The polychlorinated dibenzo-p-dioxins are a class of generally toxic compounds which are found as contaminants of preparations of polychlorinated phenols. The most toxic member of this class of compounds is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD has an LD50 in the adult male guinea pig of approximately 1 microgram/kg. Although a number of studies aimed at determining the biochemical mechanism of toxicity of TCDD have been carried out by numerous investigators, we do not, as yet, understand, even in a preliminary way, how this compound acts at the biochemical level to bring about its toxicity. These previous studies have reasonably excluded inhibition of protein or nucleic acid synthesis, inhibition of mitosis, oxidative phosphorylation, glycolysis, the action of the thyroid or glucocorticoid hormones or decreased immunocompetence as the cause of the acute lethal effects of TCDD. In the present application, additional studies of the effect of TCDD on variouss morphological and biochemical parameters in different rodent species are planned. These studies will include in vivo and in vitro studies of the metabolism of TCDD; examination for the presence of a cytosol receptor for TCDD, previously detected in hepatic cytosol of rats and mice by Poland, in other species such as the guinea pig, hamster and the nude mouse; examination of the differential toxicity of TCDD in the homozygous nude mouse vs. the heterozygous control; examination of the development of chloracne in human skin transplanted to the nude mouse; investigation of the increased liver pathology in TCDD treated rats and guinea pigs fed by total parenteral nutrition (TPN) as compared to oral ad libitum feeding; examine cholesterol and carbohydrate metabolism in TPN fed rats and guinea pigs; and examine for changes in the lipid composition of plasma membranes in TCDD treated rats.
NIH ExPorter
NIH ExPorter