Superfund Research Program
Critical Role of Mitochondrial Oxidative Stress (MOS) in Chemical Induced Cardiac Toxicity
Project Leader: Nipavan Chiamvimonvat
Grant Number: P42ES004699
Funding Period: 2017-2022
Project Summary (2017-2022)
Many Superfund (SF) chemicals (e.g., PAHs, PCBs, Chlorinated solvents) have been reported to induce reactive oxygen species (ROS) in several cell types. Preliminary studies suggest that most of the ROS induced by SF chemicals originates from the mitochondria and that CCl4-induced cardiomyocyte cell death is partly caused by impaired proteasome activity. The hypothesis that chronic exposure to xenobiotics leads to cellular dysfunction and cell death mainly via mitochondrial oxidative stress (MOS) will be tested.
MOS results in excessive production of ROS, increased levels of oxidized mitochondrial proteins, lipids, and DNA, decreased ATP levels, and depolarized mitochondrial membrane potential. This project further explores whether MOS-related increases in ROS levels affects several cellular pathways, including cellular proteostasis, apoptosis, endoplasmic reticulum (ER) function, and fibrosis. Moreover, preliminary data generated by the research team suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) produce cardiotoxicity by MOS and impaired proteostasis. Since NSAIDs, such as diclofenac, are designed to be bioactive and bioaccumulate in animals, such as fish, it is very likely that these compounds would pose a larger problem than many current SF chemicals in the near future. Among the project aims is to investigate the effects of drug (diclofenac)-SF chemical mixtures. These hypotheses will be tested in cell cultures and chronic animal models.
The research team is developing cell-based assays to evaluate the mechanistic basis of xenobiotic effects on MOS and proteostasis (with the Analytical Chemistry and Bioanalytical and Statistics Cores, and the Optimizing Bioremediation for Risk Reduction Using Integrated Bioassay, Non-Target Analysis and Genomic Mining Techniques project). This project will evaluate the effects of chronic exposure to xenobiotics on increased MOS, apoptosis, fibrosis, heart damage and associated alterations of plasma oxidized protein levels (with the Analytical Chemistry and Bioanalytical and Statistics Cores), and develop methods to monitor MOS and impaired proteostasis from chronic exposure to chemicals (with the Optimizing Bioremediation for Risk Reduction Using Integrated Bioassay, Non-Target Analysis and Genomic Mining Techniques, Field-Deployable Lab-on-a-Chip Nanosensing Platforms for Health and Environmental Monitoring and Immunoassays for Human and Environmental Health Monitoring projects as well as with the Analytical Chemistry Core and Bioanalytical and Statistics Core).
The long term goal of this work is to develop a high-content and medium throughput bioassay to test the potentials of SF chemicals to cause MOS and proteostasis, and obtain a biomarker of MOS associated biological effects for bio-fluid analysis. Overall, this project will investigate a novel hypothesis that current SF chemicals, as well as potential future SF chemicals, cause cellular dysfunction mainly via MOS.