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Abstract
Mercury is a widespread metal in the environment and consequently there are large populations that are currently exposed to low levels of mercury as a result of ubiquitous environmental factors. Mercury is highly toxic and moderate levels of exposure to mercury can cause immune system alterations and decrease host resistance to viral infections in mice. Although mercury is broadly sulfhydryl reactive, surprisingly little is understood as to the specific cellular targets and biochemical pathways targeted by this metal. The objectives of the present studies were to define the role of immune effector functions in mercury-induced immunotoxicity and related signaling cascade. Mercury interferes with lipopolysaccharide (LPS)-mediated immune response. We show here that mercury inhibited nitric oxide (NO) production and altered inflammatory cytokine expressions. This study indicates that mercury suppresses NO synthesis by inhibition of the nuclear factor .B pathway and modulates cytokine expression by p38 mitogen-activated protein kinase (MAPK) activation in J774A.1 macrophages. Mercury generates reactive oxygen species (ROS) and lipid peroxidation, suggesting that the generated ROS is involved in mercury-induced cytotoxicity. Mercury decreased mitochondrial transmembrane potential and increased ROS generation, and consequent depletion of GSH and lipid peroxidation, which is the major cause of mercury-induced cytotoxicity. In addition, alterations of calcium homeostasis are also involved in mercuryinduced cytotoxicity. Alteration of ROS regulates MAPK, one of the most important members in control cell signaling. The results of these studies revealed that mercury-induced ROS regulates MAPKs and these MAPKs are important mediator of mercury immunotoxicity. Mercury altered T lymphocyte population in spleen and thymus. Mercury altered the expression of inflammatory cytokines, c-myc, and major histocompatibility complex II in liver, kidney, spleen, and thymus. Results indicated that decreases in T lymphocyte populations in immune organs and altered cytokine gene expression contribute to the immunosuppressive effects of mercury. Additionally, mercury augment subtoxic dose of LPS-mediated proinflammatory cytokine expression by altering GSH regulated p38 MAPK in liver. Taken together, the results of these studies further strengthen the role of oxidative stress in mercury immunotoxicity. We have also identified a new mechanism by which mercury-induced ROS regulate MAPK-mediated cytokine expression.