http://www.loc.gov/mods/v3 http://www.loc.gov/standards/mods/v3/mods-3-2.xsd
Investigation of the mechanism of toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated polyaromatic hydrocarbons
The toxicity of [³H] -2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the related halogenated polyaromatic hydrocarbons (PAHs) is presumed to be mediated by a cytosolic receptor, the Ah receptor. However, for a large number of receptor agonists, there is no strict correlation between toxicity and relative ligand binding affinity. Therefore, the possibility that the variance in toxicity was due to differences in the ability of the various ligands to activate the cytosolic receptor was investigated. The five radioligands used in the study, [³H] 2,3,7,8-TCDD, [³H] 2,3,7,8-Tetrachlorodibenzofuran (TCDF), [³H] 1,2,3,7,8-Pentachlorodibenzofuran (PCDF), [³H] 1,2,3,6,7,8-Hexachlorodibenzofuran (HCDF), and [³H] Tetrachlorodibenzofuran-2 (TCDF-2), were of similar affinity: 0.44 nM, 1.3 nM, 5.2 nM, 2.3 nM, and 4.1 nM, respectively. The differences of ligand potency, as measured by thymic atrophy, body weight loss and enzyme induction varied 1 to 2 orders of magnitude. Scatchard and Hill analysis of the binding of the 5 radioligands to the Ah receptor indicated that the binding was non-cooperative. For all ligands, the Hill slope was close to 1.0, and the Scatchard plots (except for [³H]TCDD) were linear. With [³H]TCDD, the non-linearity was an experimental artifact that was produced by either a high level of non-specific binding relative to total binding and/or an under-estimation of specific binding. The dissociation kinetics of the bound receptor were complex and indicative of an increase in ligand binding affinity. Additionally, the dissociation of the receptor-ligand complex, regardless of the 'type' of bound halogenated PAH, was not fully reversible. It was not clear whether the poor reversibility was a result of receptor activation although it was evident that a stable receptor-ligand complex was formed. However, while the persistent occupation of the receptor may contribute to the toxicity of the halogenated PAHs, it does not explain differences in ligand toxicity, since, with the limited number of radioligands tested, there was no correlation between ligand toxicity and either the rate of receptor-ligand dissociation or receptor-ligand binding affinity.
Ph. D. in Toxicology Texas A & M University 1987
Includes bibliographical references (leaves 185-201).