Impact/Purpose:

Improving Linkages in the Source-to-Outcome Paradigm - Development and Implementation of Advanced Biological Models and Systems Biology

Description:

Diesel exhaust particulate matter (DEP) is a ubiquitous ambient air contaminant derived from mobile and stationary diesel fuel combustion. Exposure to DEP is associated with carcinogenic and immunotoxic effects in humans and experimental animals. At the cellular level, these health effects are underlain by genotoxic and inflammatory properties of chemical compounds present in DEP. DEP is composed of elemental, inorganic and organic compounds that vary widely in composition with the source of the fuel, engine operating conditions, sampling methods and other parameters. The genotoxic and inflammatory potencies of DEP also vary with its physicochemical properties, and these differences along with multiple health effects impede the development of targeted regulatory strategies for mitigating the impact of DEP exposure on human health. While traditional reductive toxicology approaches are not likely to succeed in quantifying relationships between DEP composition and its numerous health effects, generating a database for modeling the toxicological effects of DEP would provide a framework for quantitative hazard identification. This project proposes a systems approach to developing and applying predictive computational models that quantitatively describe relationships between the composition of DEP and its genotoxic and inflammogenic potencies.

Record Details:

Record Type:PROJECT

Projected Completion Date:09/30/2008

OMB Category:Other

Record ID: 149110

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Project Information:

Approach :The objectives of this project will be met by conducting research in three phases. In phase 1 (Specific Aim 1), 16 distinct DEP will be generated using a combination of fuels, engine types, engine loads and collection temperatures. These DEP will then be characterized through extensive chemical and physical analyses. In phase 2 (Specific Aims 2 and 3), the inflammogenic and genotoxic potencies of each of the 16 DEP will be determined quantitatively. Specific bioassays will measure the expression of the pivotal inflammatory mediator IL-8/MIP-2 in cultured human and mouse lung cells in response to DEP exposure. Signaling mechanisms that regulate the expression of IL-8/MIP-2 in response to DEP exposure will also be examined in order to provide mechanistic insight and support for the models. The genotoxicity of the 16 DEP will be assayed using bacterial mutagenicity assays. Human, mouse and bacterial gene expression arrays will be used to provide additional mechanistic insights on patterns of gene expression induced by DEP. Phase 3 (Specific Aim 4) will utilize the generated data to construct a series of statistical and mathematical models that quantitatively relate DEP composition, its inflammogenic and mutagenic effects and the relevant intracellular signaling mechanisms.

Relevance :The information generated by this multidisciplinary research program is intended for use in risk assessment aimed at mitigating the health effects of DEP exposure, including quantitative and computational approaches, cross-species extrapolation and endpoint validation. This proposal is directly responsive to priority research needs identified by NCEA, Office of Air and Radiation (OAR) as well as the ORD PM Research Program. The research will be conducted using a custom-designed diesel emission sampling system, leading edge genomics and proteomics technologies and the latest tools in bioinformatics and computational modeling software. Beyond providing biological plausibility in support of DEP regulations, the usefulness of the findings from these studies will hinge upon identifying toxicological effects mechanisms in the context of DEP characteristics. Thus, this project’s primary aim is to deliver a set of predictive models that quantitatively describe the relationship between DEP composition and its genotoxic and inflammogenic properties. An important impact of the process of developing and applying this set of models via the systems biology approach will be the generation of novel mechanistic data with the specific intent of identifying and characterizing critical paths that lead from DEP exposure to toxicity. It is anticipated that many of these data will be applicable to the study of other sources of particulate air pollution whose effects include mutagenisis or inflammatory responses. Moreover, application of the systems biology approach will represent a case study adaptable to computational studies of exposure and toxicological effects of a broad range of environmental agents. Although the reductive studies will also yield novel mechanistic information about DEP toxicity, the actual deliverable product of this research will be a series of computational models that can be used by client offices in support of assessment and regulatory efforts. These models will have particular practical application in offices responsible for DEP assessment and regulatory programs including the Office of Air and Radiation (OAR) and the National Center for Environmental Assessment (NCEA).

Project IDs:

ID Code :IA-6

Project type :Partner Specific