help	¥3,700,000 (Direct Cost: ¥3,700,000) Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000) Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000) Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
Keywords	methylmercury / neurotoxicity / mitochondria / oxidative stress / rat / antioxidants / demethylation / inorganic Hg / 酸素消費量 / 消去系酵素 / GSH / スーパーオキサイドアニオン / SOD / 無機水銀 / 生体内無機化反応 / アポトーシス
Research Abstract	In order to elucidate oxidative stress mechanism for central nervous system toxictty caused by MeHg, effects of MeHg on rat brain mitochondria were investigated. From this study, following results were obtained. 1) In the experiment using brain mitochondria fraction and its membrane fraction (SMP), it is indicated that MeHg was demethylated by O_2^- produced in brain mitochondria membrane. 2) O_2^- production in brain SMP was accelerated by in vitro exposure of MeHg or Inorganic Hg (Hg^<++>), though the accerelation was much larger in inorganic Hg than in MeHg. 3) Rat brain total Hg levels after administration of MeHg were maintained for considerable time both in cerebrum and cerebellum, whereas inorganic Hg levels were increased timedependently both in cerebrum and cerebellum. Most high levels of inorganic Hg were found in cerebellar mitochondria Brain SMP from rats administered MeHg showed increased O_2^- levels at much earlier time in cerebellum than cerebrum. 4) In mitochondria from co … More ntrol rats, the rates of H_2O_2 production were much higher in cerebellum than in cerebrum in state 3 when malate and glutamate were used as substrates. MeHg treatment increased the rates of H_2O_2 production only in cerebellum in state 4 when succinate was used as a substrate. In mitochondria from controls, GSHPx activities were much lower in cerebellum than in cerebrum, though MeHg treatment did not affect on GSHPx activities. GR activities were did not differ between cerebrum and cerebellum in both controls and MeHg treated rats. Although there was no difference in mitochondria SOD activities between cerebellum and cerebrum of controls, its activities decreased only in cerebellum by MeHg exposure. GSH concentration was much lower in cerebellum than in cerebrum in controls, and MeHg treatment decreased GSH concentration only in cerebellum. These results indicated that cerebellum is more susceptible for MeHg than cerebrum. Thus, our study suggetst that oxidative stress in brain mitochondria caused by MeHg or inorganic Hg derived from MeHg may play an important role in neurotoxicity of MeHg. Less