Genetic and Epigenetic Determinants of Sensitivity to Polycyclic Aromatic Hydrocarbons in Birds

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Risk assessment for environmental contaminants in wildlife depends on extrapolating toxicity data from a small number of model organisms to tens of thousands of species of concern. This is widely acknowledged to be problematic given that sensitivity to contaminants can vary by orders of magnitude across species and even among individuals. The long-term objective of my research program is to advance understanding of variation in sensitivity to environmental contaminants among species and individuals. This objective stems from the insight that variable responses can be used to resolve fundamental questions about mechanism of action of toxicants, and that knowledge gained can be applied to meet the grand challenge of assessing chemical risk in the face of abundant variation in the natural world. My proposed research program focusses on the effects of polycyclic aromatic hydrocarbons (PAHs) in avian embryos. PAHs are contaminants of concern in the Canadian environment, and have been studied extensively in aquatic organisms such as fish, but relatively few data are available for birds. The avian embryo is an excellent model for experimental studies because the egg is a closed system, minimally affected by environmental signals during development (unlike fish and mammals). I have chosen to focus on three species of birds that are established models in the field of ecotoxicology and for which we have developed toxicogenomic tools; two domestic species, chicken (Gallus gallus), and Japanese quail (Coturnix japonica) and a wild species, double-crested cormorant (Phalacrocorax auritus). Critically, my recent work on these species has established that they are differentially sensitive to PAHs. In addition to being topical, PAHs are a good choice for my research program because they interact with a well-described molecular pathway - the aryl hydrocarbon receptor (AHR) signaling pathway - permitting deeper mechanistic investigations. My previous research identified a strong genetic component to species sensitivity related to AHR signaling, but it is currently unclear how these findings apply to PAHs. Aims 1 and 2 of the proposed research will resolve this knowledge gap and explore additional questions relating to gene expression and toxicokinetics, as well as differences in sensitivity among individuals. In Aim 3 we will take the innovative step of focusing on epigenetic determinants of sensitivity. Epigenetics refers to a layer of information in cells that is heritable as the cell divides but is not associated with the genetic sequence itself. Epigenetic marks can contribute to variability, but have seldom been investigated in the context of sensitivity to contaminants. Building on my contributions to established knowledge about genetic determinants of sensitivity to AHR ligands in birds, and our recent progress on epigenetic determinants, we are poised to make significant breakthroughs in the next 5 years.