Grant: Discovery Grants Program - Individual

Persistent organic pollutants (POPs) are highly stable environmental contaminants that bioaccumulate in food sources, resulting in chronic human exposure and cell/tissue-specific toxicity. The long-term goal of my research program is to investigate the molecular mechanisms by which POPs impact specialized endocrine cells, using insulin-secreting pancreatic beta cells as a model system. The pancreas has rarely been studied as a target organ for environmental pollutants, yet our preliminary data suggest that human pancreas tissue may be a major reservoir for POPs. Our preliminary studies focused on the prototypical dioxin, TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), a persistent pollutant and potent inducer of cytochrome P450 oxidase (CYP) 1A enzymes. CYP enzymes are responsible for detoxifying foreign chemicals, such as prescription drugs and environmental pollutants, but they can also generate highly toxic intermediate metabolites. They are classically studied in the liver where the majority of drug metabolism occurs, but our research indicates that TCDD activates CYP1A enzymes in pancreatic endocrine cells. We also have compelling evidence that acute TCDD exposure leads to long-term suppression of insulin secretion. Therefore, our short-term goals are to: 1) characterize the dynamics of CYP1A activation in pancreatic endocrine cells by TCDD and assess the potential involvement of CYP1A enzymes in regulating insulin secretion; 2) determine if induction and/or knockdown of CYP1A enzymes impacts the susceptibility of beta cells to environmental chemicals; and 3) assess the impact of selectively overexpressing CYP1A1 specifically in beta cells.Our work will provide a foundation for broadly understanding how dioxins and dioxin-like POPs impact specialized endocrine cells. We will study endocrine cells at multiple biological levels, using cell lines, primary tissue culture, and intact mammalian animal models. Furthermore, these studies will characterize the basic biology of a fundamental enzyme pathway in pancreatic endocrine cells, not previously considered as a local site of xenobiotic metabolism. If we find that local CYP1A enzymes are involved in regulating insulin secretion, there would be broad implications, since CYP1A enzymes are induced by a wide variety of environmental pollutants, drugs, and dietary factors. This would also raise the question of whether CYP enzymes can be induced and consequently regulate hormone secretion in other specialized cell types, such neuroendocrine or enteroendocrine cells. If insulin secretion does not depend on CYP1A enzymes, we will explore their impact on other pathways, such as cell survival, proliferation, and oxidative stress. Understanding the direct impact of environmental chemicals on endocrine cells will be valuable for making recommendations for exposed populations, including First Nations communities.