Mercury and its congeners are extremely toxic substances which exist as inorganic mercury (Hg++), organic mercury, and mercury vapor (Hg0). Sources of human exposure to mercury include seafood, seeds, foodstuffs, water, and dental amalgam. In previous studies, the Principal Investigator has shown that mercury, at low concentrations, kills human lymphoid cells in a manner consistent with apoptosis. The mitochondrion is the target organelle resulting in development of the permeability transition state and oxidative stress. The hypothesis to be tested in these studies is that exposure to mercury may cause health deficits by impairing host defense mechanisms. In addition, perturbed mitochondrial function provides a major cytotoxic pathway for mercurial compounds. In this proposal, the cascade of events responsible for mercury-induced apoptosis in humans will be further defined. The immunotoxic effects of Hg0 will be characterized to determine if it kills human T cells via apoptosis as a consequence of oxidative stress. The study is divided into four specific aims. The first is to determine if mercury-induced mitochondrial dysfunction is due to direct effects of the toxicant on the expression or function of Bcl-2 protein family members of apoptotic regulatory proteins. The second specific aim is to ascertain if mercury- dependent changes in mitochondrial function promote caspase activity and induce T cell apoptosis. It is proposed that activation of the caspase cascade is a result of mercury-induced mitochondrial permeability transition. The third specific aim is to measure the effect of mercury on (a) the expression and activity of the redox sensitivity transcription factors NF-kB and AP-1, and (b) the expression of novel genes associated with oxidative stress. The fourth specific aim is to determine if Hg0-induces T cell apoptosis and learn if cell death is linked to mitochondrial dysfunction. It is proposed that exposure to Hg0 leads to rapid T cell apoptosis due to physical characteristics of the uncharged species. The goal of this application is to better understand the pathways responsible for mercury toxicity, as well as health implications associated with exposure to mercury-containing compounds.
