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Biomarkers of Exposure to Hazardous Substances (2017-2022)

The UC Davis Superfund Research Center conducts research to improve understanding of the mechanisms by which hazardous chemicals produce adverse health effects, validate novel methods to evaluate exposures, and develop innovative remediation strategies.

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Biomarkers of Exposure to Hazardous Substances (2017-2022)

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  1. Biomarkers of Exposure to Hazardous Substances (2017-2022) The UC Davis Superfund Research Center conducts research to: Improve understanding of the mechanisms by which hazardous chemicals produce adverse health affects, Develop, validate and integrate novel methods to evaluate chemical exposures, levels of contamination, and health risks, and Develops innovative remediation strategies to reduce hazardous substance exposure and toxicity. These activities improve the ability of the National Superfund Program to address legacy and emerging contaminants and associated transformation products to more comprehensively protect the U.S. population from health risks posed by hazardous substances.

  2. Biomarkers of Exposure to Hazardous Substances

  3. Core C: Community Engagement - Dr. Beth Rose Middleton, PI • In response to intensive forestry management and illegal marijuana groves, collaborative research with the Yurok Tribe Environmental Program (YTEP) will: • Conduct environmental sampling to identify contaminants and their concentrations • Implement field deployable assays for use by YTEP partners • Collaboratively identify culturally and ecologically appropriate remediation strategies

  4. Community Engagement Core - Dr. Beth Rose Middleton, PI The Community Engagement Core works to develop meaningful bi- directional communication strategies between university and tribal researchers and community partners to apply UCD Center research to address community concerns. Broadly, the chemical detection technologies, remediation strategies and training opportunities aim to provide communities with autonomous methods for addressing environmental health problems within their community while training scientists on developing equitable, respectful, and responsible projects with community partners.

  5. Core A: Analytical Chemistry Core - Dr. Jun Yang, PI • Develop analytical methods to detect hazardous chemicals for the variety of UCD-SRP projects. • Validate alternative analytical methods such as: • Immunoassays • Cell-based assays

  6. sEH inhibition and EpFA block Endoplasmic Reticulum Stress (ER Stress) Phospholipase A2 ROS IRE1α Glucose O XBP1s OH Arachidonic Acid Nucleus ERAD CYP450 ATF6 O 14,15 EET P P sEH P PERK sEH inhibitor P O ATF6(N) P OH elF2α Wagner et al. 2017 HO OH CHOP ATF4 14,15 DHET

  7. Project 5: Monitoring Endoplasmic Reticulum Stress Caused by Chronic Exposure to Chemicals, Dr. Fawaz Haj and Dr. Christophe Morisseau • Investigate new mechanistic insights into the effects of chronic exposure of Superfund (SF) chemicals on endoplasmic reticulum (ER) stress. • Effects of SF chemicals on ER stress by • Altering gene expression • Inhibition • Competition for catalysis • Increasing reactive oxygen species • BLOOD AND URINARY BIOMARKERS OF DISRUPTION OF THE ER STRESS PATHWAY TO MONITOR XENOBIOTIC EXPOSURE AND POSSIBLY DRIVE THERAPEUTIC INTERVENTION.

  8. Project 4: Critical Role of Mitochondrial Oxidative Stress (MOS) in Chemical Induced Cardiac Toxicity, Dr. Aldrin Gomes (mitochondria) and Dr. NipavanChiamvimonvat (heart) • Investigate molecular mechanisms of chronic exposure to Superfund chemicals on mitochondrial oxidative stress (MOS) and proteasome dysfunction • Target Analytes: • Pesticides • Antimicrobials • HaHs/PaHs • Commercial Chemicals • Pharmaceuticals • CELL, BLOOD AND URINARY BIOMARKERS OF DISRUPTION OF MITOCHONDRIA TO MONITOR XENOBIOTIC EXPOSURE AND POSSIBLY DRIVE THERAPEUTIC INTERVENTION.

  9. DEVELOP BIOMARKERS TO DETECT FUNDAMENTAL PROCESSES OF TOXICITY DEPRESSION CANCER TOOTH DECAY EpFA: EETS EEQS EDPS THE MITOCHONDRIAL ROS ER STRESS AXIS NEUROPATHIC PAIN MPTP TRICLOSAN PARKINSON’S PARAQUAT DIABETES INDOMETHACIN HEART FAILURE CARBONTET NITROPHENOLS INFLAMMATION DICLOFENAC IBD FIBROSIS

  10. Project 4 - Monitoring Mitochondrial Oxidative Stress and Cardiac Toxicity Caused by Chronic Exposure to Chemicals Dr. Nipavan Chiamvimonvat, Project Leader Dr. Aldrin Gomes, Co-Leader

  11. Overall aims Hypothesis: chronic exposure to xenobiotics and/or non-steroidal anti-inflammatory drugs (NSAIDs) leads to mitochondrial oxidative stress (MOS) that results in proteasome dysfunction, apoptosis, tissue fibrosis and cardiac toxicity. Focus: Heart health related diseases. Approach: used cell based assay and in vivo models to test effect of exposure to SF chemicals and/or NSAIDs on mitochondrial stress, proteasome dysfunction, apoptosis, fibrosis and associated alterations of cell, plasma and urine profile as a biomarker. Deliverable: Easier methods to monitor mitochondrial oxidative stress as a marker of xenobiotic exposure.

  12. The MIT-ROS-ER stress axis

  13. Effect of xenobiotics on cell viability, Reactive Oxygen Species (ROS) production, and mitochondrial membrane permeability (MMP) Cell viability in H9c2 cardiac cells incubated with 50µM CCl4, 100µM paraquat, 20µM naphthalene, 10 µM diclofenac (DIC) for 24 h. Pre-treatment with 20µM mito-Tempol (MT) prevented reduced cell vitality caused by CCl4. H202, 200 µM.

  14. Effect of xenobiotics on Cardiac Cell Viability

  15. Xenobiotic exposure affects mitochondrial electron chain transport activity and proteasome activity b1 b2 b5 Mitochondrial complex l activity is decreased by naphthaline (20 µM) and paraquat (100 µM) but not CCl4 (20 µM) or DIC (20 µM). Lower figures show proteasome dysfunction occurs in hearts of ibuprofen treated mice

  16. Reducing mitochondrial electron transport chain activity increases ROS and reduces cell viability Ibuprofen treated mice ROS ** ROT – Rotenone (a Complex I activity inhibitor)

  17. Current Model SF Chemicals Cardiomyocytes Mitochondrial dysfunction; Complex I and III inhibited NSAIDs ROS Δψ decreased UPS dysfunction ER stress CARDIOTOXICITY Oxidized proteins Proteasome Transfection Antioxidants Cell Death

  18. Conclusions • CCl4 naphthalene, paraquat induces cardiac toxicity, mitochondrial stress and proteasome dysfunction. • Mitochondrial-stress is induced by other xenobiotics: diclofenac, ibuprofen, naproxen. Future Directions • Expand target analysis (Pesticides, HaHs/PaHs, Commercial Chemicals and Pharmaceuticals). • Determine cell, blood and urinary biomarkers of mitochondrial dysfunction to monitor Xenobiotic exposure and possibly drive therapeutic intervention.

  19. Acknowledgements • Bruce Hammock • Natalia Vasylieva (project 3) • Fawaz G. Haj (Project 5) • Christophe Morisseau (Project 5) • Jun Yang (core A) • Daniel Tancredi (core B) Funding from: NIEHS/Superfund Research Program P42 ES004699

  20. Project 4 - Monitoring Mitochondrial Oxidative Stress and Cardiac Toxicity Caused by Chronic Exposure to Chemicals Nipavan Chiamvimonvat, MD Division of Cardiovascular Medicine

  21. Mortality rate of cardiovascular disease surpasses that of cancer Cardiovascular Disease Cancer Circ 131(4): e29-322, 2015

  22. Cardiac fibroblasts • Cardiac fibroblasts account for ~75% of all cardiac cells, but contribute only ∼10-15% of total cardiac cell volume. • The principal sources of extracellular matrix (ECM) proteins. • A heterogeneous population. • Derived from various distinct tissue niches including resident fibroblasts, endothelial cells, and bone marrow sources.

  23. Roles of cardiac fibroblasts Yue et al, Cardiovascular Res 2011

  24. Molecular mechanisms leading to cardiac fibrosis Wakili et al, 2011

  25. Flow cytometric analysis of the isolated cells from mouse hearts

  26. Recreating disease in a dishhiPSCs and hiPSC-CMs Background Fluorescence Background Fluorescence DAPI Phalloidin SSEA-4 Specific Oct3/4 Specific SSEA4 Merged DAPI 99% <1% <1% 99% Oct3/4+ hiPSCs SSEA+ hiPSCs Merged Troponin T hiPSC-CMs Side Scatter Side Scatter

  27. Activation of MAPK in hiPSC-CMs and hiPSC-fibroblasts by TNF-a

  28. Novel Cell-in-Gel Platform Single APs Spontaneous APs Novel 3D Cell-in-Gel 20 mV 20 mV 250 ms 1s

  29. Effects of mechanical stress on Ca2+ handling

  30. Conclusions • Generation of reliable platform for testing the effects of Superfund chemicals on cardiac myocytes and fibroblasts. • Development of bioassays to test the effects of exposure.

  31. Acknowledgements • Bruce Hammock • Aldrin Gomes (Project 4) • Fawaz G. Haj (Project 5) • Christophe Morisseau (Project 5) • Jun Yang (core A) • Ye Chen-Izu • Padmini Sirish Funding from: NIEHS/Superfund Research Program P42 ES004699

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