Mechanism of Action of Toxic Halogenated Aromatics

Abstract

,3,7, and related halogenated aromatic hydrocarbons are a highly toxic class of environmental contaminants, as evidenced by numerous cases of accidental poisonings of human and animal populations and their extreme toxic potency in laboratory animals. The proposed model for the mechanism of action of TCDD and related compounds is analogous to that of the stereoid hormones, which modulate gene expression through a receptor mechanism. In the steroid receptor model, the compound enters the cell cytoplasm where it acts as a specific ligand, binding selectively to a high affinity receptor protein. Bound to the appropriate ligand, the receptor concentrates in the nucleus where its increased association with chromatin leads to altered gene expression. This model has been useful in characterizing the Ah receptor; however, it does not provide a unifying hypothesis for all biochemical and toxic effects associated with exposure to halogenated aromatic hydrocarbons. Several findings suggest that a primary factor in determining TCDD toxicity might be tissue and species specific factors that control the actions of Ah receptor(s) in target tissues. Furthermore, numerous mechanisms might be involved. Clarifying the mechanism(s) for TCDD toxicity would enhance our ability to predict human health consequences to toxic halogenated aromatic hydrocarbons and would provide a more rational basis for risk analysis.

Placental markers of human exposure to polychlorinated biphenyls and polychlorinated dibenzofurans.

“…Within the framework described here it is difficult to categorize some of the responses in Yu-Cheng individuals. For example, aryl hydrocarbon hydroxylase activity is a consequence of the biologically effective dose (8)(9)(10), but induction of enzyme activity is thought not to be involved in the toxicity of the halogenated aromatics (38). Nevertheless it might be considered a good marker of exposure.…”

Identification of novel dioxin-responsive genes by representational difference analysis

“…These hazardous effects have been shown to be mediated mainly through the binding of these compounds to the AhR and subsequent activation of gene expression (reviewed by Mimura and Fujii-Kuriyama 2003). Dioxin is the most potent ligand for AhR because it has a high affinity, a very long half life, and a high degree of lipophilicity and has therefore been widely used as a model compound for AhR-mediated toxicity and carcinogenicity (reviewed by Vickers et al 1985).…”

Xenoestrogens alter mammary gland differentiation and cell proliferation in the rat.

“…TCDD treatment resulted in significantly reduced uterine-ovarian weights and mammary gland sizes. This could be a consequence of the antiestrogenic properties of TCDD (12) or extreme toxicity (24). Treatment with op'-DDT, Aroclor 1221, and Aroclor 1254 had no significant effects on body weights, uterine-ovarian weights, or mammary gland sizes.…”

“…Ie --J~ii-15000 jg 13 The overall decrease in numbers of terminal ductal structures and gland size from TCDD treatment may be due to its biological actions on estrogen metabolism (28) and the estrogen receptor (29), or as a consequence of overt toxicity (24). Aroclor 1221 and Aroclor 1254 caused slight but not statistically significant effects on the development of terminal ductal structures.…”