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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES009158-05
Application #
6332257
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Mastin, Patrick
Project Start
1997-06-01
Project End
2006-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
5
Fiscal Year
2001
Total Cost
$205,350
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Tan, Wei; Pruett, Stephen B (2015) Effects of sodium methyldithiocarbamate on selected parameters of innate immunity and clearance of bacteria in a mouse model of sepsis. Life Sci 139:1-7
Pruett, Stephen B; Fan, Ruping; Zheng, Qiang et al. (2009) Patterns of immunotoxicity associated with chronic as compared with acute exposure to chemical or physical stressors and their relevance with regard to the role of stress and with regard to immunotoxicity testing. Toxicol Sci 109:265-75
Pruett, Stephen B; Fan, Ruping; Zheng, Qiang (2006) Involvement of three mechanisms in the alteration of cytokine responses by sodium methyldithiocarbamate. Toxicol Appl Pharmacol 213:172-8
Dai, Qun; Zhang, Jun; Pruett, Stephen B (2005) Ethanol alters cellular activation and CD14 partitioning in lipid rafts. Biochem Biophys Res Commun 332:37-42
Pruett, Stephen B; Zheng, Qiang; Schwab, Carlton et al. (2005) Sodium methyldithiocarbamate inhibits MAP kinase activation through toll-like receptor 4, alters cytokine production by mouse peritoneal macrophages, and suppresses innate immunity. Toxicol Sci 87:75-85
Pruett, Stephen B; Padgett, Eric L (2004) Thymus-derived glucocorticoids are insufficient for normal thymus homeostasis in the adult mouse. BMC Immunol 5:24
Pruett, Stephen B; Fan, Ruping; Zheng, Qiang et al. (2003) Modeling and predicting immunological effects of chemical stressors: characterization of a quantitative biomarker for immunological changes caused by atrazine and ethanol. Toxicol Sci 75:343-54
Hebert, P; Pruett, S B (2001) Selective loss of viability of mouse NK cells in culture is associated with decreased NK cell lytic function. In Vitr Mol Toxicol 14:71-82
Myers, L P; Krieg, A M; Pruett, S B (2001) Bacterial DNA does not increase serum corticosterone concentration or prevent increases induced by other stimuli. Int Immunopharmacol 1:1605-14
Pruett, S B; Fan, R (2001) Quantitative modeling of suppression of IgG1, IgG2a, IL-2, and IL-4 responses to antigen in mice treated with exogenous corticosterone or restraint stress. J Toxicol Environ Health A 62:175-89

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