Distinct Orchestration and Dynamic Processes on γ-H2AX and p-H3 for Two Major Types of Genotoxic Chemicals Revealed by Mass Spectrometry Analysis
| Autor: | Bin Xu, Minmin Qu, Jia Chen, Hua Xu, Jianwei Xie, Lei Guo, Yajiao Zhang |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Chemistry DNA damage General Medicine 010501 environmental sciences Toxicology DNA Damage Repair 01 natural sciences Cell biology Histones 03 medical and health sciences Clastogen Tandem Mass Spectrometry Transcription (biology) Toxicity Tumor Cells Cultured Humans Phosphorylation Aneugen Biomarkers Cell survival Chromatography Liquid DNA Damage 030304 developmental biology 0105 earth and related environmental sciences |
| Zdroj: | Chemical Research in Toxicology. 33:2108-2119 |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/acs.chemrestox.0c00104 |
| Popis: | Genotoxic chemicals act by causing DNA damage, which, if left unrepaired, can have deleterious consequences for cell survival. DNA damage response (DDR) gets activated to repair or mitigate the effects of DNA damage. Histone H2AX and H3 phosphorylation biomarkers (γ-H2AX and p-H3) have attracted great attention as they play pivotal roles in the DDR. Simultaneous quantitation of γ-H2AX and p-H3 in exposed cells may monitor the toxicity of genotoxic chemicals and to some extent reflect the subsequent DDR process. Reported here is the first comprehensive characterization of distinct orchestration and dynamic processes on cellular γ-H2AX and p-H3 for two major types of genotoxic chemicals, clastogens and aneugens, by stable isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS). We find that clastogens significantly induce an increase in γ-H2AX and a decrease in p-H3; aneugens have no obvious effect on γ-H2AX, whereas induce either an increase or a decrease in p-H3. In addition, the specific profiles of clastogens and aneugens affecting DNA damage may be dynamically observed, which in turn provides insights into the processes involving DNA damage repair as well as transcription. Taken together, these results suggest that robust LC-MS/MS analysis of γ-H2AX and p-H3 can not only quantitatively differentiate mechanistic information on clastogens and aneugens but also dynamically present the detail profiles of DNA damage and repair processes. |
| Databáze: | OpenAIRE |
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