Automated screening for oxidative or methylation-induced DNA damage in human cells

Mack, Matthias; Schweinlin, Katharina; Mirsberger, Nicola; Zubel, Tabea; Bürkle, Alexander

doi:10.14573/altex.2001221

Cited by 4 publications

(7 citation statements)

References 29 publications

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“…Independent of the cell type tested, these studies consistently showed much a stronger increase in DNA strand break formation upon application of Fpg/Ogg1. These results are also consistent with a recent study, which demonstrated the absence of directly induced strand breaks by bromate up to a concentration of 200 µM, while Fpg-sensitive sites were detected already at 50 µM in human THP1 cells (Mack et al 2021 ). Taken together, these studies again indicate that bromate mostly induces oxidative DNA damage, which can be converted to DNA strand breaks during base excision repair.…”

Section: Modes Of Actionsupporting

confidence: 93%

“…In the latter study, significant removal of 8-oxo-dG lesions was observed after 21 h; however, it is not completely clear if this effect was due to repair or dilution of lesions as a consequences of cell proliferation. In a recent study, using a modified FADU assay, significant induction of Fpg-sensitive sites was observed after treatment of human THP1 macrophage-derived cells for 2 h already at concentrations ≥ 50 µM potassium bromate (Mack et al 2021 ).…”

Section: Modes Of Actionmentioning

confidence: 99%

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New aspects in deriving health-based guidance values for bromate in swimming pool water

et al. 2022

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Bromate, classified as a EU CLP 1B carcinogen, is a typical by-product of the disinfection of drinking and swimming pool water. The aim of this study was (a) to provide data on the occurrence of bromate in pool water, (b) to re-evaluate the carcinogenic MOA of bromate in the light of existing data, (c) to assess the possible exposure to bromate via swimming pool water and (d) to inform the derivation of cancer risk-related bromate concentrations in swimming pool water. Measurements from monitoring analysis of 229 samples showed bromate concentrations in seawater pools up to 34 mg/L. A comprehensive non-systematic literature search was done and the quality of the studies on genotoxicity and carcinogenicity was assessed by Klimisch criteria (Klimisch et al., Regul Toxicol Pharmacol 25:1–5, 1997) and SciRAP tool (Beronius et al., J Appl Toxicol, 38:1460–1470, 2018) respectively. Benchmark dose (BMD) modeling was performed using the modeling average mode in BMDS 3.1 and PROAST 66.40, 67 and 69 (human cancer BMDL10; EFSA 2017). For exposure assessment, data from a wide range of sources were evaluated for their reliability. Different target groups (infants/toddlers, children and adults) and exposure scenarios (recreational, sport-active swimmers, top athletes) were considered for oral, inhalation and dermal exposure. Exposure was calculated according to the frequency of swimming events and duration in water. For illustration, cancer risk-related bromate concentrations in pool water were calculated for different target groups, taking into account their exposure using the hBMDL10 and a cancer risk of 1 in 100,000. Convincing evidence was obtained from a multitude of studies that bromate induces oxidative DNA damage and acts as a clastogen in vitro and in vivo. Since statistical modeling of the available genotoxicity data is compatible with both linear as well as non-linear dose–response relationships, bromate should be conservatively considered to be a non-threshold carcinogen. BMD modeling with model averaging for renal cancer studies (Kurokawa et al., J Natl. Cancer Inst, 1983 and 1986a; DeAngelo et al., Toxicol Pathol 26:587–594, 1998) resulted in a median hBMDL10 of 0.65 mg bromate/kg body weight (bw) per day. Evaluation of different age and activity groups revealed that top athletes had the highest exposure, followed by sport-active children, sport-active adults, infants and toddlers, children and adults. The predominant route of exposure was oral (73–98%) by swallowing water, followed by the dermal route (2–27%), while the inhalation route was insignificant (< 0.5%). Accepting the same risk level for all population groups resulted in different guidance values due to the large variation in exposure. For example, for an additional risk of 1 in 100,000, the bromate concentrations would range between 0.011 for top athletes, 0.015 for sport-active children and 2.1 mg/L for adults. In conclusion, the present study shows that health risks due to bromate exposure by swimming pool water cannot be excluded and that large differences in risk exist depending on the individual swimming habits and water concentrations.

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Section: Modes Of Actionsupporting

confidence: 93%

Section: Modes Of Actionmentioning

confidence: 99%

New aspects in deriving health-based guidance values for bromate in swimming pool water

et al. 2022

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“…HTS methods are defined as the use of automated tools to facilitate rapid execution of a large number and variety of biological assays that may include several test substances in each assay [ 162 ]. 134 publications have been found applying the keywords “genotoxicity & high throughput“ [ 163 , 164 , 165 , 166 , 167 , 168 ], although only 14 of them related to NMs ( Table 1 ).…”

Section: High Throughput Methodsmentioning

confidence: 99%

Genotoxicity of Nanomaterials: Advanced In Vitro Models and High Throughput Methods for Human Hazard Assessment—A Review

et al. 2020

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Changes in the genetic material can lead to serious human health defects, as mutations in somatic cells may cause cancer and can contribute to other chronic diseases. Genotoxic events can appear at both the DNA, chromosomal or (during mitosis) whole genome level. The study of mechanisms leading to genotoxicity is crucially important, as well as the detection of potentially genotoxic compounds. We consider the current state of the art and describe here the main endpoints applied in standard human in vitro models as well as new advanced 3D models that are closer to the in vivo situation. We performed a literature review of in vitro studies published from 2000–2020 (August) dedicated to the genotoxicity of nanomaterials (NMs) in new models. Methods suitable for detection of genotoxicity of NMs will be presented with a focus on advances in miniaturization, organ-on-a-chip and high throughput methods.

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“…Here, we focus particularly on the detection of DNA strand breaks as one well-known type of DNA damage. In this context, two assays shall be highlighted: the comet (or single-cell gel electrophoresis) assay which is one of the most used assays for the detection of DNA strand breaks and the FADU (fluorimetric detection of alkaline DNA unwinding) assay as a new emerging semiautomated technology [19,20]. The comet assay was originally developed in 1984 by Ostling and Johanson and further modified in 1988 by Singh and colleagues [21,22] and is commonly used to determine the induction of DNA breakage by genotoxic agents and ionizing radiation at the level of individual cells.…”

Section: Introductionmentioning

confidence: 99%

“…The novel semi-automated version of this assay enables the fast assessment of DNA breakage in a 96-well-plate format and the integration of different control samples for ENM interference detection. Very recent research has extended its field of application to the detection of oxidative and methylation-induced DNA damage [19].…”

Section: Introductionmentioning

confidence: 99%

Assessing Genotoxicity of Ten Different Engineered Nanomaterials by the Novel Semi-Automated FADU Assay and the Alkaline Comet Assay

et al. 2022

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Increased engineered nanomaterial (ENM) production and incorporation in consumer and biomedical products has raised concerns about the potential adverse effects. The DNA damaging capacity is of particular importance since damaged genetic material can lead to carcinogenesis. Consequently, reliable and robust in vitro studies assessing ENM genotoxicity are of great value. We utilized two complementary assays based on different measurement principles: (1) comet assay and (2) FADU (fluorimetric detection of alkaline DNA unwinding) assay. Assessing cell viability ruled out false-positive results due to DNA fragmentation during cell death. Potential structure–activity relationships of 10 ENMs were investigated: three silica nanoparticles (SiO2-NP) with varying degrees of porosity, titanium dioxide (TiO2-NP), polystyrene (PS-NP), zinc oxide (ZnO-NP), gold (Au-NP), graphene oxide (GO) and two multi-walled carbon nanotubes (MWNT). SiO2-NPs, TiO2-NP and GO were neither cytotoxic nor genotoxic to Jurkat E6-I cells. Quantitative interference corrections derived from GO results can make the FADU assay a promising screening tool for a variety of ENMs. MWNT merely induced cytotoxicity, while dose- and time-dependent cytotoxicity of PS-NP was accompanied by DNA fragmentation. Hence, PS-NP served to benchmark threshold levels of cytotoxicity at which DNA fragmentation was expected. Considering all controls revealed the true genotoxicity for Au-NP and ZnO-NP at early time points.

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Automated screening for oxidative or methylation-induced DNA damage in human cells

Cited by 4 publications

References 29 publications

New aspects in deriving health-based guidance values for bromate in swimming pool water

New aspects in deriving health-based guidance values for bromate in swimming pool water

Genotoxicity of Nanomaterials: Advanced In Vitro Models and High Throughput Methods for Human Hazard Assessment—A Review

Assessing Genotoxicity of Ten Different Engineered Nanomaterials by the Novel Semi-Automated FADU Assay and the Alkaline Comet Assay

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