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University of California-Davis

Superfund Research Program

Development and Application of Integrated In Vitro and Cell-Based Bioassays

Project Leader: Michael S. Denison
Co-Investigator: Isaac N. Pessah
Grant Number: P42ES004699
Funding Period: 1995-2015
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Project Summary (2010-2015)

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 are being 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 are being generated to improve both cell and in vitro AhR based bioassay systems.

In Aim 2, human keratinocytes are being 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 are being used to examine the influence of Superfund chemicals on the production of regulatory lipids controlling cardiovascular diseases, inflammation and pain.

In Aim 4, structure activity relationships are being 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 are being used to identify and characterize the biochemical and toxicological effects of individual chemicals and complex mixtures of chemicals.

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