MOLECULAR TOXICOLOGY OF TCDD

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The chlorinated dibenzo-p-dioxins are among the most toxic synthetic compounds known. In addition recent evidence suggests these compounds to be extremely potent tumor promoting agents. The overall objective of the research described is to better understand the biochemical mechanism(s) by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds produce toxicity in animals. Evidence suggests the toxicity of these compounds is mediated through their specific binding to a cytosolic protein, nuclear translocation and subsequent modulation of gene expression. A variety of radioisotope, kinetic, and chromatographic techniques will be utilized to investigate the biochemical nature of the receptor, as well as obtain specific and sensitive probes for altered forms of this molecule. The information from these studies will be used to devise a scheme for the purification of the receptor molecule. The kinetics of nuclear translocation of the TCDD-receptor complex in cell-free systems and the dependence of these processes on binding, transformation, and cytoplasmic factors will be determined. Studies utilizing techniques in vivo and isolated hepatocytes in vitro will determine the temporal and dose-response relationship between nuclear occupancy of the receptor and the toxicity of TCDD. The specific responses to be measured include altered hepatic enzymes and biochemical events leading to porphyria. These studies are designed to focus on early events leading to TCDD-induced modulated gene expression and porphyria. Utilizing similar protocols, the role of TCDD receptors in the thymus in TCDD-induced thymic atrophy will be determined. The cell type(s) in the thymus in which receptor is localized will be determined so further focused biochemical studies may be planned. Finally, we will examine the ability of pregnancy, vitamin B6 deficiency, cytochrome p-450 depletion and treatments with vitamin A or hydrocortisone to alter the levels of TCDD receptor in the thymus and liver, distribution of the receptor between cytosol and nucleus, or ability for translocation of the receptor to occur in vivo. These studies may suggest what controls this receptor in vivo, as well as the possible physiological role of this molecule.