Ciguatera fish poisoning (ciguatera) is a human health problem caused by intoxications resulting from ingestion of over 400 species of toxic fish in the tropics. Ciguatera is caused by several polyether toxins produced by toxic dinoflagellates which are passed through the food chain to humans. The proposed studies represent the first effort to relate oxygen free radicals (OFRs) to a significant seafood poisoning problem in tropical countries and to test whether chemical markers of lipid peroxidation can be used for the clinical diagnosis of ciguatera. Because intravenous mannitol (a scavenger of the hydroxyl radical) is currently the treatment of choice for ciguatera, we will test the hypothesis that OFRs are a mechanistic component of ciguatera. Consequently, the proposed studies are expected to augment our understanding of the role that OFRs have in regulating the toxicity of ciguatoxins in dinoflagellates, and in mice and humans that have been exposed to these toxins. Our long term objective is to develop methods for the clinical treatment of ciguatera based on the use of antioxidants. There is still a fundamental gap in our knowledge as to how environmental factors (e.g. oxygen) regulate toxicity in dinoflagellates. Because toxic dinoflagellates frequently colonize coral reef habitats characterized by hyperoxia, we hypothesized that hyperoxia increases cellular levels of oxygen- derived radicals which may in turn increase the toxicity of polyether toxins present in these organisms possibly through increases in lipid peroxidation. Ciguatoxins are metabolized by the liver of animals and humans. Our preliminary studies have shown increased liver lipid peroxidation at various time intervals in mice injected with sublethal doses of these toxins. Understanding the interactions of OFRs with target marine toxins could lead to the development of relevant biomarkers of these interactions as well as to the development of rational strategies for the amelioration of symptoms and damage associated with ciguatera poisoning. Thus, the understanding gained in the animal studies may also provide the basis for the pharmacological use of antioxidants for ciguatera treatment. These overall objectives will be accomplished through four specific aims: 1) Test in humans, mice and dinoflagellates whether markers for lipid peroxidation can be used as diagnostic tools for ciguatera poisoning 2) Study the extent to which hyperoxia-induced lipid peroxidation is associated with an increase in toxicity in the dinoflagellates Gambierdiscus toxicus and Ostreopsis lenticularis 3) Study the effects of crude and purified ciguatera toxins on mice liver mitochondrial function by means of biochemical and ultrastructural approaches 4) Study whether antioxidants which inhibit lipid peroxidation are effective in diminishing the toxicity of cultures of the toxic dinoflagellates Gambierdiscus toxicus and Ostreopsis lenticularis and liver lipid peroxidation and in mice that have been exposed to crude toxin extracts and purified ciguatoxin.
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