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 compounds, in particular, are toxic to the human immune system. In this regard, we have previously shown that both inorganic and organic mercurials are potent human T-cell apoptogens; moreover, mitochondria appear to be a target organelle for the induction of cell death. To ascertain whether both mercury species utilize the same molecular pathway to trigger the apoptotic cascade, cells were treated with MeHgCl or HgCl2 and mitochondrial activity was examined. 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 GSH content. Since mitochondrial dysfunction and the development of a permeability transition may result in the release of cytochrome c, a factor that promotes 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 cytochrome c. We next determined whether the mercurials could alter the level of the anti-apoptotic protein Bcl-2. Our results demonstrate that HgCl2 induces a significant elevation in the Bcl-2 content of T-cells; in contrast, T-cells treated with MeHgCl did not exhibit altered levels of this anti-apoptotic protein. Regardless of whether cytochrome c is released from the mitochondria, both mercurial species were capable of activating the caspase cascade, 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.
Shenker
B J
BJ
Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Guo
T L
TL
Shapiro
I M
IM
D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line / Q000187:drug effects; D003574:Cytochrome c Group / Q000187:drug effects; D053938:DNA Fragmentation; D005260:Female; D005434:Flow Cytometry; D005978:Glutathione / Q000032:analysis; D006801:Humans; D000922:Immunotoxins / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008627:Mercuric Chloride / Q000633:toxicity*; D008767:Methylmercury Compounds / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects*
D003574:Cytochrome c Group; D000922:Immunotoxins; D008767:Methylmercury Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D008627:Mercuric Chloride; D005978:Glutathione; C004925:methylmercuric chloride