Understanding the influence of n-3 PUFA on pro-inflammatory aspects of mercury

Summary

Principal Investigator: Allen J Rosenspire
Abstract: DESCRIPTION (provided by applicant): The environmental heavy metal contaminant mercury (Hg) is a potent neurotoxin and immunomodulator that at low exposure levels has been implicated as a factor contributing to cognitive impairment as well as to inflammation and autoimmune disease in animal models and in human populations. However epidemiological studies of low level Hg intoxicated populations who also consume large amounts of fish, seem to show that these populations are more resistant to the detrimental effects of Hg than are equally Hg intoxicated populations who do not consume such large quantities of fish. Since fish have particularly high levels of n-3 polyunsaturated fatty acids (n-3 PUFA), it has been suggested that detrimental effects of low-level Hg intoxication may be counteracted by dietary ingestion of n-3 PUFA. Presently there is no mechanistic understanding of how n-3 PUFA might interact with Hg so as to prevent the harmful effects of low-level intoxication. However we have previously shown that one consequence of low-level Hg intoxication is that Fas (CD95) mediated signal transduction and activation induced cell death (AICD) in the immune system is depressed. CD95 signaling and AICD are physiologically important in maintaining immune system homeostasis, and attenuation of CD95 signaling is well known to be associated with an autoimmune proliferative syndrome characterized by lymphadenopathy and a lupus-like inflammatory immunopathology in animals and humans. On the other hand, several investigators have reported that n-3 PUFA have anti- inflammatory properties, as diets rich in these fatty acids are effective in ameliorating several autoimmune diseases. Significantly, it has also been reported that the anti-inflammatory properties of n-3 PUFA may be linked to their ability to enhance CD95 signaling and AICD. These findings lead to the hypothesis that high dietary inputs of n-3 PUFA will prevent harmful effects of low-level Hg intoxication by restoring the ability of CD95 to properly signal AICD in activated, but Hg intoxicated lymphocytes. This proposal is designed to rigorously test this hypothesis. Both in vitro and in vivo models will be employed, where the plan is to utilize western blotting techniques, as well as flow cytometric-based technology to map CD95 signaling networks.
Funding Period: 2012-08-01 - 2014-07-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Methyl Mercury Effect on Adolescent Development Renewal
    Philip W Davidson; Fiscal Year: 2013
    ..The study should also clarify the risks and benefits of fish consumption in relation to neurocognitive and cardiac morbidity that may not become clinically manifest until later in adulthood. ..
  2. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
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  3. Research Center for Pharmacology &Drug Toxicology
    L Jackson Roberts; Fiscal Year: 2013
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  4. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  5. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  6. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  7. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  8. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
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  9. BIOMARKERS OF EXPOSURE TO HAZARDOUS SUBSTANCES
    Bruce D Hammock; Fiscal Year: 2013
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  10. Maternal Methylmercury Exposure Through Rice Ingestion and Offspring Development
    SARAH ROTHENBERG; Fiscal Year: 2013
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  11. Factors Modifying the Toxicity of Methylmercury in a Fish-Eating Population
    Philip W Davidson; Fiscal Year: 2013
    ..Rand's laboratory while genes and genetic variations in those genes linked to MeHg tolerance in Drosophila by Dr. Rand can help focus Dr. Broberg's work on SNPs that appear particularly important to the neurotoxicity of MeHg. ..
  12. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
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  13. Alberta Pregnancy Outcomes and Nutrition (APrON) - Toxicant-Diet Interactions on
    JONATHAN WAYNE MARTIN; Fiscal Year: 2013
    ..It is anticipated that the results of this unique study will inform preventio strategies to help mitigate the harmful effects of classic and emerging environmental developmental neurotoxicants. ..
  14. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
    ..Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond). ..
  15. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  16. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  17. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..