October 11, 2021
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Combining Metabolic Activity, Rates, and Exposure to Refine Risk of Environmental Hazards

Exposure to hydrocarbons found at Superfund Sites induces enzymes in dose- and time-dependent patterns in mice

illustration of a mouse overlaid on chemical structures

Mice exposed to a prototypical polycyclic aromatic hydrocarbon (top) and a mixture of polycyclic aromatic hydrocarbons (bottom) showed time- and dose-dependent changes to active cytochrome P450 enzyme expression.

(Illustration by Stephanie King | Pacific Northwest National Laboratory)

The Science                                

Polycyclic aromatic hydrocarbons, or PAHs, include many possible or probable carcinogenic organic compounds produced by burning waste, wood, and fossil fuels. They are also byproducts of car exhaust and coal gasification. PAHs are found in the air, water, soil, and food. Cytochrome P450 enzymes metabolize PAHs, either detoxifying them or modifying them to be more bioavailable. Previous studies have tracked P450 induction following exposure to specific PAHs in cells and animal models. Now a multi-institutional team has quantified that induction in the context of environmental exposures. The team measured time- and dose-dependent changes to active cytochrome P450 enzyme expression in mice following exposure to an environmental mixture of PAHs.

The Impact

The researchers exposed mice to various doses of a prototypical PAH, benzo[a]pyrene, or a mixture of PAHs called Supermix-10. This mixture contains the top 10 most abundant PAHs found at the Portland Harbor Superfund Site. Exposure to Supermix-10 induced PAH-metabolizing enzymes in dose- and time-dependent patterns in mice. Accounting for specific changes in enzyme profiles, relative rates of PAH bioactivation and detoxification, and resulting risk will help translate internal dosimetry of animal models to humans and improve risk assessments of PAHs at Superfund sites.

Summary

The team prepared microsomes from the livers of mice exposed to benzo[a]pyrene (BaP) or Supermix-10. They measured induction of specific active P450 enzymes using activity-based protein profiling. They also quantified protein expression using global proteomics.

After exposure to BaP or Supermix-10, the researchers observed rapid induction of one P450 enzyme, Cyp1a1, after six hours at the lowest PAH exposures tested. After 72 hours and three daily doses of PAHs, the team noticed broadscale induction of many P450 enzymes. Supermix-10 significantly induced fewer P450 enzymes and was less potent than BaP; however, these enzymes still represented the majority of ones detectable.

Next, the team looked at the role of Cyp1a1 in PAH metabolism since it was the P450 with the most potent induction response. They observed significantly higher metabolic affinity in samples displaying Cyp1a1 induction and higher overall metabolism rates for broad scale induction of many P450 enzymes.

This study provides evidence that PAHs induce cytochrome P450 enzymes at exposures used to assess hazards with animal models and at relevant PAH mixture exposures to humans. Currently, regulators assess human risk to mixtures of PAHs using an approach that does not account for potential risk changes dues to enzyme induction in either human populations or in laboratory models. Integrating enzyme induction and metabolism rate data into physiologically based pharmacokinetic models will allow researchers to better predict consequences of enzyme induction in relative rates of bioactivation and detoxification of PAHs in animal models and translate those results to humans for better risk assessment.

Contact

Jordan N. Smith
Pacific Northwest National Laboratory

jordan.smith@pnnl.gov

Funding

This research was supported by the National Institutes of Health National Institute of Environmental Health Sciences and employed proteomics capabilities supported by the National Institute of General Medical Sciences Research Resource for Integrative Biology. A portion of the research was performed using the Environmental Molecular Sciences Laboratory, EMSL, a Department of Energy Office of Science User Facility located at Pacific Northwest National Laboratory.

Published: October 11, 2021

E.G. Stoddard, et al., “Exposure to an environmental mix of polycyclic aromatic hydrocarbons (PAHs) induces hepatic cytochrome P450 enzymes in mice.” Chemical Research in Toxicology 34, 2145-2156 (2021). [DOI: 10.1021/acs.chemrestox.1c00235]

Research topics