Arsenate-induced apoptosis in murine embryonic maxillary mesenchymal cells via mitochondrial-mediated oxidative injury.
BACKGROUND
Arsenic is a ubiquitous element that is a potential carcinogen and teratogen and can cause adverse developmental outcomes. Arsenic exerts its toxic effects through the generation of reactive oxygen species (ROS) that include hydrogen peroxide (H(2)O(2)), superoxide-derived hydroxyl ion, and peroxyl radicals. However, the molecular mechanisms by which arsenic induces cytotoxicity in murine embryonic maxillary mesenchymal (MEMM) cells are undefined.


METHODS
MEMM cells in culture were treated with different concentrations of pentavalent sodium arsenate [As (V)] for 24 or 48 hr and various end points measured.


RESULTS
Treatment of MEMM cells with the pentavalent form of inorganic arsenic resulted in caspase-mediated apoptosis, accompanied by generation of ROS and disruption of mitochondrial membrane potential. Treatment with caspase inhibitors markedly blocked apoptosis. In addition, the free radical scavenger N-acetylcysteine dramatically attenuated arsenic-mediated ROS production and apoptosis, and exposure to arsenate increased Bax and decreased Bcl protein levels in MEMM cells.


CONCLUSIONS
Taken together, these findings suggest that in MEMM cells arsenate-mediated oxidative injury acts as an early and upstream initiator of the cell death cascade, triggering cytotoxicity, mitochondrial dysfunction, altered Bcl/Bax protein ratios, and activation of caspase-9.
Singh
Saurabh
S
University of Louisville Birth Defects Center, Department of Molecular, Cellular and Craniofacial Biology, ULSD, Louisville, Kentucky 40292, USA.
Greene
Robert M
RM
Pisano
M Michele
MM
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001149:Arsenates / Q000633:toxicity*; D053453:Caspase 9 / Q000096:biosynthesis; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004336:Drug Antagonism; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D008437:Maxilla / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes; D018384:Oxidative Stress / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D001149:Arsenates; C494827:Bax protein, mouse; D016166:Free Radical Scavengers; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C009277:sodium arsenate; D053453:Caspase 9; D000111:Acetylcysteine