Mercury-induced apoptosis in human lymphoid cells: Evidence that the apoptotic pathway is mercurial species dependent

There is growing evidence that heavy metals, in general, and mercurial comp ounds, in particular, are toxic to the human immune system. In this regard, we have previously shown that both inorganic and organic mercurials are po tent human T cell apoptogens; moreover, mitochondria appear to be a target organelle for the induction of cell death. To ascertain whether both mercur y species utilize the same molecular pathway to trigger the apoptotic casca de, cells were treated with MeHgCl or HgCl2 and mitchondrial activity was e xamined. We show that both mercury species affect mitochondrial activity by inducing the development of a membrane permeability transition. This state is characterized by a decline in both the transmembrane potential and the intracellular pH, as well as the generation of reactive oxygen species. We also determined that mercury exposure results in a decline in the T-cell GS H content. Since mitochondrial dysfunction and the development of a permeab ility transition may result in the release of cytochrome c, a factor that p romotes apoptosis, we assessed the abilities of both species of mercury to induce the translocation of cytochrome c from mitochondria to the cytosol. We noted that MeHgCl caused a significant increase in cytosolic cytochrome c. Surprisingly, however, HgCl2 did not alter the level of cytosolic cytoch rome c. We next determined whether the mercurials could alter the level of the anti-apoptotic protein Bcl-2. Our results demonstrate that HgCl2 induce s a significant elevation in the Bcl-2 content of T-cells; in contrast, T-c ells treated with MeHgCl did not exhibit altered levels of this anti-apopto tic protein. Regardless of whether cytochrome c is released from the mitoch ondria, both mercurial species were capable of activating the caspase casca de, as evident by cleavage of poly (ADP-ribose) polymerase, Thus, our study shows that, whereas each of the mercury species shares common features in the apoptotic process, profound differences exist in a number of key steps in the pathway. The significance of these differences is discussed. (C) 200 0 Academic Press.