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1.
Environ Int ; 189: 108728, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38850672

RESUMO

Bisphenol A alternatives are manufactured as potentially less harmful substitutes of bisphenol A (BPA) that offer similar functionality. These alternatives are already in the market, entering the environment and thus raising ecological concerns. However, it can be expected that levels of BPA alternatives will dominate in the future, they are limited information on their environmental safety. The EU PARC project highlights BPA alternatives as priority chemicals and consolidates information on BPA alternatives, with a focus on environmental relevance and on the identification of the research gaps. The review highlighted aspects and future perspectives. In brief, an extension of environmental monitoring is crucial, extending it to cover BPA alternatives to track their levels and facilitate the timely implementation of mitigation measures. The biological activity has been studied for BPA alternatives, but in a non-systematic way and prioritized a limited number of chemicals. For several BPA alternatives, the data has already provided substantial evidence regarding their potential harm to the environment. We stress the importance of conducting more comprehensive assessments that go beyond the traditional reproductive studies and focus on overlooked relevant endpoints. Future research should also consider mixture effects, realistic environmental concentrations, and the long-term consequences on biota and ecosystems.

2.
Arch Toxicol ; 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38805047

RESUMO

Indoor air pollution is becoming a rising public health problem and is largely resulting from the burning of solid fuels and heating in households. Burning these fuels produces harmful compounds, such as particulate matter regarded as a major health risk, particularly affecting the onset and exacerbation of respiratory diseases. As exposure to polluted indoor air can cause DNA damage including DNA sd breaks as well as chromosomal damage, in this paper, we aim to provide an overview of the impact of indoor air pollution on DNA damage and genome stability by reviewing the scientific papers that have used the comet, micronucleus, and γ-H2AX assays. These methods are valuable tools in human biomonitoring and for studying the mechanisms of action of various pollutants, and are readily used for the assessment of primary DNA damage and genome instability induced by air pollutants by measuring different aspects of DNA and chromosomal damage. Based on our search, in selected studies (in vitro, animal models, and human biomonitoring), we found generally higher levels of DNA strand breaks and chromosomal damage due to indoor air pollutants compared to matched control or unexposed groups. In summary, our systematic review reveals the importance of the comet, micronucleus, and γ-H2AX assays as sensitive tools for the evaluation of DNA and genome damaging potential of different indoor air pollutants. Additionally, research in this particular direction is warranted since little is still known about the level of indoor air pollution in households or public buildings and its impact on genetic material. Future studies should focus on research investigating the possible impact of indoor air pollutants in complex mixtures on the genome and relate pollutants to possible health outcomes.

3.
Biomed Pharmacother ; 175: 116676, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38772152

RESUMO

The molecular nanomachine, human DNA topoisomerase IIα, plays a crucial role in replication, transcription, and recombination by catalyzing topological changes in the DNA, rendering it an optimal target for cancer chemotherapy. Current clinical topoisomerase II poisons often cause secondary tumors as side effects due to the accumulation of double-strand breaks in the DNA, spurring the development of catalytic inhibitors. Here, we used a dynamic pharmacophore approach to develop catalytic inhibitors targeting the ATP binding site of human DNA topoisomerase IIα. Our screening of a library of nature-inspired compounds led to the discovery of a class of 3-(imidazol-2-yl) morpholines as potent catalytic inhibitors that bind to the ATPase domain. Further experimental and computational studies identified hit compound 17, which exhibited selectivity against the human DNA topoisomerase IIα versus human protein kinases, cytotoxicity against several human cancer cells, and did not induce DNA double-strand breaks, making it distinct from clinical topoisomerase II poisons. This study integrates an innovative natural product-inspired chemistry and successful implementation of a molecular design strategy that incorporates a dynamic component of ligand-target molecular recognition, with comprehensive experimental characterization leading to hit compounds with potential impact on the development of more efficient chemotherapies.


Assuntos
DNA Topoisomerases Tipo II , Inibidores da Topoisomerase II , Humanos , DNA Topoisomerases Tipo II/metabolismo , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/química , Linhagem Celular Tumoral , Descoberta de Drogas/métodos , Antineoplásicos/farmacologia , Antineoplásicos/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Imidazóis/farmacologia , Imidazóis/química , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Antígenos de Neoplasias/metabolismo
4.
Chem Biol Interact ; 394: 110977, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38548214

RESUMO

The applications of magnetic nanoparticles (MNPs) as biocatalysts in different biomedical areas have been evolved very recently. One of the main challenges in this field is to design affective MNPs surfaces with catalytically active atomic centres, while producing minimal toxicological side effects on the hosting cell or tissues. MNPs of vanadium spinel ferrite (VFe2O4) are a promising material for mimicking the action of natural enzymes in degrading harmful substrates due to the presence of active V5+ centres. However, the toxicity of this material has not been yet studied in detail enough to grant biomedical safety. In this work, we have extensively measured the structural, compositional, and magnetic properties of a series of VxFe3-xO4 spinel ferrite MNPs to assess the surface composition and oxidation state of V atoms, and also performed systematic and extensive in vitro cytotoxicity and genotoxicity testing required to assess their safety in potential clinical applications. We could establish the presence of V5+ at the particle surface even in water-based colloidal samples at pH 7, as well as different amounts of V2+ and V3+ substitution at the A and B sites of the spinel structure. All samples showed large heating efficiency with Specific Loss Power values up to 400 W/g (H0 = 30 kA/m; f = 700 kHz). Samples analysed for safety in human hepatocellular carcinoma (HepG2) cell line with up to 24h of exposure showed that these MNPs did not induce major genomic abnormalities such as micronuclei, nuclear buds, or nucleoplasmic bridges (MNIs, NBUDs, and NPBs), nor did they cause DNA double-strand breaks (DSBs) or aneugenic effects-types of damage considered most harmful to cellular genetic material. The present study is an essential step towards the use of these type of nanomaterials in any biomedical or clinical application.


Assuntos
Compostos Férricos , Humanos , Compostos Férricos/química , Compostos Férricos/toxicidade , Células Hep G2 , Dano ao DNA/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Temperatura Alta , Vanádio/química , Vanádio/toxicidade , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/toxicidade , Calefação , Nanopartículas/química , Nanopartículas/toxicidade
5.
Arch Toxicol ; 98(2): 425-469, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38147116

RESUMO

Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a large range of substrates. A spectrum of structurally diverse secondary metabolites with toxic potential has been identified, but occurrence and relative proportion of the different metabolites in complex mixtures depend on strain, substrate, and growth conditions. This review compiles the available knowledge on hazard identification and characterization of Alternaria toxins. Alternariol (AOH), its monomethylether AME and the perylene quinones altertoxin I (ATX-I), ATX-II, ATX-III, alterperylenol (ALP), and stemphyltoxin III (STTX-III) showed in vitro genotoxic and mutagenic properties. Of all identified Alternaria toxins, the epoxide-bearing analogs ATX-II, ATX-III, and STTX-III show the highest cytotoxic, genotoxic, and mutagenic potential in vitro. Under hormone-sensitive conditions, AOH and AME act as moderate xenoestrogens, but in silico modeling predicts further Alternaria toxins as potential estrogenic factors. Recent studies indicate also an immunosuppressive role of AOH and ATX-II; however, no data are available for the majority of Alternaria toxins. Overall, hazard characterization of Alternaria toxins focused, so far, primarily on the commercially available dibenzo-α-pyrones AOH and AME and tenuazonic acid (TeA). Limited data sets are available for altersetin (ALS), altenuene (ALT), and tentoxin (TEN). The occurrence and toxicological relevance of perylene quinone-based Alternaria toxins still remain to be fully elucidated. We identified data gaps on hazard identification and characterization crucial to improve risk assessment of Alternaria mycotoxins for consumers and occupationally exposed workers.


Assuntos
Micotoxinas , Perileno , Humanos , Alternaria/metabolismo , Micotoxinas/toxicidade , Micotoxinas/análise , Mutagênicos/toxicidade , Mutagênicos/metabolismo , Lactonas/toxicidade , Lactonas/metabolismo , Medição de Risco , Contaminação de Alimentos/análise
6.
Environ Int ; 182: 108285, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37972530

RESUMO

Water scarcity, one of the most pressing challenges we face today, has developed for many reasons, including the increasing number of waterborne pollutants that affect the safety of the water environment. Waterborne human, animal and plant viruses represent huge health, environmental, and financial burden and thus it is important to efficiently inactivate them. Therefore, the main objective of this study was to construct a unique device combining plasma with supercavitation and to evaluate its efficiency for water decontamination with the emphasis on inactivation of viruses. High inactivation (>5 log10 PFU/mL) of bacteriophage MS2, a human enteric virus surrogate, was achieved after treatment of 0.43 L of recirculating water for up to 4 min. The key factors in the inactivation were short-lived reactive plasma species that damaged viral RNA. Water treated with plasma for a short time required for successful virus inactivation did not cause cytotoxic effects in the in vitro HepG2 cell model system or adverse effects on potato plant physiology. Therefore, the combined plasma-supercavitation device represents an environmentally-friendly technology that could provide contamination-free and safe water.


Assuntos
Gases em Plasma , Vírus , Animais , Humanos , Água , Gases em Plasma/farmacologia , Inativação de Vírus
7.
ACS Appl Polym Mater ; 5(7): 5270-5279, 2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37469879

RESUMO

Cationic charge has been widely used to increase polymer adsorption and flocculation of dispersions or to provide antimicrobial activity. In this work, cationization of hydroxyethyl cellulose (HEC) and polyvinyl alcohol (PVA) was achieved by covalently coupling betaine hydrochloride and choline chloride to the polymer backbones through carbonyl diimidazole (CDI) activation. Two approaches for activation were investigated. CDI in excess was used to activate the polymers' hydroxyls followed by carbonate formation with choline chloride, or CDI was used to activate betaine hydrochloride, followed by ester formation with the polymers' hydroxyls. The first approach led to a more significant cross-linking of PVA, but not of HEC, and the second approach successfully formed ester bonds. Cationic, nitrogen-bearing materials with varying degrees of substitution were obtained in moderate to high yields. These materials were analyzed by Fourier transform infrared spectroscopy, nuclear magnetic resonance, polyelectrolyte titration, and kaolin flocculation. Their dose-dependent effect on the growth of Staphylococcus aureus and Pseudomonas aeruginosa, and L929 mouse fibroblasts, was investigated. Significant differences were found between the choline- and betaine-containing polymers, and especially, the choline carbonate esters of HEC strongly inhibited the growth of S. aureus in vitro but were also cytotoxic to fibroblasts. Fibroblast cytotoxicity was also observed for betaine esters of PVA but not for those of HEC. The materials could potentially be used as antimicrobial agents for instance by coating surfaces, but more investigations into the interaction between cells and polysaccharides are necessary to clarify why and how bacterial and human cells are inhibited or killed by these derivatives, especially those containing choline.

8.
Front Toxicol ; 5: 1220998, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37492623

RESUMO

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.

10.
J Hazard Mater ; 454: 131478, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37116332

RESUMO

Bisphenols are widely recognised as toxic compounds that potentially threaten the environment and public health. Here we report the use of cold atmospheric pressure plasma (CAP) to remove bisphenol A (BPA) and bisphenol S (BPS) from aqueous systems. Additionally, methanol was added as a radical scavenger to simulate environmental conditions. After 480 s of plasma treatment, 15-25 % of BPA remained, compared to > 80 % of BPS, with BPA being removed faster (-kt = 3.4 ms-1, half-life = 210 s) than BPS (-kt = 0.15 ms-1, half-life 4700 s). The characterisation of plasma species showed that adding a radical scavenger affects the formation of reactive oxygen and nitrogen species, resulting in a lower amount of ˙OH, H2O2, and NO2- but a similar amount of NO3-. In addition, a non-target approach enabled the elucidation of 11 BPA and five BPS transformation products. From this data, transformation pathways were proposed for both compounds, indicating nitrification with further cleavage, demethylation, and carboxylation, and the coupling of smaller bisphenol intermediates. The toxicological characterisation of the in vitro HepG2 cell model has shown that the mixture of transformation products formed during CAP is less toxic than BPA and BPS, indicating that CAP is effective in safely degrading bisphenols.


Assuntos
Compostos Benzidrílicos , Peróxido de Hidrogênio , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/metabolismo , Fenóis/toxicidade , Fenóis/metabolismo
11.
Molecules ; 28(7)2023 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-37049848

RESUMO

Bisphenol A (BPA) is one of the most commonly used substances in the manufacture of various everyday products. Growing concerns about its hazardous properties, including endocrine disruption and genotoxicity, have led to its gradual replacement by presumably safer analogues in manufacturing plastics. The widespread use of BPA and, more recently, its analogues has increased their residues in the environment. However, our knowledge of their toxicological profiles is limited and their combined effects are unknown. In the present study, we investigated the toxic effects caused by single bisphenols and by the combined exposure of BPA and its two analogues, BPAP and BPC, after short (24-h) and prolonged (96-h) exposure in HepG2 spheroids. The results showed that BPA did not reduce cell viability in HepG2 spheroids after 24-h exposure. In contrast, BPAP and BPC affected cell viability in HepG2 spheroids. Both binary mixtures (BPA/BPAP and BPA/BPC) decreased cell viability in a dose-dependent manner, but the significant difference was only observed for the combination of BPA/BPC (both at 40 µM). After 96-h exposure, none of the BPs studied affected cell viability in HepG2 spheroids. Only the combination of BPA/BPAP decreased cell viability in a dose-dependent manner that was significant for the combination of 4 µM BPA and 4 µM BPAP. None of the BPs and their binary mixtures studied affected the surface area and growth of spheroids as measured by planimetry. In addition, all BPs and their binary mixtures studied triggered oxidative stress, as measured by the production of reactive oxygen species and malondialdehyde, at both exposure times. Overall, the results suggest that it is important to study the effects of BPs as single compounds. It is even more important to study the effects of combined exposures, as the combined effects may differ from those induced by single compounds.


Assuntos
Compostos Benzidrílicos , Fenóis , Humanos , Células Hep G2 , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/química , Fenóis/toxicidade , Fenóis/química , Estresse Oxidativo
12.
Int J Mol Sci ; 24(4)2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36835302

RESUMO

Over the past 20 years, numerous tyrosine kinase inhibitors (TKIs) have been introduced for targeted therapy of various types of malignancies. Due to frequent and increasing use, leading to eventual excretion with body fluids, their residues have been found in hospital and household wastewaters as well as surface water. However, the effects of TKI residues in the environment on aquatic organisms are poorly described. In the present study, we investigated the cytotoxic and genotoxic effects of five selected TKIs, namely erlotinib (ERL), dasatinib (DAS), nilotinib (NIL), regorafenib (REG), and sorafenib (SOR), using the in vitro zebrafish liver cell (ZFL) model. Cytotoxicity was determined using the MTS assay and propidium iodide (PI) live/dead staining by flow cytometry. DAS, SOR, and REG decreased ZFL cell viability dose- and time-dependently, with DAS being the most cytotoxic TKI studied. ERL and NIL did not affect viability at concentrations up to their maximum solubility; however, NIL was the only TKI that significantly decreased the proportion of PI negative cells as determined by the flow cytometry. Cell cycle progression analyses showed that DAS, ERL, REG, and SOR caused the cell cycle arrest of ZFL cells in the G0/G1 phase, with a concomitant decrease of cells in the S-phase fraction. No data could be obtained for NIL due to severe DNA fragmentation. The genotoxic activity of the investigated TKIs was evaluated using comet and cytokinesis block micronucleus (CBMN) assays. The dose-dependent induction of DNA single strand breaks was induced by NIL (≥2 µM), DAS (≥0.006 µM), and REG (≥0.8 µM), with DAS being the most potent. None of the TKIs studied induced micronuclei formation. These results suggest that normal non-target fish liver cells are sensitive to the TKIs studied in a concentration range similar to those previously reported for human cancer cell lines. Although the TKI concentrations that induced adverse effects in exposed ZFL cells are several orders of magnitude higher than those currently expected in the aquatic environment, the observed DNA damage and cell cycle effects suggest that residues of TKIs in the environment may pose a hazard to non-intentionally exposed organisms living in environments contaminated with TKIs.


Assuntos
Antineoplásicos , Hepatócitos , Animais , Humanos , Antineoplásicos/toxicidade , Hepatócitos/efeitos dos fármacos , Fígado , Pirimidinas/toxicidade , Sorafenibe/toxicidade , Peixe-Zebra
13.
Int J Mol Sci ; 24(4)2023 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-36835492

RESUMO

The study aimed to investigate toxicity and the mechanism of toxicity of two Fusarium mycotoxins, deoxynivalenol (DON) and zearalenone (ZEA). DON and ZEA were applied to HepG2 cells as single compounds and in combination at low environmentally relevant concentrations. HepG2 cells were exposed to DON (0.5, 1, and 2 µM), ZEA (5, 10, and 20 µM) or their combinations (1 µM DON + 5 µM ZEA, 1 µM DON + 10 µM ZEA and 1 µM DON + 20 µM ZEA) for 24 h and cell viability, DNA damage, cell cycle and proliferation were assessed. Both mycotoxins reduced cell viability, however, combined treatment with DON and ZEA resulted in higher reduction of cell viability. DON (1 µM) induced primary DNA damage, while DON (1 µM) in combination with higher ZEA concentrations showed antagonistic effects compared to DON alone at 1 µM. DON arrested HepG2 cells in G2 phase and significantly inhibited cell proliferation, while ZEA had no significant effect on cell cycle. The combined treatment with DON and ZEA arrested cells in G2 phase to a higher extend compared to treatment with single mycotoxins. Potentiating effect observed after DON and ZEA co-exposure at environmentally relevant concentrations indicates that in risk assessment and setting governments' regulations, mixtures of mycotoxins should be considered.


Assuntos
Micotoxinas , Zearalenona , Humanos , Zearalenona/toxicidade , Células Hep G2 , Micotoxinas/farmacologia , Ciclo Celular , Proliferação de Células , DNA/farmacologia
14.
Environ Int ; 171: 107721, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36580735

RESUMO

Bisphenol A (BPA) is one of the most widely used and versatile chemical compounds in polymer additives and epoxy resins for manufacturing a range of products for human applications. It is known as endocrine disruptor, however, there is growing evidence that it is genotoxic. Because of its adverse effects, the European Union has restricted its use to protect human health and the environment. As a result, the industry has begun developing BPA analogues, but there are not yet sufficient toxicity data to claim that they are safe. We investigated the adverse toxic effects of BPA and its analogues (BPS, BPAP, BPAF, BPFL, and BPC) with emphasis on their cytotoxic and genotoxic activities after short (24-h) and prolonged (96-h) exposure in in vitro hepatic three-dimensional cell model developed from HepG2 cells. The results showed that BPFL and BPC (formed by an additional ring system) were the most cytotoxic analogues that affected cell viability, spheroid surface area and morphology, cell proliferation, and apoptotic cell death. BPA, BPAP, and BPAF induced DNA double-strand break formation (γH2AX assay), whereas BPAF and BPC increased the percentage of p-H3-positive cells, indicating their aneugenic activity. All BPs induced DNA single-strand break formation (comet assay), with BPAP (≥0.1 µM) being the most effective and BPA and BPC the least effective (≥1 µM) under conditions applied. The results indicate that not all of the analogues studied are safer alternatives to BPA and thus more in-depth research is urgently needed to adequately evaluate the risks of BPA analogues and assess their safety for humans.


Assuntos
Compostos Benzidrílicos , Fenóis , Humanos , Compostos Benzidrílicos/toxicidade , Compostos Benzidrílicos/química , Fenóis/toxicidade , Fenóis/química , Células Hep G2 , DNA
15.
Mutagenesis ; 38(1): 21-32, 2023 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-36367406

RESUMO

Environmental studies which aim to assess the ecological impact of chemical and other types of pollution should employ a complex weight-of-evidence approach with multiple lines of evidence (LoEs). This study focused on in situ genotoxicological methods such as the comet and micronucleus assays and randomly amplified polymorphic DNA analysis as one of the multiple LoEs (LoE3) on the fish species Alburnus alburnus (bleak) as a bioindicator. The study was carried out within the Joint Danube Survey 4 (JDS4) at nine sites in the Danube River Basin in the Republic of Serbia. Out of nine sampling sites, two were situated at the Tisa, Sava, and Velika Morava rivers, and three sites were at the Danube River. The three additionally employed LoEs were: SumTUwater calculated based on the monitoring data in the database of the Serbian Environmental Protection Agency (SEPA) (LoE1); in vitro analyses of JDS4 water extracts employing genotoxicological methods (LoE2); assessment of the ecological status/potential by SEPA and indication of the ecological status for the sites performed within the JDS4 (LoE4). The analyzed biomarker responses in the bleak were integrated into the unique integrated biomarker response index which was used to rank the sites. The highest pollution pressure was recorded at JDS4 39 and JDS4 36, while the lowest was at JDS4 35. The impact of pollution was confirmed at three sites, JDS4 33, 40, and 41, by all four LoEs. At other sampling sites, a difference was observed regarding the pollution depending on the employed LoEs. This indicates the importance of implementing a comprehensive weight-of-evidence approach to ensure the impact of pollution is not overlooked when using only one LoE as is often the case in environmental studies.


Assuntos
Poluentes Químicos da Água , Animais , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análise , Monitoramento Ambiental/métodos , Sérvia , Testes para Micronúcleos , Dano ao DNA
16.
Environ Res ; 214(Pt 4): 114108, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35985485

RESUMO

Diatoms of the genus Pseudo-nitzschia are cosmopolitans spread in seas and oceans worldwide, with more than 50 described species, dozens of which have been confirmed to produce domoic acid (DA). Here, we characterized and investigated the toxicological activity of secondary metabolites excreted into the growth media of different Pseudo-nitzschia species sampled at various locations in the northern Adriatic Sea (Croatia) using human blood cells under in vitro conditions. The results revealed that three investigated species of the genus Pseudo-nitzschia were capable of producing DA indicating their toxic potential. Moreover, toxicological data suggested all three Pseudo-nitzschia species can excrete toxic secondary metabolites into the surrounding media in addition to the intracellular pools of DA, raising concerns regarding their toxicity and environmental impact. In addition, all three Pseudo-nitzchia species triggered oxidative stress, one of the mechanisms of action likely responsible for the DNA damage observed in human blood cells. In line with the above stated, our results are of great interest to environmental toxicologists, the public and policy makers, especially in light of today's climate change, which favours harmful algal blooms and the growth of DA producers with a presumed negative impact on the public health of coastal residents.


Assuntos
Diatomáceas , Croácia , Diatomáceas/genética , Diatomáceas/metabolismo , Proliferação Nociva de Algas , Humanos
17.
Artigo em Inglês | MEDLINE | ID: mdl-36031332

RESUMO

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.


Assuntos
Dano ao DNA , Mutagênicos , Causas de Morte , Morte Celular , Ensaio Cometa
18.
Toxicology ; 470: 153157, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35307467

RESUMO

Domoic acid (DA) is a marine neurotoxin produced as a defence compound by diatom Pseudo-nitzschia. Although its toxicity is well known in marine mammals and fish, data on DA cyto/genotoxicity in human non-target cells is still limited. Hence, we aimed to study the effect of DA (0.001-10 µg/mL) on cell viability and proliferation kinetics of human hepatocellular carcinoma (HepG2) cells as well as DNA damage induction after 4, 24 and 72 h of exposure. The results revealed that DA up to 10 µg/mL did not elicit significant changes in HepG2 cell viability, proliferation and cell cycle at applied conditions. DA did not generate DNA double-strand breaks, while it exhibited significant dose- and time-dependent increase of DNA damage in the form of either DNA single-strand breaks or alkali labile sites. Additionally, increased malondialdehyde level after DA treatment indicated oxidative damage to lipids. Altogether, the results showed that neurotoxin DA induced only minor adverse genotoxic effects in non-target HepG2 cells that most probably occurred resulting from the oxidative stress. However, additional research is needed to further elucidate the mechanisms of DA toxicity, particularly in terms of chronic exposure, as well as to understand its potential influence on human non-target cells.


Assuntos
Diatomáceas , Neurotoxinas , Animais , DNA/metabolismo , Diatomáceas/metabolismo , Células Hep G2 , Humanos , Ácido Caínico/análogos & derivados , Ácido Caínico/toxicidade , Mamíferos , Toxinas Marinhas/metabolismo , Toxinas Marinhas/toxicidade , Neurotoxinas/toxicidade
19.
Sci Total Environ ; 807(Pt 1): 150694, 2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-34600991

RESUMO

Pharmaceuticals as ubiquitous organic pollutants in the aquatic environment represent substances whose knowledge of environmental fate is still limited. One such compound is metoclopramide, whose direct and indirect photolysis and toxicological assessment have been studied for the first time in this study. Experiments were performed under solar radiation, showing metoclopramide as a compound that can easily degrade in different water matrices. The effect of pH-values showed the faster degradation at pH = 7, while the highly alkaline conditions at pH = 11 slowed photolysis. The highest value of quantum yield of metoclopramide photodegradation (ϕ = 43.55·10-4) was obtained at pH = 7. Various organic and inorganic substances (NO3-, Fe(III), HA, Cl-, Br-, HCO3-, SO42-), commonly present in natural water, inhibited the degradation by absorbing light. In all experiments, kinetics followed pseudo-first-order reaction with r2 greater than 0.98. The structures of the photolytic degradation products were tentatively identified, and degradation photoproducts were proposed. The hydroxylation of the aromatic ring and the amino group's dealkylation were two major photoproduct formation mechanisms. Calculated thermochemical quantities are in agreement with the experimentally observed stability of different photoproducts. Reactive sites in metoclopramide were studied with conceptual density functional theory and regions most susceptible to •OH attack were characterized. Metoclopramide and its degradation products were neither genotoxic for bacteria Salmonella typhimurium in the SOS/umuC assay nor acutely toxic for bacteria Vibrio fischeri.


Assuntos
Preparações Farmacêuticas , Poluentes Químicos da Água , Teoria da Densidade Funcional , Compostos Férricos , Cinética , Metoclopramida/toxicidade , Fotólise , Luz Solar , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
20.
Chemosphere ; 291(Pt 1): 132805, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34767844

RESUMO

3D spheroids developed from HepG2 cells were used as a biosensor-like system for the detection of (geno)toxic effects induced by chemicals. Benzo(a)pyrene (B(a)P) and amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) with well-known mechanisms of action were used for system validation. HepG2 spheroids grown for 3 days were exposed to BaP and PhIP for 24 and 72 h. The growth and viability of spheroids were monitored by planimetry and Live/Dead staining of cells. Multi-parametric flow cytometric analysis was applied for simultaneous detection of specific end-effects including cell cycle analysis (Hoechst staining), cell proliferation (KI67 marker), and DNA double-strand breaks (ℽH2AX) induced by genotoxic compounds. Depending on the exposure concentration/time, BaP reduced spheroid growth, affected cell proliferation by arresting cells in S and G2 phase and induced DNA double-strand breaks (DSB). Simultaneous staining of ℽH2AX formation and cell cycle analysis revealed that after BaP (10 µM; 24 h) exposure 60% of cells in G0/G1 phase had DNA DSB, while after 72 h only 20% of cells contained DSB indicating efficient repair of DNA lesions. PhIP did not influence the spheroid size whereas accumulation of cells in the G2 phase occurred after both treatment times. The evaluation of DNA damage revealed that at 200 µM PhIP 50% of cells in G0/G1 phase had DNA DSB, which after 72-h exposure dropped to 40%, showing lower repair capacity of PhIP-induced DSB compared to BaP-induced. The developed approach using simultaneous detection of several parameters provides mechanistic data and thus contributes to more reliable genotoxicity assessment of chemicals as a high-content screening tool.


Assuntos
Benzo(a)pireno , Técnicas Biossensoriais , Benzo(a)pireno/toxicidade , Dano ao DNA , Células Hep G2 , Humanos
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