Mechanisms of Immunotoxcity of Chemical Stressors

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DESCRIPTION (Adopted from the Applicant's Abstract): This project is a continuation of studies that demonstrated the feasibility of using the area under the concentration vs. time curve (AUC) for corticosterone to predict the effects of chemical stressors on several immunological parameters. An understanding of the quantitative contributions of stress-related neuroendocrine mediators, not just their involvement or lack of involvement, is necessary to fully understand the mechanisms of immunosuppression by chemical stressors. Therefore, the following hypothesis will be tested: Mathematical modeling using the AUC for corticosterone (in mice) or cortisol (in humans) can be used to demonstrate quantitative relationships between a) the initial molecular signaling events induced by glucocorticoids in mice, b) the effects of acute or 28-day exposure to stressors on a number of immunological parameters and on host resistance to cancer or infection in mice, and C) alteration of immunological parameters in mice and alteration of analogous parameters in humans. The Specific Aims for the project are: Specific Aim 1 - Acquire data and develop mathematical models relating corticosterone AUC in mice treated with exogenous corticosterone, restraint stress, and three chemical stressors (propanil, ethanol, and deltamethrin) to the following indicators of corticosterone-mediated signaling: translocation of glucocorticoid receptor to the nucleus, increased binding of nuclear proteins to DNA sequences known to bind glucocorticoid receptor and NF-KB, increased concentration of 1KB protein in the cytoplasm, and decreased concentration of NF-kB in the nucleus. Specific Aim 2- Acquire data and develop mathematical models using acute and 28- day exposure of mice to exogenous corticosterone, restraint stress, and three chemical stressors to relate corticosterone AUC to selected immunological parameters and to host resistance against Bi 6F1 0 tumor cells and Trichinella spiralis. Specific Aim 3- Acquire data and develop mathematical models relating cortisol AUC and selected immunological parameters in human subjects treated with an infusion of exogenous cortisol for various periods of time. Specific Aim 4 - Use the models developed in Specific Aims 1-310 determine the quantitative relationships between the parameters examined and to develop predictive models that will allow estimation of the effects of chemical stressors on immunological parameters and host resistance in humans. If the hypothesis is correct, the results obtained here will improve risk assessment by allowing rational estimates of the effects of chemical stressors on immune function and resistance to infection and cancer in humans on the basis of results from mice.