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Louisiana State University

Superfund Research Program

Environmentally Persistent Free Radicals Alter Pulmonary Immunologic Homeostasis

Project Leader: Stephania A. Cormier
Co-Investigators: Wayne L. Backes (LSU Health Sciences Center - New Orleans), James R. Reed (LSU Health Sciences Center - New Orleans), Peter D. Sly (University of Queensland)
Grant Number: P42ES013648
Funding Period: 2020-2025
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

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Project Summary (2020-2025)

Nearly 53 million people live within three miles of a Superfund remediation site. Superfund sites contain a wide variety of pollutants, including organic chemicals, metals, carbonaceous material, and silica. Although each of these components is capable of damage to organisms, their potential to combine into unique hazardous agents has been understudied. Interestingly, when these agents are present together, particularly during thermal remediation, they combine to form particulate matter (PM) with chemisorbed free radicals that persist in the environment and biological systems. Over the prior funding cycle, the researchers established that these environmentally persistent free radicals (EPFRs) represent underappreciated pollutant species, induce oxidative stress and damage, and negatively impact respiratory health. EPFRs are produced during thermal treatment (TT) of hazardous wastes, and nearly 30 percent of all Superfund sites (excluding groundwater) are remediated by TT. EPFR concentrations near Superfund sites range from 1x10^18 - 4x10^19 EPFRs/g (spins/g) of PM. This suggests a vast number of U.S. residents are exposed to PM containing EPFRs. Short-term inhalational EPFR exposure elicited a Th17 inflammatory response similar to the severe asthma phenotype in humans. Mechanistically, the researchers demonstrated a role for Th17 cells driven by the aryl hydrocarbon receptor (AhR) in this response. EPFRs also cause alterations in foreign compound metabolism. Not only is there a direct inhibition of P450-dependent activities, mediated by disruption of the complex between P450s and their redox partners, but EPFRs also induced P450s from the CYP1A family via AhR. Although there are unique features within the immunologic and metabolic aspects of the proposal, they share a common feature - AhR. The researchers’ hypothesis is that EPFRs modulate AhR signaling leading to a pleiotropic response that alters both immunologic and P450 function resulting in poor respiratory health.

Aim 1 seeks to demonstrate that EPFR-mediated activation of AhR in airway epithelial cells (AEC) induces Th17 responses. To test their hypothesis, researchers are employing mice in which AhR is selectively depleted from AECs. As part of this aim they are testing the role of the tryptophan metabolite 6-formylindolo[3,2-b]carbazole (FICZ) to activate AhR.

Aim 2 seeks to define the mechanism of EPFR inhibition of P450 function, focusing on P450 interactions with their redox partners NADPH-cytochrome P450 reductase (CPR) and cytochrome b5. These studies are demonstrating how inhibition of P450 function affects disposition of FICZ and ultimately Th17-mediated asthma. This is being accomplished by kinetic and biophysical examination of the effect of EPFRs on complex formation.

Aim 3 seeks to demonstrate an epidemiologic link between EPFR exposure and poor respiratory health in children. Measurements of glutathione sulfonamide, a biomarker of pulmonary neutrophilia and associated with Th17-mediated asthma, is being used to relate EPFR exposure and respiratory health. Responding to SRP Mandates 1 and 2 – "Advance techniques for the detection, assessment, and evaluation of the effect of hazardous substances on human health" and "Develop methods to assess the risks to human health presented by hazardous substances" — this project seeks to demonstrate that EPFR exposure impacts child respiratory health and provide mechanism(s) by which EPFRs contribute to disease.

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