Activated neutrophils (PMNs) play a role in host defense against pathogens. Depression of PMN function due to exposure to hazardous substances may lead to impaired ability to mount an adequate immune response. On the other hand, stimulation of PMNs due to chemical exposure may lead to inappropriate activity, such as release of superoxide anion (O2) or lysosomal enzymes that could initiate or potentiate tissue injury. Thus, PMNs may serve as useful biological markers of effect of exposure to hazardous chemicals and as monitors of biological activity of products of biodegradation of environmental contaminants. Accordingly, the overall goals of the proposed research are to test the hypotheses that hazardous chemicals and/or their metabolites affect PMN function, and that these alterations contribute to tissue injury. An additional goal is to determine whether remediation products of hazardous chemicals alter PMN function. The effects of selected hazardous chemicals (volatile organic chemicals, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons) on function of rat peritoneal and human blood PMNs in vitro will be examined, and mechanisms will be explored. Secondly, metabolites generated by rat liver cells exposed in culture to the hazardous chemicals will be tested for the ability to alter PMN function in vitro. In addition, in vitro function of PMNs from rats exposed in vivo to hazardous chemicals and their metabolites on differentiation of stem cells to PMNs. To address the role of activated PMNs in tissue injury, toxicity to isolated liver cells cocultured with PMNs and exposed to hazardous chemicals will be assessed. PMN-dependent toxicity in vivo will be evaluated in rats treated with hazardous chemicals alone or in combination. These studies will increase our understanding of effects of hazardous chemicals on PMN function and how those effects contribute to tissue injury.

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Michigan State University
East Lansing
United States
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Nault, Rance; Doskey, Claire M; Fader, Kelly A et al. (2018) Comparison of Hepatic NRF2 and Aryl Hydrocarbon Receptor Binding in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Treated Mice Demonstrates NRF2-Independent PKM2 Induction. Mol Pharmacol 94:876-884
Dornbos, Peter; LaPres, John J (2018) Incorporating population-level genetic variability within laboratory models in toxicology: From the individual to the population. Toxicology 395:1-8
Zhang, Shuai; Liu, Qinfu; Gao, Feng et al. (2018) Interfacial Structure and Interaction of Kaolinite Intercalated with N-methylformamide Insight from Molecular Dynamics Modeling. Appl Clay Sci 158:204-210
Fader, Kelly A; Nault, Rance; Raehtz, Sandi et al. (2018) 2,3,7,8-Tetrachlorodibenzo-p-dioxin dose-dependently increases bone mass and decreases marrow adiposity in juvenile mice. Toxicol Appl Pharmacol 348:85-98
Zhang, Shuai; Liu, Qinfu; Cheng, Hongfei et al. (2018) Mechanism Responsible for Intercalation of Dimethyl Sulfoxide in Kaolinite: Molecular Dynamics Simulations. Appl Clay Sci 151:46-53
Zhang, Qiang; Li, Jin; Middleton, Alistair et al. (2018) Bridging the Data Gap From in vitro Toxicity Testing to Chemical Safety Assessment Through Computational Modeling. Front Public Health 6:261
Fader, K A; Nault, R; Kirby, M P et al. (2018) Corrigendum to ""Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERB?/? activation in aryl hydrocarbon receptor-elicited hepatotoxicity"" [Toxicol. Appl. Pharmacol. 321 (2017) 1-17]. Toxicol Appl Pharmacol 344:74
Konganti, Kranti; Ehrlich, Andre; Rusyn, Ivan et al. (2018) gQTL: A Web Application for QTL Analysis Using the Collaborative Cross Mouse Genetic Reference Population. G3 (Bethesda) 8:2559-2562
Zhang, Shuai; Liu, Qinfu; Gao, Feng et al. (2018) Molecular Dynamics Simulation of Basal Spacing, Energetics, and Structure Evolution of a Kaolinite-Formamide Intercalation Complex and Their Interfacial Interaction. J Phys Chem C Nanomater Interfaces 122:3341-3349
Fader, Kelly A; Nault, Rance; Zhang, Chen et al. (2017) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-elicited effects on bile acid homeostasis: Alterations in biosynthesis, enterohepatic circulation, and microbial metabolism. Sci Rep 7:5921

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