Molecular Basis of Dioxin Actions: Evidence Supporting Chemoprotection

Abstract

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD or dioxin), a highly publicized environmental contaminant, was shown to be chemoprotective against breast cancer in both rats and mice in bioassays conducted in the late 1970s. This fi nding went largely unnoticed as investigators focused on animal tumors that were increased by dioxin. The position that dioxin causes human tumors remains a subject for debate; however, recent epidemiological studies of a population highly exposed to dioxin in 1976 as a result of an industrial accident suggest that women with higher dioxin body burdens may have a lower incidence of breast cancer. With the growth of new knowledge about the molecular basis of dioxin actions in humans and animals, it is clear that most of the responses produced by this agent are initiated by a specifi c recognition protein (designated the Ah receptor) found in almost all animal and human tissues and organs. The recognition event between the Ah receptor and environmental agents like dioxin is due to the formation of a complex. We have observed that in the presence of dioxin, the Ah receptor turns off proliferation in tumor cells and suppresses the ability of these cells to invade normal tissue. We believe that these fi ndings provide a molecular and biochemical basis for understanding the chemoprotective mechanisms suggested by the fi ndings of rodent bioassays and could lead to the development of novel therapeutic agents targeting the Ah receptor.

Keywords

TCDD Ah receptor cell cycle regulation chemoprotection ligand switch gene transcription

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