Hazardous waste sites contain complex mixtures of a wide variety of toxic chemicals. Unfortunately, development of rapid and inexpensive detection of specific chemicals or chemical classes in environmental and biological samples has been hampered by the lack of specific bioassay/biomarker systems. Accordingly, the overall goals of this project are to develop and validate a series of mechanistically-based cell and in vitro bioassays/biomarkers with applications to chemical detection and screening. Since effective development and application of bioassays/biomarkers is greatly facilitated by an understanding of the specific responses of cell to a given toxicant(s), each of the four proposed approaches will exploit information derived from analysis of the mechanisms by which selected chemicals affect cellular receptors, signal transduction pathways and/or cellular/enzyme functions.
In Aim 1, stably transfected cell lines will be developed as bioassays for ultra-low levels of dioxin-like or steroid hormone-like chemicals with the induction of receptor-dependent reporter gene expression. Chemical-specific recombinant AhRs will be generated to improve both cell and in vitro AhR based bioassay systems.
In Aim 2, human keratinocytes will be used to examine specific intracellular proteomic changes that occur in response to exposure to arsenicals and to identify potential biomarkers specifically altered by these chemicals.
In Aim 3, high throughput in vitro and cell-based bioassays will be used to examine the influence of Superfund chemicals on the production of regulatory lipids controlling cardiovascular diseases, inflammation and pajn.
In Aim 4, structure activity relationships will be established for a series of brominated flame retardants and their metabolites and the antimicrobial agent triclosan for their ability to alter ryanodine receptor signaling functions and the resulting impact on neuron growth and plasticity. In the final Aim, integrated bioassay/biomarkers will be used to identify and characterize the biochemical and toxicological effects of individual chemicals and complex mixtures of chemicals.

Public Health Relevance

These studies will increase our basic knowledge of the biological/toxicological effects of various Superfund priority chemicals and will generate rapid mechanistically-based bioassay screening systems for detection of toxicants and toxicant exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES004699-26
Application #
8375382
Study Section
Special Emphasis Panel (ZES1-LWJ-M)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
26
Fiscal Year
2012
Total Cost
$560,787
Indirect Cost
$198,897
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Bettaieb, Ahmed; Koike, Shinichiro; Chahed, Samah et al. (2017) Podocyte-specific soluble epoxide hydrolase deficiency in mice attenuates acute kidney injury. FEBS J 284:1970-1986
Frederich, Bert J; Timofeyev, Valeriy; Thai, Phung N et al. (2017) Electrotaxis of cardiac progenitor cells, cardiac fibroblasts, and induced pluripotent stem cell-derived cardiac progenitor cells requires serum and is directed via PI3'K pathways. Heart Rhythm 14:1685-1692
Denison, Michael S; Faber, Samantha C (2017) And Now for Something Completely Different: Diversity in Ligand-Dependent Activation of Ah Receptor Responses. Curr Opin Toxicol 2:124-131
Islam, Oliul; Patil, Prashanth; Goswami, Sumanta K et al. (2017) Inhibitors of soluble epoxide hydrolase minimize ischemia-reperfusion-induced cardiac damage in normal, hypertensive, and diabetic rats. Cardiovasc Ther 35:
Bettaieb, Ahmed; Koike, Shinichiro; Hsu, Ming-Fo et al. (2017) Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia. Biochim Biophys Acta 1861:2758-2765
Hvorecny, Kelli L; Bahl, Christopher D; Kitamura, Seiya et al. (2017) Active-Site Flexibility and Substrate Specificity in a Bacterial Virulence Factor: Crystallographic Snapshots of an Epoxide Hydrolase. Structure 25:697-707.e4
Fan, Jinzhen; Villarreal, Fernando; Weyers, Brent et al. (2017) Multi-dimensional studies of synthetic genetic promoters enabled by microfluidic impact printing. Lab Chip 17:2198-2207
Zhang, Yue; Hong, Gina; Lee, Kin Sing Stephen et al. (2017) Inhibition of soluble epoxide hydrolase augments astrocyte release of vascular endothelial growth factor and neuronal recovery after oxygen-glucose deprivation. J Neurochem 140:814-825
Vasylieva, Natalia; Barnych, Bogdan; Wan, Debin et al. (2017) Hydroxy-fipronil is a new urinary biomarker of exposure to fipronil. Environ Int 103:91-98
Rand, Amy A; Barnych, Bogdan; Morisseau, Christophe et al. (2017) Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids. Proc Natl Acad Sci U S A 114:4370-4375

Showing the most recent 10 out of 1104 publications