No abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, 1 dioxin) represents the prototype for a class of structurally related halogenated aromatic hydrocarbons, including polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls (1, 2). These man-made compounds are mostly by-products of industrial processes involving chlorine chemistry and combustion of fuels. Many such chemicals are also widespread and persistent environmental contaminants. TCDD is the most potent among the chemicals; animals exposed to TCDD exhibit a wide range of toxic and adaptive responses, including a wasting syndrome, tumor promotion in skin and liver, cleft palate, chloracne, immune and endocrine dysfunctions, and induction of drug metabolizing enzymes (2-6). The health effect of TCDD on human beings remains a matter of debate. Humans exposed to TCDD exhibit certain skin lesions such as chloracne; the possibility that TCDD exposure causes certain neuro-and psychopathological alterations (7, 8), some forms of cancers and diabetic conditions (9, 10), and reproductive lesions is a particular concern of public health.The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with a basic helix-loop-helix PAS (bHLH/ PAS) modular structure (2, 3, 11, 12). Mouse genetic studies implicate AhR in most of the biological responses to TCDD, presumably by affecting the expression of target genes (13-15). Recent observations also imply that AhR plays certain roles in embryonic development and liver and immune functions in mice (16,17), and modulate the growth, differentiation, and apoptotic processes in certain cell lines and mouse liver (18 -22); these activities or functions of AhR were observed in the absence of known exogenous agonists, implicating a mechanism(s) of activating AhR under physiological conditions in vivo. Because of the broad range and the complexity of the biological responses that AhR contributes to, it is conceivable that the signal transduction of AhR involves a complex process during which AhR is regulated through different cellular mechanisms in a tissue-, species-, and developmental stage-dependent manner.The TCDD-inducible CYP1A1 gene encodes cytochrome P4501A1, a major inducible form of microsomal P450 in mammalian species; P4501A1 oxygenates polycyclic aromatic hydrocarbons, such as the carcinogen benzo(a)pyrine (23), as the initial step in the metabolism of the chemicals to water soluble metabolites for excretion from body. Studies on the induction of CYP1A1 gene expression by TCDD provided major mechanistic understanding of the mechanism of action and regulation of AhR (2, 3). In uninduced cells, AhR is localized in the cytoplasm, complexed with hsp90 (24) and AIP, an immunophillintype chaperon protein (25)(26)(27). Binding with an agonist triggers the dissociation of AhR from the associated proteins and translocation into nucleus, where AhR dimerizes with Arnt, another bHLH/PAS transcription factor (28). The AhR/Arnt dimer binds to a specific nucleotide sequence termed DRE (dioxin responsive element) in th...