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.