Journal
TOXICOLOGY
Volume 204, Issue 2-3, Pages 175-185Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.tox.2004.06.023
Keywords
methylmercury; PC12; GSH; ROS; time-lapse confocal microscopy; necrapoptosis
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Low doses, chronic exposure to mercurial organic compounds is a worldwide health concern and could be pathogenetically relevant as co-factor in several neurodegenerative diseases. In this in vitro study we wanted to further improve our knowledge on the mechanisms of toxicity of methylmercury hydroxide (MeHgOH) in the unprimed PC12 cell line. Cell viability, mitochondrial function, redox state, and cell morphology were recorded at different time points to sequence the events leading to cell death. The lowest cytotoxic concentration and EC50 were 0.3 and 1.3 muM, respectively. 5 muM MeHgOH was fatal for 80% of the cell population after 24 h; within 1 h it caused glutathione (GSH) depletion and a partial dissipation of Deltapsi(m). At this concentration, reactive oxygen species (ROS) generation was only slight and delayed. After 6 h more than 50% of ATP was available and caspase 3 was active. Time-lapse confocal microscopy showed that only a fraction of the cells completed apoptosis while others turned toward necrosis (necrapoptosis). Pre-incubation with N-acetylcysteine (NAC) and GSH but not Cyclosporin A rescued over 80% of the cells. These results provide experimental evidence that, in this cell model, MeHgOH triggers cell death via a primary depletion of GSH but in the absence of ROS overproduction. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
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