Transcriptomic dose-response modeling to support ecological risk assessment

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A major challenge in ecotoxicology is to assess the environmental safety of the thousands of chemicals used in the world economy. Traditional test methods are limited to short-term overt effects such as lethality and cannot reliably detect more subtle long-term effects such as reproductive and developmental toxicity. To address this issue, efforts have been invested in expanding the breadth of biological effects that can be detected in toxicological tests. One of the most promising approaches is the use of gene expression technology (i.e. transcriptomics). This technology measures effects across a very broad spectrum of biological pathways, and changes related to long-term effects can be detected shortly after chemical exposure. Furthermore, recent advances in transcriptomic sequencing technology now make it economically feasible to include large numbers of doses and time-points in a single experiment, permitting advanced quantitative modeling. Modern transcriptomic dose-response modeling (TDRM) approaches can provide estimates of a chemical's potential long-term toxicity that can be used in ecological risk assessment. For example, we showed that TDRM analysis after short-term exposures provided robust estimates long-term toxicity for fish exposed to endocrine disrupting chemicals. Challenges still remain before TDRM can be used routinely for ecological risk assessment. Several applications have been demonstrated in principle, but need to be validated across a broad suite of chemical classes, in various species and in different model systems. Another major challenge specific to ecotoxicology is that the species of interest often have very poorly characterized genomes, which can restrict the application and interpretation of latest and most economic transcriptomic technologies. This proposed research will address the challenges that restrict the use of TDRM in ecological risk assessment. The specific goals of this research are: Develop TDRM assays for ecologically relevant species including fish and birds Validate TDRM in short-term tests to estimate long-term ecotoxicity for a broad range of chemical classes Develop and validate animal-alternative testing applications of TDRM, such as early life stage embryo models Test whether TDRM can be used to compare species differences in toxicity Demonstrate the utility of TDRM in real-world ecological risk assessment case studies This research program will yield a new toxicogenomics approach that will have direct applications to ecological risk assessment process. The work proposed provides an opportunity for collaboration between ecologists, molecular biologists, biostatisticians and risk assessors. This research will help create the much-needed bridge between science and policy to ensure the development of approaches that are robust, effective, ethical, and most importantly, will be used to support environmental protection in Canada.