Uranyl acetate induces oxidative stress and activates apoptotic signaling pathway in RL-65 epithelial cells.

摘要

Uranium is a natural and commonly occurring radioactive element. It is present to some degree in almost everything in our environment including soil, rocks, water, and air. It is a reactive metal, so it is not found as free uranium in the environment. Uranium can enter the human body through inhalation, ingestion, or penetration through the skin. Inhalation of depleted uranium dust is the most likely route of exposure. Several reports have shown that uranium or depleted uranium induces oxidative stress causing DNA damage, mutagenic cancer and other neurological defects. The DNA damage caused by uranium may be caused by an alteration in the related signaling mechanism. Hence, effective management and proper disposal of uranium wastes are necessary, as it may have adverse effects on the health of human population. To evaluate the role of oxidative stress in signaling cascade induced by UA, rat lung epithelial (RL-65) cell culture was used as a model system. In the present study UA was found to induce oxidative stress significantly with a decrease in viable cell proliferation by 72 h. The decreased in cell number may be caused by increased cell death or decrease in the cell proliferation mechanism. UA also reduced the levels of glutathione and super oxide dismutase, the antioxidant protective mechanism present in LE cells. Oxidative stress may lead to apoptotic signaling pathways and in order to investigate this possibility caspases 8 and 3 assays were conducted. Cytochrome c oxidase content of various cell fractions was also measured. Treatment of cells with UA activates both caspase 8 and 3 significantly compared to control; Inhibitor of caspase 8 and 3 down regulated the activities of caspase 8, 3 and blocked the apoptosis induced by UA, also demonstrated that induction of UA with LE cells results DNA fragmentation from apoptotic signaling cascades. Cell damage and apoptosis were found to be dose dependent. UA is genotoxic at concentrations of 0.25 mM and induces caspase dependent apoptotic cell death in LE cells. This suggested that oxidative stress induced by UA activates apoptotic signaling pathway in rat lung epithelial cells.