Molecular Switch Circuits in Toxicology: A Dimmer Switch for Dioxin
Cody Wilson · Toxicological Sciences · 2004
The U.S. Environmental Protection Agency reassessment of the health effects of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related compounds in part re-evaluates approaches to low-dose extrapolation of risk for these compounds (U.S. EPA, 2000). While a multitude of models describing the low-dose effects of TCDD have been presented over the past decade, an understanding of some of the biological factors defining the shape of the dose-response curve at low doses has become increasingly detailed only in the last few years, with the application of quantitatively sensitive technical approaches. Clearly, understanding the early events leading to molecular and cellular responses to TCDD exposure is crucial for low-dose extrapolation of risk. The mechanistic basis of action of TCDD and related compounds is one of the most extensively studied in toxicology, and a hallmark of exposure to these compounds in experimental systems is induction of the cytochrome P4501A and 1B (CYP1A, CYP1B) family of enzymes. CYP1A1 induction in experimental systems is one of the most frequently cited markers of exposure to TCDD and related compounds because of its low level of constitutive expression and robust increase in response to aryl hydrocarbon receptor (AhR) ligand. The mechanism of CYP1A1 induction has been well characterized. However, a full understanding of the obligate molecular and cellular events that precede physiological and toxic responses to AhR ligands has not hitherto been described.