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Systems Biology Approach for Understanding MOA, Dose-Response and Susceptibility to Environmental Chemicals
Citation:
SIMMONS, S. Systems Biology Approach for Understanding MOA, Dose-Response and Susceptibility to Environmental Chemicals. Presented at Environmental Mutagen Society 41st Annual Meeting, Ft. Worth, TX, October 23 - 27, 2010.
Impact/Purpose:
This presentation will highlight the advances made in developing highthroughput assays for toxicity screening based on cellular stress response pathways and how these assays are used to establish quantitative biological activity relationships to characterize toxicant mode of action.
Description:
There is an increasing need for assays for the rapid and efficient assessment of toxicities of large numbers of environmental chemicals. To meet this need, we have developed a battery of cell-based reporter assays that measure the activation of key cellular stress pathways. These low-cost, high-throughput assays exploit nodal points in each pathway that integrate multiple upstream signaling inputs. Preliminary data from quantitative high-throughput screening experiments uncovered important compound-specific activity patterns. Diverse toxicants activated distinct subsets of stress response pathways and exhibited marked differences with respect to both efficacy and relative potency of these activations. Additionally, important cell type-dependent differences in biological response patterns were manifested. Taken together these data suggest that a systems view of stress response pathway biology can effectively resolve the landscape of environmental chemicals in a manner that not only allows for identification of toxicants, but also classification with respect to putative modes of action. These tools can also be used in a variety of model systems beyond cultured cells that may help to fill knowledge gaps that arise from inter-species and in vitro to in vivo extrapolations. (This is an abstract of a proposed presentation and does not necessarily reflect EPA policy).