The Research Support Core A (Computational Core) will develop mathematical models of toxicity pathways perturbed by the environmental contaminant 2,3,7,8-tetrachlorodiobenzo-p-dioxin (TCDD) and related compounds acting via the aryl hydrocarbon receptor (AhR) in support of Research Projects 1, 2, 3, and 4. The proposed models will be structured at a level of detail appropriate to the toxicological endpoints being pursued in the Projects, including immunotoxicity, embryotoxicity and bioenergetic disruption. Representing working hypotheses about the functions of the biological systems being studied and their perturbation by AhR ligands, these models will contain components and interactions that are experimentally well-validated as well as more tentative ones that are the focus of the proposed collaborative research. The potential of multidisciplinary collaborations is exemplified by our success in the last funding period, where coordinated modeling and experimental research has led to much improved understanding of how TCDD suppresses B lymphocyte differentiation through interfering with a bistable gene network and how stochastic gene expression influences the shape of dose response curves. None of these findings could have been made by laboratory experimentation or computational modeling alone. An essential feature of the current proposal is to continue this approach of coordinating laboratory studies with development of computational models, only more extensively.
Specific Aim 1 will implement a model of key regulatory motifs for the activation of primary human B cells by multiple cytokines and antigens, and the disruption of the activation processes by TCDD (in supporting Projects 1 and 2).
Under Specific Aim 2 a multi-organ model of bioenergetics will be developed, with the goal of better understanding how TCDD perturbs hepatic energy homeostasis, leading to fatty liver, alteration of choline metabolism, and disruption of mitochondrial function (in supporting Projects 3 and 4).
Under Specific Aim 3 we will support Project 2 by developing a computational model of early mouse pregnancy to investigate the mechanism by which TCDD suppresses embryonic implantation and study dose responses. Finally, in coordination with the Training Core, Specific Aim 4 will offer computational toxicology courses to Research Project trainees and investigators and the general Superfund Research community.

Public Health Relevance

Core A develops computational models of mechanisms of dioxin toxicity in cooperation with laboratory studies. This integrated approach - computational modeling and laboratory studies - efficiently generates new understanding of toxic mechanisms. The result is better characterization of the exposure-health risk relationship for the immune, liver and developmental effects of dioxins.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1-LWJ-D)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Michigan State University
East Lansing
United States
Zip Code
Stedtfeld, Robert D; Stedtfeld, Tiffany M; Waseem, Hassen et al. (2017) Isothermal assay targeting class 1 integrase gene for environmental surveillance of antibiotic resistance markers. J Environ Manage 198:213-220
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
Waseem, Hassan; Williams, Maggie R; Stedtfeld, Tiffany et al. (2017) Virulence factor activity relationships (VFARs): a bioinformatics perspective. Environ Sci Process Impacts 19:247-260
Fader, Kelly A; Nault, Rance; Kirby, Mathew P et al. (2017) Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERB?/? activation in aryl hydrocarbon receptor-elicited hepatotoxicity. Toxicol Appl Pharmacol 321:1-17
Kovalova, Natalia; Nault, Rance; Crawford, Robert et al. (2017) Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells. Toxicol Appl Pharmacol 316:95-106
Samhan, Farag A; Stedtfeld, Tiffany M; Waseem, Hassan et al. (2017) On-filter direct amplification of Legionella pneumophila for rapid assessment of its abundance and viability. Water Res 121:162-170
Li, Jinpeng; Bhattacharya, Sudin; Zhou, Jiajun et al. (2017) Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis. J Immunol 199:3504-3515
Stedtfeld, Robert D; Brett Sallach, J; Crawford, Robert B et al. (2017) TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal. Appl Microbiol Biotechnol 101:7409-7415
Dornbos, Peter; LaPres, John J (2017) Incorporating population-level genetic variability within laboratory models in toxicology: From the individual to the population. Toxicology 395:1-8
Ahmad, Farhan; Stedtfeld, Robert D; Waseem, Hassan et al. (2017) Most probable number - loop mediated isothermal amplification (MPN-LAMP) for quantifying waterborne pathogens in <25min. J Microbiol Methods 132:27-33

Showing the most recent 10 out of 390 publications