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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE010873-09
Application #
6516464
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Kousvelari, Eleni
Project Start
1994-02-01
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
9
Fiscal Year
2002
Total Cost
$271,270
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Shenker, Bruce J; Pankoski, Lisa; Zekavat, Ali et al. (2002) Mercury-induced apoptosis in human lymphocytes: caspase activation is linked to redox status. Antioxid Redox Signal 4:379-89
Shenker, B J; Guo, T L; Shapiro, I M (2000) Mercury-induced apoptosis in human lymphoid cells: evidence that the apoptotic pathway is mercurial species dependent. Environ Res 84:89-99
Close, A H; Guo, T L; Shenker, B J (1999) Activated human T lymphocytes exhibit reduced susceptibility to methylmercury chloride-induced apoptosis. Toxicol Sci 49:68-77
Shenker, B J; Guo, T L; O, I et al. (1999) Induction of apoptosis in human T-cells by methyl mercury: temporal relationship between mitochondrial dysfunction and loss of reductive reserve. Toxicol Appl Pharmacol 157:23-35
Guo, T L; Miller, M A; Shapiro, I M et al. (1998) Mercuric chloride induces apoptosis in human T lymphocytes: evidence of mitochondrial dysfunction. Toxicol Appl Pharmacol 153:250-7
Guo, T L; Miller, M A; Datar, S et al. (1998) Inhibition of poly(ADP-ribose) polymerase rescues human T lymphocytes from methylmercury-induced apoptosis. Toxicol Appl Pharmacol 152:397-405
Shenker, B J; Guo, T L; Shapiro, I M (1998) Low-level methylmercury exposure causes human T-cells to undergo apoptosis: evidence of mitochondrial dysfunction. Environ Res 77:149-59
InSug, O; Datar, S; Koch, C J et al. (1997) Mercuric compounds inhibit human monocyte function by inducing apoptosis: evidence for formation of reactive oxygen species, development of mitochondrial membrane permeability transition and loss of reductive reserve. Toxicology 124:211-24