Mercury vapor (HgO) and mercury containing compounds are extremely toxic substances. Recent studies point to dental amalgam as a point source of HgO. This has lead to speculation and concern regarding the effect of amalgam on the health of both the dental practitioner and the patient. While there is some dispute concerning the actual amount of mercury released from amalgam and absorbed into the body, there is universal agreement that the organic forms of mercury account for most of the ingested and absorbed mercury. Therefore, the objective of this investigation is to conduct a comprehensive study of the effect of organic mercury on the human immune system and to determine the mechanisms by which the metal compromises immunological function. The fundamental hypothesis to be tested is that exposure to mercury may lead to immunological abnormality that either directly or indirectly compromises the health of the exposed individual.
The specific aims of this proposal are: (1) To determine if exposure of cells to low concentrations of inorganic mercury exacerbate the immunotoxic effects of organic mercury. Furthermore, we will extend these to determine if other forms of organic mercury are immunotoxic and if inorganic mercury alters the toxicity of these chemical species as well. In these studies we will determine the relative immunotoxicity of MeHg, ethyl mercury and phenyl mercury and determine if all effects on T-cell responses require monocytes. (2) To determine if mercuric compounds alter monocyte function and to explore the basis for the heightened sensitivity of monocytes to the toxic effects of mercury. We plan to determine the basis for the requirement of monocytes in mercury-mediated alterations in T-cell responsiveness. Also, we will test the hypothesis that the differences in lymphocyte and monocyte sensitivity to organic mercury is due to its rapid bioconversion to Hg++, which is a catalase dependent reaction. (3) To define the molecular basis for the immunomodulatory effects of organic mercury and the basis for the relative sensitivities of lymphoid cells to organic mercury. We will test the hypothesis that the mechanism by which mercury alters lymphocyte responsiveness is via the alteration in GSH and/or thiol status of the cell. (4) To develop an in vivo model system to study the immunotoxic effects of mercury on human lymphoid cells. We will utilize the SCID mouse system to extend our in vitro observations to an in vivo format that allows for biotransformations and """"""""sinks"""""""", to study the immunotoxicity of organic mercury, HgCl2 and HGO. Together, the results of these studies will further our understanding of mercury immunotoxicity. Furthermore, they will provide a basis for understanding the health implication associated with the use, abuse and disposal of these noxious compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE010873-05
Application #
2654442
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1994-02-01
Project End
1999-03-31
Budget Start
1998-02-01
Budget End
1999-03-31
Support Year
5
Fiscal Year
1998
Total Cost
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