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METABOLOMICS AS A TOOL FOR DISCRIMINATING AMONG ADAPTIVE, COMPENSATORY, AND TOXIC RESPONSES UPON EXPOSURE OF SMALL FISH TO EDCS
Citation:
EKMAN, D. R., T. W. COLLETTE, Q. TENG, G. T. ANKLEY, D. MARTINOVIC, K. M. JENSEN, AND D. L. VILLENEUVE. METABOLOMICS AS A TOOL FOR DISCRIMINATING AMONG ADAPTIVE, COMPENSATORY, AND TOXIC RESPONSES UPON EXPOSURE OF SMALL FISH TO EDCS. Presented at Society for Environmental Toxicology and Chemistry Annual Meeting, Milwaukee, WI, November 13 - 17, 2007.
Impact/Purpose:
This task is divided into four major research areas: (1) Development of computational tools and databases for screening-level modeling of the environmental fate of organic chemicals; (2) Metabolism of xenobiotics: Enhancing the development of a metabolic simulator; (3) Metabonomics: The use of advanced analytical tools to identify toxicity pathways; and (4) Software infrastructure to support development and application of transformation/metabolic simulators.
For many chemicals, multiple transformation/metabolic pathways can exist. Consequently, transformation/metabolic simulators must utilize transformation rate data for prioritization of competing pathways. The prioritization process thus requires the integration of reliable rate data. When this data is absent, it is necessary to generate a database with metabolic and transformation rate constants based on: (1) experimentally measured values, including those requiring the use of advanced analytical techniques for measuring metabolic rate constants in vivo and in vitro; (2) rate constants derived from SPARC and mechanistic-based QSAR models; and (3) data mined from the literature and Program Office CBI. A long-term goal of this project is to build this database. This information will be used to enhance the predictive capabilities of the transformation/metabolic simulators. As indicated previously, exposure genomics, which provide early signs of chemical exposure based on changes in gene expression, will be used to guide chemical fate and metabolism studies. The incorporation of exposure genomics into fate studies will provide information concerning (1) the minimal concentrations at which biological events occur; and (2) the identification of biologically relevant chemicals(s) in mixtures.
The capability of categorizing chemicals and their metabolites based on toxicity pathway is imperative to the success of the CompTox Research Program. Metabonomics, which is the multi-parametric measurement of metabolites in living systems due to physiological stimuli and/or genetic modification, provides such a capability. The application of metabonomics to toxicity testing involves the elucidation of changes in metabolic patterns associated with chemical toxicity based on the measurement of component profiles in biofluids, and enables the generation of spectral profiles for a wide range of endogenous metabolites. Metabolic profiles can provide a measure of the real outcome of potential changes as the result of xenobiotic exposure.
Description:
Determining the impact(s) of exposure on aquatic organisms by endocrine disrupting compounds (EDCs) is essential for determining the risks that these chemicals pose. However, to accurately evaluate these risks, beyond simply measuring a before and after exposure snapshot, researchers must assess the ability of the exposed organisms to adapt or compensate for the presence of these compounds. The extent of true harm from sub-lethal exposure is often a complex relationship of both time and chemical concentration. Due to the large number of samples required to map this complex response profile, a robust molecular technique with low per-sample cost of analysis is desirable. Therefore, we have employed a metabolomics approach for studying these responses in small fish toxicity models (e.g., fathead minnow) using nuclear magnetic resonance (NMR) spectroscopy. This approach provides the ability to measure molecular responses in different tissue and biofluid types, both rapidly and inexpensively, making it ideal for this application. Using this approach, we have been able to observe apparent compensatory responses to the presence of EDCs over the duration of an exposure. Furthermore, it appears that after the chemical has been removed from the water (i.e. during a depuration phase) that fish are able in some cases to return to a near pre-exposure state, providing evidence of partial recovery. These results demonstrate the potential of this approach for improving the assessment of risk(s) that various EDCs pose to sentinel small fish species.