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 available 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 that have application for chemical detection and screening. Since effective development and application of bioassays/biomarkers is greatly facilitated by an understanding of the specific response of a cell to a given toxicant or class of toxicants, each of the four proposed approaches will exploit information derived from an analysis of the basic molecular mechanisms by which selected chemicals affect cellular receptors, signal transduction pathways and cellular/enzyme functions.
In Aim 1, stably transfected cell lines will be developed which respond to dioxin-like chemicals, steroid/thyroid hormones or hormone-like chemicals with the induction or inhibition of receptor-dependent expression of firefly luciferase or green fluorescent protein reporter genes. We will also develop a novel portable in vitro AhR-based bioassay for detection of dioxin-like chemicals.
In Aim 2, human keratinocytes will be used to examine genomic, proteomic and metabolomic effects following exposure to metals/metalloids and chemicals that produce oxidative stress to identify potential biomarkers that are specifically altered by these chemicals.
In Aim 3 in vitro and cell based bioassay systems will be used to examine the influence of superfund chemicals on regulatory lipids that control inflammation and to identify xenobiotics that alter expression and activity of soluble epoxide hydrolase.
Aim 4 proposes to develop and validate ryanodine receptor-based in vitro and intact cell bioassays to identify and characterize non-coplanar halogenated persistent organic pollutants that can affect calcium signaling pathways. In the final Aim, these assay systems will be integrated and optimized and then used in a series of validation studies for the detection and relative quantitation of toxic chemicals present in complex mixtures of chemicals extracted from a variety of matrices. Overall, the proposed studies will not only increase our basic knowledge of the biological and toxicological effects of a variety of Superfund priority chemicals, but the resulting specific bioassays and biomarkers that will be developed will provide rapid mechanistically-based screening systems for the 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 #
2P42ES004699-19
Application #
6900544
Study Section
Special Emphasis Panel (ZES1-SET-A (S4))
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
19
Fiscal Year
2005
Total Cost
$429,231
Indirect Cost
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Guedes, A G P; Aristizabal, F; Sole, A et al. (2018) Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t-TUCB in horses with experimentally induced radiocarpal synovitis. J Vet Pharmacol Ther 41:230-238
Heikenfeld, J; Jajack, A; Rogers, J et al. (2018) Wearable sensors: modalities, challenges, and prospects. Lab Chip 18:217-248
Minaz, Nathani; Razdan, Rema; Hammock, Bruce D et al. (2018) An inhibitor of soluble epoxide hydrolase ameliorates diabetes-induced learning and memory impairment in rats. Prostaglandins Other Lipid Mediat 136:84-89
Lassabe, Gabriel; Kramer, Karl; Hammock, Bruce D et al. (2018) Noncompetitive Homogeneous Detection of Small Molecules Using Synthetic Nanopeptamer-Based Luminescent Oxygen Channeling. Anal Chem 90:6187-6192
?ertíková Chábová, V?ra; Kujal, Petr; Škaroupková, Petra et al. (2018) Combined Inhibition of Soluble Epoxide Hydrolase and Renin-Angiotensin System Exhibits Superior Renoprotection to Renin-Angiotensin System Blockade in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats with Established Chronic Kidney Disease. Kidney Blood Press Res 43:329-349
Kodani, Sean D; Bhakta, Saavan; Hwang, Sung Hee et al. (2018) Identification and optimization of soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase. Bioorg Med Chem Lett 28:762-768
Rand, Amy A; Helmer, Patrick O; Inceoglu, Bora et al. (2018) LC-MS/MS Analysis of the Epoxides and Diols Derived from the Endocannabinoid Arachidonoyl Ethanolamide. Methods Mol Biol 1730:123-133
Li, Xueshu; Holland, Erika B; Feng, Wei et al. (2018) Authentication of synthetic environmental contaminants and their (bio)transformation products in toxicology: polychlorinated biphenyls as an example. Environ Sci Pollut Res Int 25:16508-16521
Mao, Yuxin; Pan, Yang; Li, Xuan et al. (2018) High-precision digital droplet pipetting enabled by a plug-and-play microfluidic pipetting chip. Lab Chip 18:2720-2729
Burmistrov, Vladimir; Morisseau, Christophe; Harris, Todd R et al. (2018) Effects of adamantane alterations on soluble epoxide hydrolase inhibition potency, physical properties and metabolic stability. Bioorg Chem 76:510-527

Showing the most recent 10 out of 1149 publications