Next Article in Journal
Melatonin and Female Hormone Secretion in Postmenopausal Overweight Women
Previous Article in Journal
Revealing the Supramolecular Nature of Side-Chain Terpyridine-Functionalized Polymer Networks
Previous Article in Special Issue
Biomarkers of Treatment Toxicity in Combined-Modality Cancer Therapies with Radiation and Systemic Drugs: Study Design, Multiplex Methods, Molecular Networks
Article Menu
Issue 1 (January) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2015, 16(1), 1008-1029; doi:10.3390/ijms16011008

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

BioSeek, a Division of DiscoveRx Corp., 310 Utah Ave., Suite 100, South San Francisco, CA 94080, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Dale Johnson
Received: 5 September 2014 / Accepted: 23 December 2014 / Published: 5 January 2015
View Full-Text   |   Download PDF [1299 KB, uploaded 5 January 2015]   |  

Abstract

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
Figures

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

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.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top