2,3,7,8-Tetrachlorodibenzo-p-Dioxin and Related Halogenated Aromatic Hydrocarbons: Examination of the Mechanism of Toxicity

Abstract

In this review, we have examined the biochemical and toxic responses produced by halogenated aromatic hydrocarbons and have tried to develop a model for their mechanism of action. These compounds bind to a cellular receptor and evoke a sustained pleiotropic response. In many tissues this response consists of the expression of a battery of enzymes which are, for the most part, involved in drug metabolism, but in other tissues, those which develop toxicity, an additional set of genes is expressed which effects cellular involution, division, and/or differentiation. The toxicity of these compounds appears to be due to the sustained expression of a normal cellular regulatory system, of which we were previously unaware. In future investigations it is hoped that we will learn the nature and physiologic role of this regulatory system. Only then can we hope to understand the mechanism of toxicity of these compounds.

Thyroid Hormone Suppression and Cell-Mediated Immunomodulation in American Kestrels ( Falco sparverius ) Exposed to PCBs

“…For example, mass mortalities from viral infections in seals were associated with immunosuppression likely due to PCB exposure (Ross 1995). PCBs have been documented to cause immune modulation in avian (Fairbrother 1994;Smits and Bortolotti 2001) and mammalian species (Poland and Knutson 1982;Ross 1995). In nestling herring gulls (Larus argentatus) and Caspian terns (Sterna caspia) exposed to persistent organochlorine contaminants on the Great Lakes, T cell-mediated immunosuppression was expressed through a decreased response to the phytohemagglutinin (PHA) skin test (Grasman et al 1996).…”

Docking and 3D-QSAR studies on the Ah receptor binding affinities of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs)

“…Previous QSAR analyses suggested that steric, electrostatic, hydrophobic, hydrogen bonding and dispersion properties might be important for receptor binding affnity (Poland and Knutson, 1982;Tuppurainen and Ruuskanen, 2000;Giesy et al, 2002). Based on the mechanism consideration, three-dimension (3D) molecular structural descriptors that describe electronic and steric properties of molecules were selected to describe the interaction between compounds and AhR, which was calculated using the DRAGON 2.1 (Mauri et al, 2006).…”

Endocrine disruptors and falling sperm counts: lessons learned or not!

“…Since environmental samples and human residues of these organohalogen compounds (OCs) (or persistent organic pollutants) are complex mixtures of PCB, polychlorinated dibenzofuran and polychlorinated dibenzo-p-dioxin isomers and congeners, my laboratory initially focused on structure-activity and quantitative structureactivity relationships among these compounds. 1-3 2,3,7,8-tetrachlorodibenzo-p-dioxin was identified as the most toxic OC, and Poland and co-workers 4,5 initially hypothesized and demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds induce their toxic responses through activation of the aryl hydrocarbon receptor (AHR). Our quantitative structure-activity relationship studies contributed to development of the toxic equivalence factor approach for hazard assessment of OC mixtures which has been adopted by the World Health Organization and regulatory agencies worldwide to regulate and decrease emissions of OCs from multiple sources.…”