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Profiling of the Tox21 Chemical Collection for Mitochondrial Function: I. Compounds that Decrease Mitochondrial Membrane Potential
Citation:
Attene-Ramos, M., R. Huang, S. Michael, K. Witt, A. Richard, R. Tice, A. Simeonov, C. Austin, AND M. Xia. Profiling of the Tox21 Chemical Collection for Mitochondrial Function: I. Compounds that Decrease Mitochondrial Membrane Potential. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 123(1):49-56, (2015).
Impact/Purpose:
Purpose of study is to screen a large set of environmental chemicals for their ability to disrupt cellular processes potentially relevant to in vivo toxicity mechanisms using modern quantitative high-throughput screening technologies (qHTS) as part of the federal collaborative Tox21 project (an extension of EPA's ToxCast program). This study reports the results of a qHTS assay that evaluates the ability of diverse chemicals to disrupt mitochodrial function, which has been implicated in a variety of human diseases. Several structure features appear to be enriched within the active chemical structure-based clusters that could serve as the basis of SAR predictive models.
Description:
Mitochondrial dysfunction has been implicated in the pathogenesis of a variety of disorders including cancer, diabetes, and neurodegenerative and cardiovascular diseases. Understanding how different environmental chemicals and drug-like molecules impact mitochondrial function represents an initial step in predicting exposure-related toxic effects and defining a possible role for such compounds in the onset of various diseases. OBJECTIVES: To identify individual chemicals and general structural features associated with the disruption of mitochondrial membrane potential (MMP). METHODS: We used a multiplexed quantitative high throughput screening (qHTS) approach combined with informatics tools to screen the Tox21 10,000 compound library (~8300 unique chemicals) at 15 concentrations in triplicate to identify chemicals and structural features that are associated with changes in MMP in HepG2 cells. RESULTS: In the primary screening, approximately 11% of the compounds (913 unique compounds) decreased the MMP after 1 h of treatment without affecting cell viability. Additionally, 309 compounds decreased MMP over a concentration range that also produced measurable cytotoxicity [half maximal inhibitory concentration (IC50) in MMP assay/IC50 in viability assay) ≤ 3, p<0.05]. Over 11% of the structural clusters that constitute the Tox21 library (76 of 651 clusters) were significantly enriched for compounds that decreased the MMP. CONCLUSIONS: Our multiplexed qHTS approach allowed us to generate a robust and reliable dataset to evaluate the ability of thousands of drugs and environmental compounds to decrease MMP. The use of structure-based clustering analysis allowed us to identify molecular features that are likely responsible for the observed activity.
