Grant: Project Grant

Dioxins and related chemicals are a class of persistent environmental pollutants that, despite their tight regulation, still contaminate the global environment. Laboratory animals exposed to dioxins show a range of toxic responses including fatty liver, reproductive problems and weight loss leading to a lethal wasting syndrome. Although the toxic effects of dioxins in humans seem to be less severe, dioxin exposure has been linked to reproductive disorders, metabolic syndrome and increased cancer risk. The aryl hydrocarbon receptor (AHR) is the signalling protein that is responsible for mediating the toxic effects of dioxins. More recently, however, the importance of AHR signalling in inflammation, intestinal immunity and overall gut health has led to the development of therapeutic agents that target AHR for the treatment of a variety of human diseases, including colitis, multiple sclerosis, arthritis and cancer. Despite extensive research efforts, our understanding of the normal biological roles of AHR and of how dioxins cause their wide variety of toxic effects remain poorly understood. We have found that another protein called TCDD-inducible poly-ADP-ribose polymerase (TIPARP) turns off AHR signalling, and it may therefore represent another key regulator of both the toxic and beneficial actions of the activated AHR. Our laboratory uses molecular and cell biology techniques combined with unique animal models to determine the role of the AHR-TIPARP signaling axis in either the toxicity or the beneficial effects of dioxin-like and other food-derived chemicals. By better understanding the function of TIPARP and its role in AHR action our research may lead to the development of new strategies to treat human disease, and allow for better prediction of both the health risks and the benefits associated with exposure to various chemicals that activate AHR.