Superfund Research Program
Monitoring Endoplasmic Reticulum Stress Caused by Chronic Exposure to Chemicals
Project Leader: Fawaz G. Haj
Grant Number: P42ES004699
Funding Period: 2017-2022
Project Summary (2017-2022)
Hazardous waste sites contain complex mixtures of a wide variety of toxic chemicals that contaminate and linger in the environment. The acute toxicities of numerous Superfund (SF) chemicals have been extensively investigated; however, further studies are needed to determine their chronic effects on human health. Several SF chemicals (e.g. naphthalene, PCBs, and CCl4), which are found in environmental samples from the Yurok Tribe of the Klamath River basin, and in California air, have been shown to induce endoplasmic reticulum (ER) stress in cultured cells. Furthermore, in animal models, long-term exposure to CCl4 leads to ER stress in tissues, resulting in fibrosis and organ damage. Thus, the central hypothesis for this project is that chronic exposure to xenobiotics leads to ER stress that then contributes to chronic inflammation, tissue fibrosis and eventual organ failure.
Based on the novel concept that the magnitude of ER stress is proportional to the amount of chronic exposure to chemicals, and monitoring ER stress will help predict resulting biological effects, the long term goal of this project is to develop a high-content and medium throughput bioassay to test the potential of SF chemicals to induce ER stress, and a biomarker of ER stress-associated biological effects for bio-fluid analysis. Toward these objectives, cell-based assays are being used to understand the mechanisms by which exposure to environmental toxins leads to ER stress. In addition, in animal models (with the Critical Role of Mitochondrial Oxidative Stress (MOS) in Chemical Induced Cardiac Toxicity project), this project is evaluating the effects of chronic exposure to hazardous chemicals on ER stress, and test if seric oxylipids are surrogate biomarkers for ER stress (with the Analytical Chemistry and Bioanalytical and Statistics Cores).
The methodology developed and data obtained from the cell cultures and animal models will be directly translated in developing biomarker assays (with the Field-Deployable Lab-on-a-Chip Nanosensing Platforms for Health and Environmental Monitoring and Immunoassays for Human and Environmental Health Monitoring projects, and with the Analytical Chemistry and Bioanalytical and Statistics Cores). Finally, research findings will be utilized to serve the community at large by testing field samples collected from the Klamath River basin, the Central Valley and the Sierra Nevada foothills in California, and at or around SF-sites across the U.S. (with the Optimizing Bioremediation for Risk Reduction Using Integrated Bioassay, Non-Target Analysis and Genomic Mining Techniques project, and the Bioanalytical and Statistics, Community Engagement and Research Translation Cores), as well as transferring to the scientists of the Yurok Tribe Environmental Program (with the Interdisciplinary Training Core).
Accordingly, the overall goals of this project are to:
- Test lipid mediators as potential diagnostic biomarkers for the magnitude of ER stress response that often contributes to organ damage,
- Develop fast, inexpensive and reliable new cell-based bioassays to detect, assess and quantitate the effects of hazardous substances on ER stress,
- Provide new mechanistic insights into the effects of chronic exposure to SF chemicals on ER stress and fibrotic diseases,
- Develop biomarkers assays for bio-fluids for the quantification of tissue-specific effects of xenobiotics on ER stress, and
- Translate findings by assessing risk on human health, by analyzing field samples.