Citation:

COLLETTE, T. W. METABOLOMICS IN SMALL FISH TOXICOLOGY AND OTHER ENVIRONMENTAL APPLICATIONS. Presented at Fort Johnson Marine Science Seminar Series, Charleston, SC, October 19, 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:

Although lagging behind applications targeted to human endpoints, metabolomics offers great potential in environmental applications, including ecotoxicology. Indeed, the advantages of metabolomics (relative to other 'omic techniques) may be more tangible in ecotoxicology because there is often not a sequenced genome available for ecologically relevant species. We are conducting metabolomics studies on small fish, such as the fathead minnow, that are used both as model organisms in ecotoxicology research, and in regulatory testing programs. Our goal is to use information from these studies to meet EPA's mission to protect ecosystems from potentially harmful effects of chemical pollutants. For example, as part of a project involving a large, interdisciplinary team of scientists from US government, academia, and industry, we are integrating transcriptomic, proteomic, and metabolomic data to describe endocrine disruption in the fathead minnow. We seek to understand how chemical exposures are linked through early molecular changes to whole-organism adverse outcomes and, ultimately, to changes in population status. To achieve this goal, a systems-based approach is being used to define toxicity pathways for model chemicals with well defined modes of action within the hypothalamic-pituitary-gonadal (HPG) axis of the fathead minnow. We will describe the unique role that metabolomics plays in this, and in other, important environmental applications.

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