E-Thesis 38 views 9 downloads
An investigation on the Mutagenicity of Compounds using Benchmark Dose and Dose-Response Data for Research in Genetic Toxicology / YUSUF HUSSIEN
Swansea University Author: YUSUF HUSSIEN
DOI (Published version): 10.23889/SUthesis.72022
Abstract
Despite the current availability of analytical techniques for genotoxicity studies, limitations in quantitative methods restrict researchers from numerically analysing and explaining how various environmental, chemical, and physical sources cause genetic damage to cells. Benchmark dose serves as an...
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Swansea
2026
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| Institution: | Swansea University |
| Degree level: | Doctoral |
| Degree name: | Ph.D |
| Supervisor: | Johnson, George ; Chapman, Kathetine |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa72022 |
| Abstract: |
Despite the current availability of analytical techniques for genotoxicity studies, limitations in quantitative methods restrict researchers from numerically analysing and explaining how various environmental, chemical, and physical sources cause genetic damage to cells. Benchmark dose serves as an important metric when gathering dose-response data from genotoxic compounds and multiple studies assess information on both to appropriately determine doses that result in genetic abnormalities for visualisation, interpretation, and review. The ability to map different compounds according to their genotoxicity allows for the comparative analysis of these compounds to be normalised and formatted in a coherent manner whilst retaining the depth and complexity that they initially had during the processing phase of each dataset. This investigation utilises data generated across multiple tests and assays (Litron Multiflow Genotoxicity Assay, Toxys ToxTracker Assay, TGx-DDI transcriptomic biomarker test, iScreen image analysis and in vitro-to-in vivo extrapolation) to quantitatively measure the genotoxic effects of various mutagenic compounds on cellular biomarkers (e.g. p53, γH2aX. phospho-histone H3, TGx-DDi, Bscl2, CENPA, MPM2, etc) using raw response (imaging induction or fold change/percentage) data generated from multiplexed flow cytometry imaging techniques to expand our understanding of mutagenicity whilst revealing the potential use of data analysis techniques to aid in genetics/cancer research. PROAST was used to calculate benchmark dose confidence intervals (BMD CI) that provide information on potency, and ToxPi was used to analyse the BMD CI across each endpoint and chemical, using approaches such as hierarchical clustering, principal component analysis (PCA) and providing a potency score. In conjunction with a weight-of-evidence approach, this combined analysis will inform us of the chemical grouping and potency across the multiple genetic toxicity endpoints and allow a quicker and more precise assessment of complex datasets. There will be benefits for hazard and risk assessment, while also providing increased weight to in vitro data sets. |
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| Item Description: |
ORCiD identifier: https://orcid.org/0009-0004-6023-3663 |
| Keywords: |
Genetic Toxicology, Data Science, Bioinformatics, Genetics, Medicine, Biology, Assays |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
Partially funded by HESI GTTC. |