This project will develop and implement a novel integrative biology approach to investigate chemical-induced stress and injury mechanisms at the cell and tissue level caused by selected PAHs. Precision cut tissue slices of liver and kidney will be exploited to non-invasively detect and analyze well-chosen endpoints using a novel """"""""cellulomics"""""""" approach in order to begin bridging the gap between in vitro and in vivo models for mechanistic analysis of cellular injury. Animal models of susceptible phenotypes including mice with polymorphic variations of the AhR that result in dioxin-sensitive (C57BL6J) and resistant (DBA2) phenotypes, a transgenic mouse possessing the human AhR (hAhR; the hAhR knock-in) and an AhR knock-out mouse will be utilized to identify PAH effects on altered cellular homeostasis and how this may contribute to disease risk. While the proposed investigations will initially focus on a few PAHs and two organ systems, the tools and approaches developed will have wide applicability to high throughput organ- and tissue-level assessment of cellular responses caused by model PAHs and complex mixtures as well as for new and/or untested chemicals. Model PAH compounds selected for this investigation include benzo[a]pyrene (BaP), benzo[e]pyrene (BeP), 5-methylchrysene (5MCr), and 3-methylcholanthrene (SMC). The inherent fluorescence of PAHs will be utilized to map the distribution and in situ metabolism of BaP, BeP, 5MCr and SMC in the precision-cut liver and kidney slices of the mouse models. Cellular homeostasis mechanisms will also be assessed and include analysis of intracellular Ca2+ homeostasis and signaling mechanisms as both a sentinel and an effector of cellular injury along with a combination of other functional homeostasis parameters including gap junction mediated intercellular communication, reactive oxygen species and nitric oxide production, glutathione and glutathione-S-transferase activity, mitochondrial function, lipid peroxidation, cytochrome P450 enzyme induction, P-glycoprotein induction and apoptosis/necrosis. Once optimized, these cellulomics investigations will be extended to binary and complex mixtures of PAHs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES004917-19
Application #
7404534
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
19
Fiscal Year
2007
Total Cost
$130,172
Indirect Cost
Name
Texas A&M University
Department
Type
DUNS #
078592789
City
College Station
State
TX
Country
United States
Zip Code
77845
Phillips, Tracie D; Richardson, Molly; Cheng, Yi-Shing Lisa et al. (2015) Mechanistic relationships between hepatic genotoxicity and carcinogenicity in male B6C3F1 mice treated with polycyclic aromatic hydrocarbon mixtures. Arch Toxicol 89:967-77
Barhoumi, Rola; Mouneimne, Youssef; Chapkin, Robert S et al. (2014) Effects of fatty acids on benzo[a]pyrene uptake and metabolism in human lung adenocarcinoma A549 cells. PLoS One 9:e90908
dela Cruz, Albert Leo N; Cook, Robert L; Dellinger, Barry et al. (2014) Assessment of environmentally persistent free radicals in soils and sediments from three Superfund sites. Environ Sci Process Impacts 16:44-52
Wlodarczyk, Bogdan J; Zhu, Huiping; Finnell, Richard H (2014) Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity. Toxicol Appl Pharmacol 275:22-7
Taylor, John F; Robinson, Abraham; Mitchell, Nicole J et al. (2013) In vivo efficacy of ferrihydrite as an enterosorbent for arsenic: short-term evaluation in rodents. J Toxicol Environ Health A 76:167-75
Theodorakis, Christopher W; Bickham, John W; Donnelly, Kirby C et al. (2012) DNA damage in cichlids from an oil production facility in Guatemala. Ecotoxicology 21:496-511
Dash, Bhagirathi; Phillips, Timothy D (2012) Molecular characterization of a catalase from Hydra vulgaris. Gene 501:144-52
Barhoumi, Rola; Mouneimne, Youssef; Ramos, Ernesto et al. (2011) Multiphoton spectral analysis of benzo[a]pyrene uptake and metabolism in a rat liver cell line. Toxicol Appl Pharmacol 253:45-56
Kelley, Matthew A; Gillespie, Annika; Zhou, Guo-Dong et al. (2011) In situ biomonitoring of caged, juvenile Chinook salmon (Oncorhynchus tshawytscha) in the Lower Duwamish Waterway. Mar Pollut Bull 62:2520-32
Rinner, Brian P; Matson, Cole W; Islamzadeh, Arif et al. (2011) Evolutionary toxicology: contaminant-induced genetic mutations in mosquitofish from Sumgayit, Azerbaijan. Ecotoxicology 20:365-76

Showing the most recent 10 out of 268 publications