Role of key microbial populations of the gut microbiome in formulating host response as a result of 2,3,7,8- tetrahlorodibenzo-p-dioxin (TCDD) exposure is only beginning to be studied. Evidence suggests that gut microbiome is intricately linked to the host response and is also impacted directly and indirectly by exposure to environmental contaminants. In this project two such interactions are proposed to be studied using C57BL/6 germ free, mono-associated, cocktail associated and traditionally raised mouse models. The first is related to Treg/Th17 immune regulatory system and its dysbiosis in response to dioxin exposure and the second is related to choline-trimethylamine (TMA) pathway and its modulation. Dysbiosis of Treg/Th17 system has a broad range of health effects due to its central role in the immune regulatory system. It may lead to autoimmune diseases such as arthritis, inflammatory bowel disease, and skin cancer. Recently, specific members of the gut community, such as segmented filamentous bacteria (SFBs for which whole genome sequences are now available) and cluster IV and XlVa Clostridia, and Bacteroides fragilis have been implicated in regulating the Treg/Th17 system. The Treg/Th17 balance is also impacted by dioxin because AhR promotes the generation of Foxp3+ Treg and suppresses the differentiation to IL-17 producing ROR-yt Thi7. Thus specific populations of the gut microbiome, the Treg/Th17 balance, and TCDD via its AhR system are interconnected. Its mis-regulation may lead to disease outcomes. Project 4 establishes these specific and opposing """"""""mechanisms"""""""" of regulation in germ-free mice using SFBs, 6. fragilis, and cluster IV and XlVa Clostridia and studies the role of these gut microbial populations in making the host less or more susceptible to health effects of dioxins. Evaluation of the transcriptome response of cluster IV and XlVa Clostridia and SFBs in response to TCDD, 2,3,4,7,9-PeCDF, and 2,3,7,8-TCDF exposure is also proposed. Project 4 also examines the effects of TCDD and related compounds on the metabolism of choline by the host and the gut microbiome, and the potential roles in the development of fatty liver and altering urinary trimethylamine/trimethylamine-N-oxide (TMA/TMAO) ratios. The effects are being studied in collaboration with Projects 1 (Kaminski/Kaplan), 3 (Zacharewski), 5 (Zylstra), and 6 (Boyd) and Research Support Cores A and B. The results are disseminated to communities and researchers through the Community Engagement Core and Research Translation Core. Student projects are designed to be incorporated in the Training Core.

Public Health Relevance

Selected bacterial members of the gut are emerging as regulators of the immune system. In this project, the role of three leading groups of bacteria in modulating the immune system and their interaction with the host in response to dioxin exposure will be evaluated using germ-free mouse models. Results of this study will be useful in determining the protective role of gut bacteria against environmental exposure to dioxin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES004911-23
Application #
8695354
Study Section
Special Emphasis Panel (ZES1-LWJ-D)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
23
Fiscal Year
2014
Total Cost
$246,113
Indirect Cost
$82,277
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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; 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

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