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Final Progress Reports: University of California-Davis: Analytical Chemistry Core

Superfund Research Program

Analytical Chemistry Core

Project Leader: Jun Yang
Co-Investigators: Bruce D. Hammock, Bruce A. Buchholz (Lawrence Livermore National Laboratory)
Grant Number: P42ES004699
Funding Period: 1995-2023
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Final Progress Reports

Year:   2014  2009  2004 

The analytical core provides service to the program, while advancing analytical technology to provide more sophisticated service in the future.  As an example of this approach, in the last competitive renewal the core proposed to develop the new field of metabolomics.  Like other high throughput technologies, metabolomics is based on the hypothesis that it is often as easy to monitor many analytes as one.  Just as transcriptomics monitors transcripts and proteomics monitors proteins, metabolomics monitors metabolites or small molecules.  There are two divergent approaches to generating metabolomic data.  One monitors all of the metabolites that can be reached by a given platform, while the other is to develop highly quantitative, accurate and precise analytical methods for all of the metabolites in a family or pathway.  These methods are not mutually exclusive, and the long-term goal is to gain insight from quantitative data on many metabolites.  Although many platforms can be used, mass spectrometry and nuclear magnetic resonance are the two techniques most commonly used and form the basis of the team’s efforts.

During the last several years the analytical core has developed an analytical method to monitor over 50 oxylipin metabolites of polyunsaturated lipids.  These metabolites are important regulators of cell proliferation, glucose metabolism, inflammation and both vascular and renal physiology.  Past approaches have monitored only several metabolites, while it is now possible to monitor representative metabolites of the COX, LOX, and P450 branches of these cascades. These procedures are being used to investigate changes in inflammatory signaling associated with both nitro-naphthalene and arsenic exposure.

Systems have been developed to monitor structural and nutritional lipids.  Such assays may provide great insight as obesity, diabetes and other metabolomic diseases are increasing.  In collaboration with the NIEHS Children’s Center the researchers have developed a method to monitor metabolites in the tryptophan pathway to test the hypothesis that alterations in this pathway lead to neurological symptoms.  The team is also developing methods for the vitamin D cascade related to calcium regulation and obesity.  This work has largely been done by LC-MS on a triple quadrupole instrument.

AMS served 2 research projects in 2004, with 94 measurements made for the Cellular Biomarkers project and 180 measurements for the Reproductive Biomarkers project.  Cell Biomarkers of exposure to the recently banned gasoline additive MTBE were sought by exposing cells to MTBE containing 14C isotopic labels. AMS then quantified the amount of 14C found in cellular proteins that had been isolated and purified. Very little 14C was found in the proteins, but the proteins had been treated to a harsh preparation method that left them unfolded. The investigators conclude that the MTBE that is taken into cells does not bind strongly to proteins, but may bind loosely to them by capture in folded pockets. Reproductive Biomarkers that can be quantified in animal droppings, such as the hormone testosterone, indicate environmental influences on animals without the need to handle the wild animals, such as birds. AMS quantified the metabolites of testosterone containing a 14C isotope label from Japanese quails. The goal is to find which of the many metabolites from testosterone are the best stress indicators for development of immunoassays for field work.  Only isotopic labeling of the hormone can reveal all of the metabolites that can be found in the droppings, even if their identities are not known. The researchers’ technique is the only method of getting quantitative measures of all metabolites from a single dropping of a single small bird. This provides greater discrimination of natural variations from unnatural environmental effects.

Finally the core also is approaching the broad based analysis of metabolites using LC-time of flight (TOF) MS.  The method yields very data-rich files, which the team is interpreting with the statistics core.  Using these methods novel biomarker of arsenic exposure has been observed in cell culture systems. Elucidation of the identity of this molecule is a current priority.  The researchers are also exploring the use of FT-MS and NMR approaches for broad profiling.

There are broad implications of this work.  One of the most far reaching will be individual diagnosis where the team moves from a Chem20 panel to a Chem200 or 2000.  The goal is not to simply present medical professionals data, but rather deliver understanding of health and disease.  Of course the major short-term application will be as a research tool to elucidate the effects of environmental contaminants on living systems using both metabolomic data individually and data integrated with the output from other omic technologies.

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