ARYL HYDROCARBON SIGNAL TRANSDUCTION MECHANISMS IN FISH

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The overall objective of this project is to understand the molecular mechanisms of the toxic effects of dioxin and other halogenated aromatic hydrocarbons (HAH) in fish, using the estuarine teleost Fundulus heteroclitus as a model system. These compounds are common pollutants which result from many manufacturing processes. Their effects, including tumor promotion, teratogenesis, immunosuppression, and wasting, are mediated through an intracellular receptor. Although the basic scheme of HAH signal transduction is thought to be conserved between vertebrate species, the wide interspecific range of HAH toxicity, the large variation in molecular mass of HAH receptors (AhR) in different species, and the recent discovery of multiple forms of AhR in F. heteroclitus suggest that key differences may exist Specific aims of this project are (1) to clone the aryl hydrocarbon receptor nuclear translocator (ARNT) gene or genes in this species, (2) to characterize interactions between ARNT(s), the multiple AhR forms, and their target DNA sequences, and (3) to identify tissue specific patterns of expression of AhR and ARNT genes which may govern their physiological roles. The study of HAH signal transduction in fish is important for the validation of fish as model systems for in vivo toxicological testing of compounds posing potential human hazards. Knowledge of the molecular mechanisms governing the metabolism and accumulation of HAH compounds in fish will also have important implications for the assessment of the safety of fish consumption by humans and the use of fish as biomarkers for pollutant exposure.