Dataset Information

A Quantitative Toxicogenomics Assay for High-throughput and Mechanistic Genotoxicity Assessment and Screening of Environmental Pollutants.

ABSTRACT: The ecological and health concern of mutagenicity and carcinogenicity potentially associated with an overwhelmingly large and ever-increasing number of chemicals demands for cost-effective and feasible method for genotoxicity screening and risk assessment. This study proposed a genotoxicity assay using GFP-tagged yeast reporter strains, covering 38 selected protein biomarkers indicative of all the seven known DNA damage repair pathways. The assay was applied to assess four model genotoxic chemicals, eight environmental pollutants and four negative controls across six concentrations. Quantitative molecular genotoxicity end points were derived based on dose response modeling of a newly developed integrated molecular effect quantifier, Protein Effect Level Index (PELI). The molecular genotoxicity end points were consistent with multiple conventional in vitro genotoxicity assays, as well as with in vivo carcinogenicity assay results. Further more, the proposed genotoxicity end point PELI values quantitatively correlated with both comet assay in human cell and carcinogenicity potency assay in mice, providing promising evidence for linking the molecular disturbance measurements to adverse outcomes at a biological relevant level. In addition, the high-resolution DNA damaging repair pathway alternated protein expression profiles allowed for chemical clustering and classification. This toxicogenomics-based assay presents a promising alternative for fast, efficient and mechanistic genotoxicity screening and assessment of drugs, foods, and environmental contaminants.

SUBMITTER: Lan J

PROVIDER: S-EPMC6321748 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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A Quantitative Toxicogenomics Assay for High-throughput and Mechanistic Genotoxicity Assessment and Screening of Environmental Pollutants.

Lan Jiaqi J Gou Na N Rahman Sheikh Mokhles SM Gao Ce C He Miao M Gu April Z AZ

Environmental science & technology 20160302 6

The ecological and health concern of mutagenicity and carcinogenicity potentially associated with an overwhelmingly large and ever-increasing number of chemicals demands for cost-effective and feasible method for genotoxicity screening and risk assessment. This study proposed a genotoxicity assay using GFP-tagged yeast reporter strains, covering 38 selected protein biomarkers indicative of all the seven known DNA damage repair pathways. The assay was applied to assess four model genotoxic chemic ...[more]

PMID: 26855253

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Project description:The incomplete mineralization of contaminants of emerging concern (CECs) during the advanced oxidation processes can generate transformation products that exhibit toxicity comparable to or greater than that of the original contaminant. In this study, we demonstrated the application of a novel, fast, and cost-effective quantitative toxicogenomics-based approach for the evaluation of the evolution and nature of toxicity along the electro-Fenton oxidative degradation of three representative CECs whose oxidative degradation pathways have been relatively well studied, bisphenol A, triclosan, and ibuprofen. The evolution of toxicity as a result of the transformation of parent chemicals and production of intermediates during the course of degradation are monitored, and the quantitative toxicogenomics assay results revealed the dynamic toxicity changes and mechanisms, as well as their association with identified intermediates during the electro-Fenton oxidation process of the selected CECs. Although for the three CECs, a majority (>75%) of the parent compounds disappeared at the 15 min reaction time, the nearly complete elimination of toxicity required a minimal 30 min reaction time, and they seem to correspond to the disappearance of identified aromatic intermediates. Bisphenol A led to a wide range of stress responses, and some identified transformation products containing phenolic or quinone group, such as 1,4-benzoquinone and hydroquinone, likely contributed to the transit toxicity exhibited as DNA stress (genotoxicity) and membrane stress during the degradation. Triclosan is known to cause severe oxidative stress, and although the oxidative damage potential decreased concomitantly with the disappearance of triclosan after a 15 min reaction, the sustained toxicity associated with both membrane and protein stress was likely attributed at least partially to the production of 2,4-dichlorophenol that is known to cause the production of abnormal proteins and affect the cell membrane. Ibuprofen affects the cell transporter function and exhibited significantly high membrane stress related to both membrane structure and function. Oxidative degradation of ibuprofen led to a shift in its toxicity profile from mainly membrane stress to one that exhibited not only sustained membrane stress but also protein stress and DNA stress. The information-rich and high-resolution toxicogenomics results served as "fingerprints" that discerned and revealed the toxicity mechanism at the molecular level among the CECs and their oxidation transformation products. This study demonstrated that the quantitative toxicogenomics assay can serve as a useful tool for remediation technology efficacy assessment and provide guidance about process design and optimization for desired toxicity elimination and risk reduction.

Project description:Genotoxicity is a critical component of a comprehensive toxicological profile. The Tox21 Program used five quantitative high-throughput screening (qHTS) assays measuring some aspect of DNA damage/repair to provide information on the genotoxic potential of over 10?000 compounds. Included were assays detecting activation of p53, increases in the DNA repair protein ATAD5, phosphorylation of H2AX, and enhanced cytotoxicity in DT40 cells deficient in DNA-repair proteins REV3 or KU70/RAD54. Each assay measures a distinct component of the DNA damage response signaling network; >70% of active compounds were detected in only one of the five assays. When qHTS results were compared with results from three standard genotoxicity assays (bacterial mutation, in vitro chromosomal aberration, and in vivo micronucleus), a maximum of 40% of known, direct-acting genotoxicants were active in one or more of the qHTS genotoxicity assays, indicating low sensitivity. This suggests that these qHTS assays cannot in their current form be used to replace traditional genotoxicity assays. However, despite the low sensitivity, ranking chemicals by potency of response in the qHTS assays revealed an enrichment for genotoxicants up to 12-fold compared with random selection, when allowing a 1% false positive rate. This finding indicates these qHTS assays can be used to prioritize chemicals for further investigation, allowing resources to focus on compounds most likely to induce genotoxic effects. To refine this prioritization process, models for predicting the genotoxicity potential of chemicals that were active in Tox21 genotoxicity assays were constructed using all Tox21 assay data, yielding a prediction accuracy up to 0.83. Data from qHTS assays related to stress-response pathway signaling (including genotoxicity) were the most informative for model construction. By using the results from qHTS genotoxicity assays, predictions from models based on qHTS data, and predictions from commercial bacterial mutagenicity QSAR models, we prioritized Tox21 chemicals for genotoxicity characterization.

Project description:BACKGROUND:Health risks linked with dioxin in fish remain a complex policy issue. Fatty Baltic fish contain persistent pollutants, but they are otherwise healthy food. We studied the health benefits and risks associated with Baltic herring and salmon in four countries to identify critical uncertainties and to facilitate an evidence-based discussion. METHODS:We performed an online survey investigating consumers' fish consumption and its motivation in Denmark, Estonia, Finland, and Sweden. Dioxin and methylmercury concentrations were estimated based on Finnish studies. Exposure-response functions for several health endpoints were evaluated and quantified based on the scientific literature. We also quantified the infertility risk of men based on a recent European risk assessment estimating childhood dioxin exposure and its effect on sperm concentration later in life. RESULTS:Baltic herring and salmon contain omega-3 fatty acids and vitamin D, and the beneficial impact of these fishes on cardiovascular diseases, mortality, and the risk of depression and cancer clearly outweighs risks of dioxins and methylmercury in people older than 45?years of age and in young men. Young women may expose their children to pollutants during pregnancy and breast feeding. This study suggests that even in this critical subgroup, the risks are small and the health benefits are greater than or at least similar to the health risks. Value of information analysis demonstrated that the remaining scientific uncertainties are not large. In contrast, there are several critical uncertainties that are inherently value judgements, such as whether exceeding the tolerable weekly intake is an adverse outcome as such; and whether or not subgroup-specific restrictions are problematic. CONCLUSIONS:The potential health risks attributable to dioxins in Baltic fish have more than halved in the past 10 years. The new risk assessment issued by the European Food Safety Authority clearly increases the fraction of the population exceeding the tolerable dioxin intake, but nonetheless, quantitative estimates of net health impacts change only marginally. Increased use of small herring (which have less pollutants) is a no-regret option. A more relevant value-based policy discussion rather than research is needed to clarify official recommendations related to dioxins in fish.

Dataset Information

A Quantitative Toxicogenomics Assay for High-throughput and Mechanistic Genotoxicity Assessment and Screening of Environmental Pollutants.

Publications

A Quantitative Toxicogenomics Assay for High-throughput and Mechanistic Genotoxicity Assessment and Screening of Environmental Pollutants.

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