Oxidative stress in neurotoxic effects of methylmercury poisoning.
The effects of methylmercuric chloride (MMC) on the rate of oxygen uptake were determined in purified cultures of oligodendrocytes, astrocytes, and cerebral cortical and cerebellar granular neurons obtained from embryonic and neonatal rat brains. Rapid and profound inhibition of oxygen uptake took place in all cell types following MMC exposure. However, the sensitivity of cellular respiration to the toxic effects of MMC appeared to parallel the normal oxygen demands of the cell type. To assess the effects of MMC on mitochondrial electron transport chain (ETC) activity, complex-specific electron donating substrates were used to stimulate the mitochondria obtained from both control and MMC-injected rat brains. Significant increases in reactive oxygen species (ROS) and thiobarbituric acid-reactive substances (TBARS), and a reduction in glutathione levels were observed in the MMC group following stimulation of complex III, but not with stimulation of either complex I or II, suggesting that MMC induces alterations in electron transport in the ubiquinol: cytochrome c oxidoreductase region. The rapidity of oxygen uptake inhibition by MMC in cultured CNS cells and the demonstration of MMC effects on specific enzyme complexes in the mitochondrial ETC strongly support the contention that mitochondria may be the earliest target of MeHg neurotoxicity, and that the mitochondrial ETC is the most likely site where excess ROS are generated in the brain to induce oxidative stress in MeHg poisoning.
Yee
S
S
Department of Pathology, University of California, Irvine 92717, USA.
Choi
B H
BH
D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D002478:Cells, Cultured; D008767:Methylmercury Compounds / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D009836:Oligodendroglia / Q000187:drug effects; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000187:drug effects; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
D008767:Methylmercury Compounds; D017392:Thiobarbituric Acid Reactive Substances; C004925:methylmercuric chloride