Cell- and Mathematical-based Model of PXR/AhR-mediated Metabolism in Zebrafish

Using current methods It is not practically and ethically possible to assess the toxicity of all the chemicals that are being released into the aquatic environment due to the sheer number of chemicals and endless possible combinations.The aim of this project is to assess and predict chemical mixture toxicity by developing a cell- and mathematical-based model system of two major detoxification pathways in fish liver, the AhR and PXR signaling pathways.

Current cell-line models lack or have minimized signaling of the PXR signaling pathway which substantially undermines their usefulness in understanding detoxification mechanisms and accurately assessing toxicity.

Via CRISPR-Cas9 mediated gene editing we will generate the first zebrafish liver cell lines that includes both functional signaling pathways, which will also include developing the first complete transgene CRISPR-Cas9 knockin method in fish.

Data collected from these new cell lines will then be used to develop a mathematical model that describes these detoxification pathways to provide insight into toxicity mechanisms, pinpoint further informative experiments, and ultimately better predict adverse mixture toxicities.

Enhanced understanding of the molecular mechanisms behind chemical mixture toxicity and the novel model system developed within this project are key steps in developing safe and sustainable chemical regulations to reach the goal of a sustainable society.