The Toxmatrix: Chemo-Genomic Profiling Identifies Interactions That Reveal Mechanisms of ToxicityClick to copy article linkArticle link copied!
- Zhi-Bin Tong
- Ruili Huang
- Yuhong Wang
- Carleen A. Klumpp-Thomas
- John C. Braisted
- Zina Itkin
- Paul Shinn
- Menghang Xia
- Anton Simeonov
- David L. Gerhold
Abstract
A chemical genomics “Toxmatrix” method was developed to elucidate mechanisms of cytotoxicity using neuronal models. Quantitative high-throughput screening (qHTS) was applied to systematically screen each toxicant against a panel of 70 modulators, drugs or chemicals that act on a known target, to identify interactions that either protect or sensitize cells to each toxicant. Thirty-two toxicants were tested at 10 concentrations for cytotoxicity to SH-SY5Y human neuroblastoma cells, with results fitted to the Hill equation to determine an IC50 for each toxicant. Thirty-three toxicant:modulator interactions were identified in SH-SY5Y cells for 14 toxicants, as modulators that shifted toxicant IC50 values lower or higher. The target of each modulator that sensitizes cells or protects cells from a toxicant suggests a mode of toxicant action or cellular adaptation. In secondary screening, we tested modulator-toxicant pairs identified from the SH-SY5Y primary screening for interactions in three differentiated neuronal human cell lines: dSH-SY5Y, conditionally immortalized dopaminergic neurons (LUHMES), and neural stem cells. Twenty toxicant-modulator pairs showed pronounced interactions in one or several differentiated cell models. Additional testing confirmed that several modulators acted through their primary targets. For example, several chelators protected differentiated LUHMES neurons from four toxicants by chelation of divalent cations and buthionine sulphoximine sensitized cells to 6-hydroxydopamine and 4-(methylamino)phenol hemisulfate by blocking glutathione synthesis. Such modulators that interact with multiple neurotoxicants suggest these may be vulnerable toxicity pathways in neurons. Thus, the Toxmatrix method is a systematic high-throughput approach that can identify mechanisms of toxicity and cellular adaptation.
Cited By
This article is cited by 9 publications.
- Andreas Zeller, Alessandro Brigo, Andreas Brink, Melanie Guerard, Dieter Lang, Wolfgang Muster, Frank Runge, Andreas Sutter, Esther Vock, Jörg Wichard, Simone Schadt. Genotoxicity Assessment of Drug Metabolites in the Context of MIST and Beyond. Chemical Research in Toxicology 2020, 33
(1)
, 10-19. https://doi.org/10.1021/acs.chemrestox.9b00348
- Zhi-Bin Tong, Hyunhee Kim, Lara El Touny, Anton Simeonov, David Gerhold. LUHMES Dopaminergic Neurons Are Uniquely Susceptible to Ferroptosis. Neurotoxicity Research 2022, 40
(5)
, 1526-1536. https://doi.org/10.1007/s12640-022-00538-y
- David Gerhold, Hyun Hee Kim, Zhi-Bin Tong. Biomarkers of Neurotoxicity Inform Mechanisms of Vulnerability and Resilience in Dopaminergic Neurons. 2022, 223-237. https://doi.org/10.1007/978-3-031-15080-7_183
- David Gerhold, Hyun Hee Kim, Zhi-Bin Tong. Biomarkers of Neurotoxicity Inform Mechanisms of Vulnerability and Resilience in Dopaminergic Neurons. 2021, 1-15. https://doi.org/10.1007/978-3-030-71519-9_183-1
- Zhi-Bin Tong, John Braisted, Pei-Hsuan Chu, David Gerhold. The MT1G Gene in LUHMES Neurons Is a Sensitive Biomarker of Neurotoxicity. Neurotoxicity Research 2020, 38
(4)
, 967-978. https://doi.org/10.1007/s12640-020-00272-3
- Christian T. Meyer, David J. Wooten, Carlos F. Lopez, Vito Quaranta. Charting the Fragmented Landscape of Drug Synergy. Trends in Pharmacological Sciences 2020, 41
(4)
, 266-280. https://doi.org/10.1016/j.tips.2020.01.011
- Kristin Robin Ko, Nicky W. Tam, Alyne G. Teixeira, John P. Frampton. SH‐SY5Y and LUHMES cells display differential sensitivity to MPP+, tunicamycin, and epoxomicin in 2D and 3D cell culture. Biotechnology Progress 2020, 36
(2)
https://doi.org/10.1002/btpr.2942
- Petra Kranaster, Christiaan Karreman, Jeremias E. G. A. Dold, Alice Krebs, Melina Funke, Anna-Katharina Holzer, Stefanie Klima, Johanna Nyffeler, Stefan Helfrich, Valentin Wittmann, Marcel Leist. Time and space-resolved quantification of plasma membrane sialylation for measurements of cell function and neurotoxicity. Archives of Toxicology 2020, 94
(2)
, 449-467. https://doi.org/10.1007/s00204-019-02642-z
- Johannes Delp, Melina Funke, Franziska Rudolf, Andrea Cediel, Susanne Hougaard Bennekou, Wanda van der Stel, Giada Carta, Paul Jennings, Cosimo Toma, Iain Gardner, Bob van de Water, Anna Forsby, Marcel Leist. Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants. Archives of Toxicology 2019, 93
(6)
, 1585-1608. https://doi.org/10.1007/s00204-019-02473-y
Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.