Extensive communication exists between the central nervous system (CNS) and the immune system, involving shared transmitters and modulators. Thus, composure to the gram-negative bacteria cell wall component lipopolysaccharide (LPS), a ubiquitous environmental contaminant, results in neural and immune alterations including long-lasting reductions in brain dopamine (DA) concentrations and an elicitation of an inflammatory response. Similarly, exposure to polychlorinated biphenyls (PCBs), a widely distributed environmental toxicant, causes neuro- and immunotoxic effects including a reduction in brain DA concentrations and alterations in immune functions such as increased respiratory burst activity of neutrophils. In order to further understanding of the PCBs alter CNS and immune functions we will assess neural and immune function in mice following exposure to PCBs and LPS alone or in combination. Analysis of mixtures of environmental agents are critical for risk assessments. Since both agents are widely distributed in the environment there is likelihood for a combined exposure to the two. Because of the extreme cross-talk between the nervous and immune systems we will (i) experimentally alter the activity of each system and determine the neurological and immunological consequences to the initially unperturbed system (by striatal DA depletion and LPS challenge) and (ii) determine the neurological and immunological consequences of exposure to PCBs, either alone or in combination with LPS. We hypothesize that combined exposure to PCB mixture and LPS causes a greater depletion in striatal DA and in augmented inflammatory response compared to exposure to PCBs or LPS alone. Many past studies have addressed the neurotoxic and immunotoxic effects of PCBs, but none addressed effects on the regulatory neuro endocrine immune circuit including the involvement of dopaminergic neurons. Striatal DA will be reduced pharmacologically and the effect of the reduction on central and peripheral cytokine production and on peripheral immune reactivity will be assessed. Next, the role of central reduction on central and peripheral cytokine production and on peripheral immune reactivity will be assessed. Next, the role of central and peripheral LPS and PCB mixture administration separately or in combination on brain dopamine, cytokines, and peripheral immune reactivity will be examined. Successful completion of the proposed research will help reveal the role of brain dopamine on peripheral immune reactivity and how combined exposure to PCBs and LPS alter the neurotoxic and inflammatory/immune responses compared to an exposure to PCBs or LPS alone.
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