Genetic Toxicity:
            <i>In Vitro</i>
            Approaches for Hit and Lead Profiling

Walmsley, Richard M.; Billinton, Nicholas

doi:10.1002/9783527627448.ch11

Cited by 1 publication

(1 citation statement)

References 56 publications

(59 reference statements)

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“…7,30 In recent years, high-throughput genotoxicity assessment has been reported where the activation of single or selected biomarkers indicative of DNA damage recognition and repair are used to indicate potential genotoxicity. 7,[32][33][34][35][36][37] Our group has recently developed and validated a new quantitative toxicogenomics-based assay based on real time protein expression profiling of known DNA damage and repair pathways ensemble. [38][39][40][41] Compared to other biomarkerbased tests, our assay derives quantitative end points that correlate with conventional genotoxicity end points and promises to be a cost-effective and mechanistic genotoxicity assessment assay.…”

Section: Introductionmentioning

confidence: 99%

Genotoxicity Assessment of Drinking Water Disinfection Byproducts by DNA Damage and Repair Pathway Profiling Analysis

Lan

Rahman

Gou

et al. 2018

Environ. Sci. Technol.

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Genotoxicity is considered a major concern for drinking water disinfection byproducts (DBPs). Of over 700 DBPs identified to date, only a small number has been assessed with limited information for DBP genotoxicity mechanism(s). In this study, we evaluated genotoxicity of 20 regulated and unregulated DBPs applying a quantitative toxicogenomics approach. We used GFP-fused yeast strains that examine protein expression profiling of 38 proteins indicative of all known DNA damage and repair pathways. The toxicogenomics assay detected genotoxicity potential of these DBPs that is consistent with conventional genotoxicity assays end points. Furthermore, the high-resolution, real-time pathway activation and protein expression profiling, in combination with clustering analysis, revealed molecular level details in the genotoxicity mechanisms among different DBPs and enabled classification of DBPs based on their distinct DNA damage effects and repair mechanisms. Oxidative DNA damage and base alkylation were confirmed to be the main molecular mechanisms of DBP genotoxicity. Initial exploration of QSAR modeling using moleular genotoxicity end points (PELI) suggested that genotoxicity of DBPs in this study was correlated with topological and quantum chemical descriptors. This study presents a toxicogenomics-based assay for fast and efficient mechanistic genotoxicity screening and assessment of a large number of DBPs. The results help to fill in the knowledge gap in the understanding of the molecular mechanisms of DBP genotoxicity.

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Section: Introductionmentioning

confidence: 99%