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.

Public Health Relevance

Epidemiological studies suggest that diets high in n-3 polyunsaturated fatty acids (n-3 PUFA) can counteract detrimental effects associated with low-level mercury (Hg) intoxication. Our previous work has shown that at least one reason why low-level Hg exposure is harmful is because Fas (CD95) signaling in the immune system is disrupted. The purpose of this research is to investigate whether n-3 PUFA counteracts the harmful effects of Hg intoxication because signaling through the CD95 pathway is restored.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZES1-LWJ-J (DI))
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Kirshner, Annette G
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Wayne State University
Schools of Medicine
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Gill, R; Jen, K L; McCabe, M J J et al. (2016) Dietary n-3 PUFAs augment caspase 8 activation in Staphylococcal aureus enterotoxin B stimulated T-cells. Toxicol Appl Pharmacol 309:141-8
Gill, Randall; Lanni, Lydia; Jen, K-L Catherine et al. (2015) Docosahexaenoic acid counteracts attenuation of CD95-induced cell death by inorganic mercury. Toxicol Appl Pharmacol 282:61-7