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Building an Adverse Outcome Pathway Network for Arsenic-Induced DIseases-Poster
Citation:
Druwe, I., J. Davis, J. Gift, I. Cote, AND J. Lee. Building an Adverse Outcome Pathway Network for Arsenic-Induced DIseases-Poster. Society of Toxicology, Baltimore, MD, March 10 - 14, 2019.
Impact/Purpose:
The goal of this project was to perform MOA analyses to aid in informing low dose extrapolation by using the adverse outcome pathway framework.
Description:
Arsenic exposure has been associated with numerous diseases ranging from cancers of the bladder, skin and lung, to metabolic diseases such as cardiovascular disease and diabetes mellitus, as well as adverse pregnancy outcomes such as spontaneous abortions, low birth weights, and cognitive impairments of young children exposed either in the womb and or in early life. Multiple epidemiologic as well as animal studies have provided evidence that arsenic exposure can increase the human health risk for these diseases; however, the molecular events by which arsenic contributes to these diverse disease states is yet to be fully elucidated. Adverse outcome pathways (AOPs) are data-informed constructs that illustrate a series of biological events leading to adverse effects. Our goal was to use the AOP framework to organize the abundance of information about arsenic-related diseases and identify important key events and possible knowledge gaps, specifically using a cancer example (bladder cancer) and a noncancer example (diabetes). To construct AOPs for these independent disease states, we performed a literature search in PubMed and identified peer reviewed medical reviews that focused on the molecular events involved in these idiopathic diseases. Using these publications we identified key events and key event relationships in the progression of these diseases and built the AOPs. We then compared these AOPs against the idiopathic disease pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG), and observed that our AOP constructs aligned well with the pathways in the KEGG database. We then began overlaying information from published arsenic mechanistic studies, and in doing so, we identified key events in the progression and culmination of arsenic-induced bladder cancer and arsenic-induced diabetes. This approach was helpful in informing susceptibility and identifying key mechanistic steps and data gaps in the onset of these two arsenic-related diseases. The views expressed in this abstract are those of the authors and do not necessarily reflect the views or policies of the U.S. EPA. Mention of trade names or commercial products does not constitute endorsement or recommendations for use.