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Elucidating Mechanisms of Toxicity Using Phenotypic Data from Primary Human Cell Systems—A Chemical Biology Approach for Thrombosis-Related Side Effects

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Int. J. Mol. Sci. 2015, 16(1), 1008-1029; https://doi.org/10.3390/ijms16011008
Received: 5 September 2014 / Accepted: 23 December 2014 / Published: 5 January 2015
Here we describe a chemical biology approach for elucidating potential toxicity mechanisms for thrombosis-related side effects. This work takes advantage of a large chemical biology data set comprising the effects of known, well-characterized reference agents on the cell surface levels of tissue factor (TF) in a primary human endothelial cell-based model of vascular inflammation, the BioMAP® 3C system. In previous work with the Environmental Protection Agency (EPA) for the ToxCast™ program, aryl hydrocarbon receptor (AhR) agonists and estrogen receptor (ER) antagonists were found to share an usual activity, that of increasing TF levels in this system. Since human exposure to compounds in both chemical classes is associated with increased incidence of thrombosis-related side effects, we expanded this analysis with a large number of well-characterized reference compounds in order to better understand the underlying mechanisms. As a result, mechanisms for increasing (AhR, histamine H1 receptor, histone deacetylase or HDAC, hsp90, nuclear factor kappa B or NFκB, MEK, oncostatin M receptor, Jak kinase, and p38 MAPK) and decreasing (vacuolar ATPase or V-ATPase) and mTOR) TF expression levels were uncovered. These data identify the nutrient, lipid, bacterial, and hypoxia sensing functions of autophagy as potential key regulatory points controlling cell surface TF levels in endothelial cells and support the mechanistic hypothesis that these functions are associated with thrombosis-related side effects in vivo. View Full-Text
Keywords: thrombosis; toxicity; primary human cells; endothelial cells; inflammation; cholesterol; aryl hydrocarbon receptor; nutrient sensing; pathway; tissue factor; bacterial sensing; hypoxia thrombosis; toxicity; primary human cells; endothelial cells; inflammation; cholesterol; aryl hydrocarbon receptor; nutrient sensing; pathway; tissue factor; bacterial sensing; hypoxia
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Berg, E.L.; Polokoff, M.A.; O'Mahony, A.; Nguyen, D.; Li, X. Elucidating Mechanisms of Toxicity Using Phenotypic Data from Primary Human Cell Systems—A Chemical Biology Approach for Thrombosis-Related Side Effects. Int. J. Mol. Sci. 2015, 16, 1008-1029.

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