1. Hazard characterization of the mycotoxins enniatins and beauvericin to identify data gaps and improve risk assessment for human healthAnne-Cathrin Behr, Christiane Kruse Fæste, Amaya Azqueta, Ana P. M. Tavares, Anastasia Spyropoulou, Anita Solhaug, Ann-Karin Olsen, Ariane Vettorazzi, Bojana Žegura, Matjaž Novak, 2025, pregledni znanstveni članek Povzetek: Enniatins (ENNs) and beauvericin (BEA) are cyclic hexadepsipeptide fungal metabolites which have demonstrated antibiotic, antimycotic, and insecticidal activities. The substantial toxic potentials of these mycotoxins are associated with their ionophoric molecular properties and relatively high lipophilicities. ENNs occur extensively in grain and grain-derived products and are considered a food safety issue by the European Food Safety Authority (EFSA). The tolerable daily intake and maximum levels for ENNs in humans and animals remain unestablished due to key toxicological and toxicokinetic data gaps, preventing full risk assessment. Aiming to find critical data gaps impeding hazard characterization and risk evaluation, this review presents a comprehensive summary of the existing information from in vitro and in vivo studies on toxicokinetic characteristics and cytotoxic, genotoxic, immunotoxic, endocrine, reproductive and developmental effects of the most prevalent ENN analogues (ENN A, A1, B, B1) and BEA. The missing information identified showed that additional studies on ENNs and BEA have to be performed before sufficient data for an in-depth hazard characterisation of these mycotoxins become available.
Ključne besede: enniatins, beauvericin, genotoxicity, endocrine effects, immunotoxicology, toxicokinetics
Objavljeno v DiRROS: 14.04.2025; Ogledov: 146; Prenosov: 60
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2. New approach methodologies to facilitate and improve the hazard assessment of non-genotoxic carcinogens : a PARC projectMarc Audebert, Ann-Sophie Assmann, Amaya Azqueta, Pavel Babica, Emilio Benfenati, Martina Štampar, Bojana Žegura, 2023, pregledni znanstveni članek Povzetek: Carcinogenic chemicals, or their metabolites, can be classified as genotoxic or non-genotoxic carcinogens (NGTxCs). Genotoxic compounds induce DNA damage, which can be detected by an established in vitro and in vivo battery of genotoxicity assays. For NGTxCs, DNA is not the primary target, and the possible modes of action (MoA) of NGTxCs are much more diverse than those of genotoxic compounds, and there is no specific in vitro assay for detecting NGTxCs. Therefore, the evaluation of the carcinogenic potential is still dependent on long-term studies in rodents. This 2-year bioassay, mainly applied for testing agrochemicals and pharmaceuticals, is time-consuming, costly and requires very high numbers of animals. More importantly, its relevance for human risk assessment is questionable due to the limited predictivity for human cancer risk, especially with regard to NGTxCs. Thus, there is an urgent need for a transition to new approach methodologies (NAMs), integrating human-relevant in vitro assays and in silico tools that better exploit the current knowledge of the multiple processes involved in carcinogenesis into a modern safety assessment toolbox. Here, we describe an integrative project that aims to use a variety of novel approaches to detect the carcinogenic potential of NGTxCs based on different mechanisms and pathways involved in carcinogenesis. The aim of this project is to contribute suitable assays for the safety assessment toolbox for an efficient and improved, internationally recognized hazard assessment of NGTxCs, and ultimately to contribute to reliable mechanism-based next-generation risk assessment for chemical carcinogens.
Ključne besede: non-genotoxic carcinogens, NGTxC, new approach methodologies, NAM, PARC
Objavljeno v DiRROS: 05.08.2024; Ogledov: 484; Prenosov: 262
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3. Minimum Information for Reporting on the Comet Assay (MIRCA) : recommendations for describing comet assay procedures and resultsPeter Møller, Amaya Azqueta, Elisa Boutet-Robinet, Gudrun Koppen, Stefano Bonassi, Mirta Milić, Goran Gajski, Solange Costa, Bojana Žegura, Matjaž Novak, 2020, izvirni znanstveni članek Povzetek: The comet assay is a widely used test for the detection of DNA damage and repair activity. However, there are interlaboratory differences in reported levels of baseline and induced damage in the same experimental systems. These differences may be attributed to protocol differences, although it is difficult to identify the relevant conditions because detailed comet assay procedures are not always published. Here, we present a Consensus Statement for the Minimum Information for Reporting Comet Assay (MIRCA) providing recommendations for describing comet assay conditions and results. These recommendations differentiate between ‘desirable’ and ‘essential’ information: ‘essential’ information refers to the precise details that are necessary to assess the quality of the experimental work, whereas ‘desirable’ information relates to technical issues that might be encountered when repeating the experiments. Adherence to MIRCA recommendations should ensure that comet assay results can be easily interpreted and independently verified by other researchers.
Objavljeno v DiRROS: 22.07.2024; Ogledov: 567; Prenosov: 335
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4. DNA damage in circulating leukocytes measured with the comet assay may predict the risk of deathStefano Bonassi, Marcello Ceppi, Peter Møller, Amaya Azqueta, Mirta Milić, Gunnar Brunborg, Gudrun Koppen, Marco Bruzzone, Juliana Da Silva, Danieli Benedetti, Silvia Moretti, Patrizia Riso, Patrizia Russo, Ricardo Marcos, Goran Gajski, Biljana Spremo-Potparević, Lada Živković, Elisa Boutet-Robinet, Maria Dusinska, Andrew Collins, Bojana Žegura, 2021, izvirni znanstveni članek Povzetek: The comet assay or single cell gel electrophoresis, is the most common method used to measure strand breaks and a variety of other DNA lesions in human populations. To estimate the risk of overall mortality, mortality by cause, and cancer incidence associated to DNA damage, a cohort of 2,403 healthy individuals (25,978 person-years) screened in 16 laboratories using the comet assay between 1996 and 2016 was followed-up. Kaplan–Meier analysis indicated a worse overall survival in the medium and high tertile of DNA damage (p < 0.001). The effect of DNA damage on survival was modelled according to Cox proportional hazard regression model. The adjusted hazard ratio (HR) was 1.42 (1.06–1.90) for overall mortality, and 1.94 (1.04–3.59) for diseases of the circulatory system in subjects with the highest tertile of DNA damage. The findings of this study provide epidemiological evidence encouraging the implementation of the comet assay in preventive strategies for non-communicable diseases.
Objavljeno v DiRROS: 19.07.2024; Ogledov: 591; Prenosov: 341
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5. Do cytotoxicity and cell death cause false positive results in the in vitro comet assay?Amaya Azqueta, Helga Stopper, Bojana Žegura, Maria Dusinska, Peter Møller, 2022, izvirni znanstveni članek Povzetek: The comet assay is used to measure DNA damage induced by chemical and physical agents. High concentrations of test agents may cause cytotoxicity or cell death, which may give rise to false positive results in the comet assay. Systematic studies on genotoxins and cytotoxins (i.e. non-genotoxic poisons) have attempted to establish a threshold of cytotoxicity or cell death by which DNA damage results measured by the comet assay could be regarded as a false positive result. Thresholds of cytotoxicity/cell death range from 20% to 50% in various publications. Curiously, a survey of the latest literature on comet assay results from cell culture studies suggests that one-third of publications did not assess cytotoxicity or cell death. We recommend that it should be mandatory to include results from at least one type of assay on cytotoxicity, cell death or cell proliferation in publications on comet assay results. A combination of cytotoxicity (or cell death) and proliferation (or colony forming efficiency assay) is preferable in actively proliferating cells because it covers more mechanisms of action. Applying a general threshold of cytotoxicity/cell death to all types of agents may not be applicable; however, 25% compared to the concurrent negative control seems to be a good starting value to avoid false positive comet assay results. Further research is needed to establish a threshold value to distinguish between true and potentially false positive genotoxic effects detected by the comet assay.
Ključne besede: comet assay, cytotoxicity, genotoxicity, DNA damage, cell death
Objavljeno v DiRROS: 17.07.2024; Ogledov: 558; Prenosov: 375
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