MOLECULAR MECHANISMS OF RESISTANCE IN VERTEBRATES

University Of Kentucky, Lexington KY

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Adapted from the Investigator's Abstract): Halogenated aromatic hydrocarbons (HAHs) and polynuclear aromatic hydrocarbons (PAHs) are powerful environmental contaminants that can cause cancer. Some chronically exposed fish populations develop resistance to the toxic effects of these chemicals which is characterized by decreased inducibility of the drug metabolizing enzyme, cytochrome P4501A (CYP1A). Under normal conditions CYP1A is inducible by HAHs and PAHs acting through the aryl hydrocarbon receptor (AHR). The purpose of this research project is to study molecular mechanisms and metabolic repercussions of CYP1A non-inducibility in resistant fish (Fundulus heteroclitus). The specific objectives are to determine the level of CYP1A suppression, if there is cross-resistance to different chemical classes, if the AHR pathway is involved, and if suppressed CYP1A alters metabolites and/or DNA-adduct levels. To accomplish this, HAH-resistant and responsive fish will be treated with HAHs and PAHs, and measure CYP1A expression to evaluate cross-resistance and the level (transcription or translation) of suppression. Benzo[a]pyrene metabolism, DNA adducts, AHR levels and binding activity, and sequencing of the CYP1A promoter region of responsive and non-responsive fish will also be compared. This will provide valuable information on mechanisms of molecular resistance to toxicants relevant to chronic exposure in humans.