Superfund Research Program
Elucidating Metabolic and Physicochemical Mechanisms of PAH Susceptibility in Toxicity Test Systems and Humans
Project Summary (2020-2025)
Lack of understanding of the molecular basis for susceptibility across toxicity test systems is a long-standing barrier to improved risk assessment, improved cleanup decisions for SRP sites, and successful health mitigations. This project's objective is to develop transformative, activity-based proteomic probes and multi-modal chemical microscopy to measure the metabolic and distributional processes that contribute to differential susceptibility to PAH exposure. Justin Teeguarden, Ph.D., and his team hypothesize that measurable but commonly ignored differences in tissue distribution and metabolic capacity to activate and/or detoxify PAHs contributes to differential susceptibility. To test this hypothesis, the team will complete three objectives:
- Identify the complete set of active P450, glutathione-Stransferase and UDP-glucuronosyltransferase enzymes that metabolize PAHs & PAH metabolites. Activity-based probes will be incubated in tissue samples to enrich and identify active enzymes using a proteomics platform.
- Develop a single assay to determine both PAH metabolic rates and metabolic susceptibility by relating PAH metabolic rates to global measures of enzyme activity. Activity-based probes will be incubated in tissues while conducting standard PAH metabolism assays to determine substrate specificity and metabolic constants for active enzymes.
- Determine how exposure susceptibility across test systems and humans depends upon PAH physicochemical properties, tissue composition, and body composition.
Tissue composition will be measured across the Program's systems and the team will predict the disposition of PAHs across these systems, and humans. The products of this research directly enhance the relevance and impact of each project and core for stakeholders. These innovations (ABPP and multi-modal chemical microscopy) will open new scientific horizons in the understanding of two key molecular determinants of differential susceptibility. The work will satisfy explicit expectations for SRP by a) demonstrating "that the hazardous substance, its dose, exposure pathway and model organisms are considered within the context of timing, prevalence, and detection of exposure" and by b) assuring that the "work is contextualized in terms of its relevance to human exposure." This project's research results will directly inform and improve human health assessment for PAHs at Superfund sites.