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1.
Chemosphere ; 241: 125016, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31683446

RESUMO

2,4-dichlorophenoxyacetic acid (2,4-D) is a herbicide that is used worldwide in agricultural and urban activities to control pests, reaching natural environments directly or indirectly. The research on 2,4-D toxicology and mutagenicity has advanced rapidly, and for this reason, this review summarizes the available data in Web of Science (WoS) to provide insights into the specific characteristics of 2,4-D toxicity and mutagenicity. Contrary to traditional reviews, this study uses a new method to quantitatively visualize and summarize information about the development of this field. Among all countries, the USA was the most active contributor with the largest publication and centrality, followed by Canada and China. The WoS categories 'Toxicology' and 'Biochemical and Molecular Biology' were the areas of greatest influence. 2,4-D research was strongly related to the keywords glyphosate, atrazine, water and gene expression. The studies trended to be focused on occupational risk, neurotoxicity, resistance or tolerance to herbicides, and to non-target species (especially aquatic ones) and molecular imprinting. In general, the authors have worked collaboratively, with concentrated efforts, allowing important advances in this field. Future research on 2,4-D toxicology and mutagenicity should probably focus on molecular biology, especially gene expression, assessment of exposure in human or other vertebrate bioindicators, and pesticide degradation studies. In summary, this scientometric analysis allowed us to make inferences about global trends in 2,4-D toxicology and mutagenicity, in order to identify tendencies and gaps and thus contribute to future research efforts.


Assuntos
Ácido 2,4-Diclorofenoxiacético/toxicidade , Poluição Ambiental/efeitos adversos , Herbicidas/toxicidade , Atrazina , Expressão Gênica , Glicina/análogos & derivados , Humanos , Mutagênicos/toxicidade
2.
J Biochem Mol Toxicol ; 34(1): e22418, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31714658

RESUMO

The human-pathogenic bacteria have become highly resistant to conventional antibiotics; for this reason, a new biosynthesized nanomaterial might be a solution. The culture filtrate of two isolates of Fusarium oxysporum (14, 17) was used in the biosynthesis of nanosilver (AgNPs). The size of the nanoparticles produced by isolate F14 ranged from 19 to 30 nm, whereas the size of those formed via isolate F17 ranged between 16 and 25 nm. Moreover, the produced bio-nanosilver was tested against the human-pathogenic bacteria Proteus vulgaris, Escherichia coli, Staphylococcus aureus, and Klebsiella pneumonia and the outcome results displayed great antibacterial efficacy in a different manner compared with the three different biogenic antibiotics. Collectively, the results depicted that the silver nanoparticles (AgNPs) showed a three and a half times greater activity than the used antibiotics. Differential display reverse transcription-polymerase chain reaction was used to study gene regulation in the treated E. coli (F14) compared with the nontreated ones. Different upregulated and downregulated genes were observed. The cytotoxicity of the produced AgNPs was examined on rats with an average body weight of 200 g each; these animals were grouped into three different groups. The obtained AgNPs showed very low toxicity on the treated rats in comparison to the control group. The physiological parameters, for example, alanine aminotransferase, aspartate transaminase, albumin, creatinine, and urea in the treated animals were changed within to a lower degree compared with those in the nontreated animals. The current study exhibited that AgNPs might be favorable antibacterial agents, especially against multidrug-resistant bacteria.


Assuntos
Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Mutagênicos/toxicidade , Prata/química , Animais , Bactérias/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Testes de Mutagenicidade , Ratos , Difração de Raios X
3.
J Chromatogr A ; 1609: 460512, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31542208

RESUMO

The simultaneous use of nitrite and sorbate as preservatives in meat products may produce mutagenic compounds such as the ethylnitrolic acid and 2-methyl-1,4-dinitro-pyrrole. We developed a sensitive analytical method with high metrological reliability. After assessing several extraction approaches and chromatographic separation modes, a modified Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) approach was chosen for sample preparation, which were analyzed by reversed-phase liquid chromatography (with C18 as stationary phase) coupled to tandem mass spectrometry. After validation, we confirmed that this method is fit-for-purpose, since it was applied to the analysis of several meat products. Limits of detection were set from 5 to 20 µg kg-1. Satisfactory results were obtained for both compounds, such as precision (CV > 20%) and recoveries (77-92%). This method determine these carcinogenic compounds in processed meats, contributing to the preservation of public health and the improvement of food regulation and control.


Assuntos
Métodos Analíticos de Preparação de Amostras , Hidroxilaminas/análise , Produtos da Carne/análise , Mutagênicos/análise , Nitrilos/análise , Pirróis/química , Espectrometria de Massas em Tandem/métodos , Calibragem , Cromatografia Líquida , Cromatografia de Fase Reversa , Reprodutibilidade dos Testes
4.
Sci Total Environ ; 698: 134272, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31783468

RESUMO

Arsenic (As) is a metalloid and a toxicant that is found naturally in many environmental compartments, soils included. Soils with high levels of As occur worldwide and might pose a threat not only to humans, but also to many ecosystems. Considering the scarcity of studies regarding cytogenotoxic effects of model plants in As-contaminated soil, mainly in tropical areas, this study proposes the use of Allium cepa root tip bioassays for a fast-track assessment of As toxicity in tropical soils. For this end, root tip cells of A. cepa were exposed to an Oxisol, an Inceptisol and a Tropical Artificial Soil (TAS) contaminated with increasing doses of As (0, 8, 14.5, 26, 46.5, 84, 150, and 270 mg kg-1). The effects of As on cell cycle, micronucleus formation, and DNA fragmentation were evaluated. In general, root tip cells exposure to As increases the frequency of chromosome abnormalities and micronucleus, in turn, decreasing the frequency of mitotic index. As-treated cells also presented an increase in the percentage of DNA damage observed in comet assay. Overall, the effects of As in TAS were more pronounced, than in the Oxisol, being the Inceptisol the less toxic. A discussion of each As effect in cells and the link with the soil type is presented and reveals that clastogenic effects of As in A. cepa cells seemed to be the mode of action of this soil contaminant.


Assuntos
Arsênico/toxicidade , Fragmentação do DNA , Poluentes do Solo/toxicidade , Bioensaio , Ciclo Celular , Aberrações Cromossômicas , Ensaio Cometa , Dano ao DNA , Ecossistema , Meristema , Índice Mitótico , Mutagênicos , Cebolas , Raízes de Plantas , Solo , Testes de Toxicidade
5.
Water Res ; 168: 115204, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669779

RESUMO

Effect-directed analysis (EDA) has shown its added value for the detection and identification of compounds with varying toxicological properties in water quality research. However, for routine toxicity assessment of multiple toxicological endpoints, current EDA is considered labor intensive and time consuming. To achieve faster EDA and identification, a high-throughput (HT) EDA platform, coupling a downscaled luminescent Ames and cell-based reporter gene assays with a high-resolution fraction collector and UPLC-QTOF MS, was developed. The applicability of the HT-EDA platform in the analysis of aquatic samples was demonstrated by analysis of extracts from WWTP influent, effluent and surface water. Downscaled assays allowed detection of mutagenicity and androgen, estrogen and glucocorticoid agonism following high-resolution fractionation in 228 fractions. From 8 masses tentatively identified through non-target analysis, 2 masses were further investigated and chemically and biologically confirmed as the mutagen 1,2,3-benzotriazole and the androgen androstenedione. The compatibility of the high-throughput EDA platform with analysis of water samples and the incorporation of mutagenic and endocrine disruption endpoints allow for future application in routine monitoring in drinking water quality control and improved identification of (emerging) mutagens and endocrine disruptors.


Assuntos
Disruptores Endócrinos , Poluentes Químicos da Água , Monitoramento Ambiental , Mutagênicos , Águas Residuárias , Água
6.
Chemosphere ; 238: 124574, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31445332

RESUMO

Waste landfills represent a global problem, which is more pronounced in developing countries because of the lack of resources to implement procedures that include separation and waste processing. The aim of this research was to analyze leachate and ground waters samples at the site, upstream and downstream from the landfill during different year seasons on a registered non-hazardous waste dump and to conduct physico-chemical and biological assays to determine potential risk for the ecosystem. Potential cytotoxic, prooxidative and mutagenic effects of leachates and water samples were evaluated on human laryngeal cell line (HEp2). Leachates collected at landfill site caused genotoxic effect and had a higher pH, chemical oxygen demand (COD), biochemical oxygen demand (BOD) and elevated concentrations of phosphorus, chloride, nitrogen compounds and sulphate. Genotoxicity of the leachate was increased in samples collected in dry and warm period of the year. These results are in accordance to the physico-chemical analysis which revealed that during summer period, because of intense degradation process at high temperatures increased concentrations of different chemicals can be found in leachate. Groundwater collected downstream and upstream from landfill did not show statistically significant (geno)toxic effect, irrespective of the sampling season. Chemical analysis revealed that all compounds in groundwater were below permitted values. Purification process at landfill is effective and compounds that reach groundwater do not represent a toxicological threat.


Assuntos
Água Subterrânea/química , Mutagênicos/análise , Eliminação de Resíduos/métodos , Instalações de Eliminação de Resíduos , Poluentes Químicos da Água/análise , Análise da Demanda Biológica de Oxigênio , Ecossistema
7.
Nat Commun ; 10(1): 5349, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836706

RESUMO

Increased levels and non-telomeric roles have been reported for shelterin proteins, including RAP1 in cancers. Herein using Rap1 null mice, we provide the genetic evidence that mammalian Rap1 plays a major role in hematopoietic stem cell survival, oncogenesis and response to chemotherapy. Strikingly, this function of RAP1 is independent of its association with the telomere or with its known partner TRF2. We show that RAP1 interacts with many members of the DNA damage response (DDR) pathway. RAP1 depleted cells show reduced interaction between XRCC4/DNA Ligase IV and DNA-PK, and are impaired in DNA Ligase IV recruitment to damaged chromatin for efficient repair. Consistent with its role in DNA damage repair, RAP1 loss decreases double-strand break repair via NHEJ in vivo, and consequently reduces B cell class switch recombination. Finally, we discover that RAP1 levels are predictive of the success of chemotherapy in breast and colon cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA , DNA Ligase Dependente de ATP/metabolismo , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Proteína Quinase Ativada por DNA/metabolismo , Fluoruracila/farmacologia , Raios gama , Instabilidade Genômica/efeitos dos fármacos , Instabilidade Genômica/efeitos da radiação , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos da radiação , Humanos , Camundongos Knockout , Mutagênicos/toxicidade , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/efeitos da radiação , Proteínas Proto-Oncogênicas c-myc/metabolismo , Análise de Sobrevida
8.
Mutat Res ; 782: 108283, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31843137

RESUMO

Immuno-spin trapping detection of DNA radicals with the nitrone spin trap 5,5-dimethyl-1-pyrrloine N-oxide (DMPO) has made important contributions towards the understanding of DNA radicalization and genotoxicity at sites of inflammation. At sites of inflammation, one-electron oxidants and chloramines decay induce oxidation of genomic DNA, genotoxicity and cell transformation. Radicalization of DNA can result in either single- or double-strand breaks, or end-oxidation products at the sugar or bases. If not repaired, these modifications can lead to mutations and cell transformation. If trapped with DMPO, DNA-centered radical decay and subsequent formation of end-oxidation products are blocked. Herein we discuss recent literature regarding the use of immuno-spin trapping with DMPO to study DNA-centered radicals and their involvement in genotoxicity. This technique has shown the critical role of DNA radicalization in 8-oxo-dG formation and DNA strand breaks in isolated DNA, cells and in whole animals. Combination of technologies, including immuno-spin trapping and powerful chromatographic and sequencing techniques are needed to move forward the field towards the detection of specific genes that are susceptible to oxidative damage in cells located at sites of inflammation. This is important in order to provide novel information about genotoxicity mechanisms, as well as therapeutic possibilities of DMPO or its derivatives for preventing DNA-centered radical-mediated carcinogenesis.


Assuntos
Óxidos N-Cíclicos/efeitos adversos , Dano ao DNA/efeitos dos fármacos , DNA/efeitos dos fármacos , Radicais Livres/química , Mutagênicos/efeitos adversos , Óxidos de Nitrogênio/efeitos adversos , Óxidos de Nitrogênio/química , Animais , Inflamação/genética , Detecção de Spin/métodos
9.
Aquat Toxicol ; 217: 105345, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715477

RESUMO

Lethal and sublethal effects of trinitrotoluene (TNT) and its degradation products 2-amino-4,6-dinitrotoluene (2-ADNT) and 4-amino-2,6-dinitrotoluene (4-ADNT) to zebrafish embryos (Danio rerio) were investigated in a 120 h exposure scenario. Lethal concentrations (LC50) were 4.5 mg/l for TNT, 13.4 mg/l for 2-ADNT and 14.4 mg/l for 4-ADNT. Embryos exposed to 2-ADNT or 4-ADNT revealed a high proportion of chorda deformations among the surviving individuals. Genotoxicity of the nitroaromatic compounds in zebrafish embryos was investigated by comet assay isolating cells from whole embryos after 48 h in vivo exposure. Significant genotoxicity was induced by all three compounds tested, in comparison to the corresponding controls at 0.1 mg/l and 1.0 mg/l as lowest tested concentrations. The genotoxicity caused by TNT was about three to four times higher than that of 2-ADNT and 4-ADNT. To our knowledge, this is the first study demonstrating the genotoxicity of TNT in fish embryos by in vivo exposure. The results are discussed in the context of dumped munition in the marine environment.


Assuntos
Dano ao DNA , Embrião não Mamífero/efeitos dos fármacos , Mutagênicos/toxicidade , Trinitrotolueno/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Compostos de Anilina/toxicidade , Animais , Peixe-Zebra/genética
10.
Ecotoxicol Environ Saf ; 186: 109822, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31634658

RESUMO

Nitroaromatic compounds (NACs) are an important type of environmental organic pollutants. However, it is lack of sufficient information relating to their potential adverse effects on human health and the environment due to the limited resources. Thus, using in silico technologies to assess their potential hazardous effects is urgent and promising. In this study, quantitative structure activity relationship (QSAR) and classification models were constructed using a set of NACs based on their mutagenicity against Salmonella typhimurium TA100 strain. For QSAR studies, DRAGON descriptors together with quantum chemistry descriptors were calculated for characterizing the detailed molecular information. Based on genetic algorithm (GA) and multiple linear regression (MLR) analyses, we screened descriptors and developed QSAR models. For classification studies, seven machine learning methods along with six molecular fingerprints were applied to develop qualitative classification models. The goodness of fitting, reliability, robustness and predictive performance of all developed models were measured by rigorous statistical validation criteria, then the best QSAR and classification models were chosen. Moreover, the QSAR models with quantum chemistry descriptors were compared to that without quantum chemistry descriptors and previously reported models. Notably, we also obtained some specific molecular properties or privileged substructures responsible for the high mutagenicity of NACs. Overall, the developed QSAR and classification models can be utilized as potential tools for rapidly predicting the mutagenicity of new or untested NACs for environmental hazard assessment and regulatory purposes, and may provide insights into the in vivo toxicity mechanisms of NACs and related compounds.


Assuntos
Poluentes Ambientais , Hidrocarbonetos Aromáticos , Mutagênicos , Nitrocompostos , Algoritmos , Simulação por Computador , Poluentes Ambientais/química , Poluentes Ambientais/toxicidade , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/toxicidade , Aprendizado de Máquina , Mutagênicos/química , Mutagênicos/toxicidade , Nitrocompostos/química , Nitrocompostos/toxicidade , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética
11.
PLoS Pathog ; 15(9): e1007921, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31568537

RESUMO

Humans are frequently exposed to bacterial genotoxins involved in digestive cancers, colibactin and Cytolethal Distending Toxin (CDT), the latter being secreted by many pathogenic bacteria. Our aim was to evaluate the effects induced by these genotoxins on nuclear remodeling in the context of cell survival. Helicobacter infected mice, coculture experiments with CDT- and colibactin-secreting bacteria and hepatic, intestinal and gastric cells, and xenograft mouse-derived models were used to assess the nuclear remodeling in vitro and in vivo. Our results showed that CDT and colibactin induced-nuclear remodeling can be associated with the formation of deep cytoplasmic invaginations in the nucleus of giant cells. These structures, observed both in vivo and in vitro, correspond to nucleoplasmic reticulum (NR). The core of the NR was found to concentrate ribosomes, proteins involved in mRNA translation, polyadenylated RNA and the main components of the complex mCRD involved in mRNA turnover. These structures are active sites of mRNA translation, correlated with a high degree of ploidy, and involve MAPK and calcium signaling. Additional data showed that insulation and concentration of these adaptive ribonucleoprotein particles within the nucleus are dynamic, transient and protect the cell until the genotoxic stress is relieved. Bacterial genotoxins-induced NR would be a privileged gateway for selected mRNA to be preferably transported therein for local translation. These findings offer new insights into the context of NR formation, a common feature of many cancers, which not only appears in response to therapies-induced DNA damage but also earlier in response to genotoxic bacteria.


Assuntos
Toxinas Bacterianas/toxicidade , Helicobacter/patogenicidade , Ribonucleoproteínas/metabolismo , Animais , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Sobrevivência Celular , Dano ao DNA , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Mutagênicos/toxicidade , Peptídeos/toxicidade , Policetídeos/toxicidade , RNA Mensageiro/metabolismo
12.
J Environ Manage ; 251: 109515, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31569020

RESUMO

Mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is known as a potent factor in inducing DNA damage and increasing cancer risk. MX is a chlorination disinfection byproduct that comes from the reaction of humic acids and chlorine in drinking water. The purpose of this study was to evaluate the effects of significant factors (including pH, reaction time, chlorine and the concentration of organic materials (TOC)) and their interactions on the MX formation rate in chlorinated drinking water using Box-Behnken Design (BBD) and response surface method (RSM). For this purpose, the simulation of water chlorination disinfection process was carried out in a laboratory scale. A quadratic model was chosen to determine the mathematical relations between the response and the effective factors. All linear parameters, as well as second-degree components except chlorine, were statistically significant. Also, the interactions of contact time with TOC, free chlorine residual with TOC, and chlorine with pH were also statistically significant. Statistical results showed that the pH had a great effect on the potential of MX formation, and then the factors of TOC, chlorine and contact time were effective, respectively. The percentage of contribution (PC) of each component in the formation of MX. The highest significant percentage of contribution (48.36%) was allocated to the pH. Under the optimum conditions (contact time of 48.38 min, chlorine concentration of 0.79 mg/L, TOC concentration of 0.53 mg/L, and pH of 7.98), minimum value of MX was equal to 28.6.


Assuntos
Água Potável , Furanos , Cloro , Mutagênicos , Abastecimento de Água
13.
Environ Mol Mutagen ; 60(9): 845-856, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31569270

RESUMO

Black cohosh extract (BCE) is a popular botanical dietary supplement marketed to relieve symptoms of various gynecological ailments. Studies conducted by the National Toxicology Program (NTP) showed that BCE induces micronucleated erythrocytes in female rats and mice. Subsequently, the NTP showed that a variety of BCEs, including the sample that induced micronuclei (MN) in vivo ("NTP BCE") had a similar effect in human TK6 cells. Further testing with the MultiFlow® DNA Damage Assay revealed that TK6 cells exposed to NTP BCE, as well as a BCE reference material (BC XRM), exhibited a signature consistent with aneugenic activity in TK6 cells. Results from experiments reported herein confirmed these in vitro observations with NTP BCE and BC XRM. We extended these studies to include a novel test system, the MultiFlow Aneugen Molecular Mechanism Assay. For these experiments, TK6 cells were exposed to NTP BCE and BC XRM over a range of concentrations in the presence of fluorescent Taxol (488 Taxol). After 4 h, nuclei from lysed cells were stained with a nucleic acid dye and labeled with fluorescent antibodies against phospho-histone H3 (p-H3) and Ki-67. Whereas BCEs did not affect p-H3:Ki-67 ratios (a signature of aneugenic mitotic kinase inhibitors), 488 Taxol-associated fluorescence (a tubulin binder-sensitive endpoint) was affected. More specifically, 488 Taxol-associated fluorescence was reduced over the same concentration range that was previously observed to induce MN. These results provide direct evidence that BCEs destabilize microtubules in vitro, and this is the molecular mechanism responsible for the aneugenicity findings. Environ. Mol. Mutagen. 2019. © 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.


Assuntos
Aneugênicos/efeitos adversos , Núcleo Celular/efeitos dos fármacos , Cimicifuga/efeitos adversos , Mutagênicos/efeitos adversos , Extratos Vegetais/efeitos adversos , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Suplementos Nutricionais/efeitos adversos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Histonas/metabolismo , Humanos , Testes para Micronúcleos/métodos , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade/métodos
14.
Ecotoxicol Environ Saf ; 185: 109733, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31580980

RESUMO

Presence of missing data points in datasets is among main challenges in handling the toxicological data for nanomaterials. As the processing of missing data is an important part of data analysis, we have introduced a read-across approach that uses a combination of supervised and unsupervised machine learning techniques to fill the missing values. A series of classification models (supervised learning) was developed to predict class label, and self-organizing map approach (unsupervised learning) was used to estimate relative distances between nanoparticles and refine results obtained during supervised learning. In this study, genotoxicity of 49 silicon and metal oxide nanoparticles in Ames and Comet tests. Collected literature data did not demonstrate significant variations related to the change of size including selected bulk materials. Genotoxicity-related features of nanomaterials were represented by ionic characteristics. General tendencies found in the current study were convincingly linked to known theories of genotoxic action at nano-level. Mechanisms of primary and secondary genotoxic effects were discussed in the context of developed models.


Assuntos
Dano ao DNA , Nanopartículas Metálicas/toxicidade , Modelos Teóricos , Mutagênicos/toxicidade , Aprendizado de Máquina não Supervisionado , Linhagem Celular , Ensaio Cometa , Humanos , Nanopartículas Metálicas/classificação , Mutagênicos/classificação , Óxidos/classificação , Óxidos/toxicidade , Relação Quantitativa Estrutura-Atividade , Salmonella typhimurium/genética
15.
J Toxicol Sci ; 44(10): 701-709, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588061

RESUMO

Genotoxicity and carcinogenicity profiles of drugs occasionally vary across species due to species difference in drug metabolic profile. To clarify the effect of species differences in the metabolic profile on micronucleus induction, we conducted an in vitro micronucleus test for seven clastogens (benzo[a]pyrene: BaP, cyclophosphamide monohydrate: CPA coumarin, diclofenac, piroxicam, lansoprazole, and chlorpheniramine) with rat, mouse, monkey, dog, or human liver S9. BaP, CPA, coumarin, diclofenac, piroxicam, and lansoprazole induced micronucleus formation with all species of S9s, whereas chlorpheniramine did not induce micronucleus formation in any of the S9s. BaP and CPA revealed remarkable species differences in micronucleus induction, whereas coumarin, diclofenac, piroxicam, and lansoprazole did not present any differences. Interestingly, the amounts of hydroxy-BaP-epoxides and phosphamide mustard, which might be associated with micronucleus induction by BaP and CPA, respectively, were correlated with the degree of micronucleus induction among the five species. In conclusion, the species difference in micronucleus induction by BaP and CPA was attributable to the differences in the metabolic profiles of these drugs among species. Our results indicate that it is crucial to understand the effect of species differences in the metabolic profile of drug candidates on genotoxicity and carcinogenicity potential and to predict their risk in human.


Assuntos
Fígado/metabolismo , Metaboloma , Mutagênicos/toxicidade , Animais , Cães , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos Endogâmicos C3H , Testes para Micronúcleos , Ratos Sprague-Dawley , Especificidade da Espécie
16.
mSphere ; 4(5)2019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578245

RESUMO

Colibactin is a polyketide/nonribosomal peptide produced by Escherichia coli strains that harbor the pks island. This toxin induces DNA double-strand breaks and DNA interstrand cross-links in infected eukaryotic cells. Colibactin-producing strains are found associated with colorectal cancer biopsy specimens and promote intestinal tumor progression in various murine models. Polyamines are small polycationic molecules produced by both microorganisms and eukaryotic cells. Their levels are increased in malignancies, where they contribute to disease progression and metastasis. In this study, we demonstrated that the endogenous spermidine synthase SpeE is required for full genotoxic activity of colibactin-producing E. coli Supplying spermidine in a ΔspeE pks + E. coli strain restored genotoxic activity. Spermidine is involved in the autotoxicity linked to colibactin and is required for direct damaging activity on DNA. The production of the colibactin prodrug motif is impaired in ΔspeE mutants. Therefore, we demonstrated that spermidine has a direct impact on colibactin synthesis.IMPORTANCE Colibactin-producing Escherichia coli strains are associated with cancerous and precancerous colorectal tissues and are suspected of promoting colorectal carcinogenesis. In this study, we describe a new interplay between the synthesis of the genotoxin colibactin and the polyamine spermidine. Polyamines are highly abundant in cancer tissue and are associated with cell proliferation. The need for spermidine in genotoxic activity provides a new perspective on the role of these metabolites in the pathogenicity of colibactin-producing E. coli strains in colorectal cancer.


Assuntos
Escherichia coli/patogenicidade , Mutagênicos/metabolismo , Peptídeos/metabolismo , Policetídeos/metabolismo , Espermidina Sintase/metabolismo , Espermidina/metabolismo , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Células HeLa , Humanos , Mutação , Poliaminas/metabolismo , Espermidina Sintase/genética
17.
Environ Sci Pollut Res Int ; 26(31): 32368-32373, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31605360

RESUMO

Lead (Pb) persists among the most hazardous contaminant metals. Pb-induced genotoxic effects remain a matter of debate as they are a major cause of plant growth impairment, but assessing Pb genotoxicity requires the selection of Pb-sensitive genotoxic biomarkers. Seedlings of the ecotoxicological model species Pisum sativum L. were exposed to Pb2+ (≤ 2000 mg L-1). Flow cytometry (FCM) revealed that 28 days after, Pb2+ arrested root cell cycle at G2 but no eu/aneuploidies were found. Comet assay and FCM-clastogenicity assays showed that Pb2+ increased DNA breaks in roots at concentrations as low as 20 mg L-1. Leaves showed no variation in DNA-ploidy or cell cycle progression but had increased DNA breaks at the highest Pb2+ dose. We conclude that both Comet assay and the full-peak coefficient of variation (FPCV) were the most relevant endpoints of Pb-phytogenotoxicity. Also, the Pb-induced DNA breaks may be related with the arrest at the G2-checkpoint. Data will be relevant to better define Pb2+ ecogenotoxicological effects and their measuring tools and may contribute to a regulatory debate of this pollutant limits.


Assuntos
Poluentes Ambientais/química , Chumbo/metabolismo , Mutagênicos/toxicidade , Ervilhas/efeitos dos fármacos , Folhas de Planta/metabolismo , Plântula/efeitos dos fármacos , Divisão Celular , Ensaio Cometa , Dano ao DNA , Poluentes Ambientais/metabolismo , Chumbo/química , Ervilhas/química , Desenvolvimento Vegetal , Folhas de Planta/química
18.
Molecules ; 24(19)2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31569643

RESUMO

Chronic inflammation is closely associated with cancer development. One possible mechanism for inflammation-induced carcinogenesis is DNA damage caused by reactive halogen species, such as hypochlorous acid, which is released by myeloperoxidase to kill pathogens. Hypochlorous acid can attack genomic DNA to produce 8-chloro-2'-deoxyguanosine (ClG) as a major lesion. It has been postulated that ClG promotes mutagenic replication using its syn conformer; yet, the structural basis for ClG-induced mutagenesis is unknown. We obtained crystal structures and kinetics data for nucleotide incorporation past a templating ClG using human DNA polymerase ß (polß) as a model enzyme for high-fidelity DNA polymerases. The structures showed that ClG formed base pairs with incoming dCTP and dGTP using its anti and syn conformers, respectively. Kinetic studies showed that polß incorporated dGTP only 15-fold less efficiently than dCTP, suggesting that replication across ClG is promutagenic. Two hydrogen bonds between syn-ClG and anti-dGTP and a water-mediated hydrogen bond appeared to facilitate mutagenic replication opposite the major halogenated guanine lesion. These results suggest that ClG in DNA promotes G to C transversion mutations by forming Hoogsteen base pairing between syn-ClG and anti-G during DNA synthesis.


Assuntos
Dano ao DNA/efeitos dos fármacos , DNA/química , Guanina/análogos & derivados , Mutagênicos/farmacologia , DNA Polimerase beta/metabolismo , Replicação do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Guanina/química , Guanina/farmacologia , Halogenação , Humanos , Ligações de Hidrogênio , Cinética , Modelos Biológicos , Conformação Molecular , Mutagênicos/química
19.
Ecotoxicol Environ Saf ; 185: 109693, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31550565

RESUMO

The objective of this study was to investigate chemical, biological and eco-toxicological parameters of a compost produced through the co-composting of dewatered primary sludge (DPS) and date palm waste to evaluate in which extent it can exploited as a bio-fertilizer. DPS and date palm waste were co-composted in aerobic conditions for 210 days. Physico-chemical parameters were evaluated during composting (total organic carbon, total nitrogen, pH, available forms of phosphorus). Furthermore, heavy metals (Cd, Cu, Cr, Pb, Ni, Zn) and antibiotics (fluoroquinolones, macrolides and tetracyclines) content were analyzed in the DPS. To evaluate the genotoxicity of substrates, Vicia faba micronucleus test was carried out. Single and combined toxicities of a mixture of antibiotics (ciprofloxacin, enroflxacin, nalidixic acid, roxithromycin and sulfapyridin) and chromium (Cr2 (SO4)3 and K2Cr2O7) were examined. Although the final compost product showed a significant decrease of the genotoxicity, almost 50% of the micronucleus frequency still remained, which could be explained by the persistence of several recalcitrant compounds such as chromium and some antibiotics. Overall, the presence of antibiotics and chromium showed that some specific combination of contaminants represent an ecological risk for soil health and ecosystems even at environmentally negligible concentrations.


Assuntos
Antibacterianos/toxicidade , Cromo/toxicidade , Compostagem , Mutagênicos/toxicidade , Esgotos/química , Poluentes do Solo/toxicidade , Vicia faba/efeitos dos fármacos , Ecossistema , Fertilizantes/análise , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , Solo/química , Vicia faba/genética
20.
Aquat Toxicol ; 216: 105291, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31525644

RESUMO

Most pesticides used in agriculture end up in the aquatic environment through runoff and leaching of treated crops. One of the most commonly used herbicides is glyphosate. This compound or its metabolites are frequently detected in surface water in Europe. In the present study, in vivo and in vitro studies were carried out using the early life stages of rainbow trout (Oncorhynchus mykiss) and the cell line RTL-W1 (a liver cell line from rainbow trout) to characterize the toxic effects of glyphosate at environmentally-realistic concentrations. Both studies were performed using the commercial formulation Roundup® GT Max, and technical-grade glyphosate for the in vitro study. Eyed-stage embryos were exposed for 3 weeks to sub-lethal concentrations (0.1 and 1 mg/L) of glyphosate using Roundup. Numerous toxicity endpoints were recorded such as survival, hatching success, larval biometry, developmental abnormalities, swimming activity, genotoxicity (formamidopyrimidine DNA-glycosylase Fpg-modified comet assay), lipid peroxidation (TBARS), protein carbonyls and target gene transcription. Concentrations neither affected embryonic or larval survival nor increased developmental abnormalities. However, a significant decrease was observed in the head size of larvae exposed to 1 mg/L of glyphosate. In addition, a significant increase in mobility was observed for larvae exposed to glyphosate at 0.1 mg/L. TBARS levels were significantly decreased on larvae exposed to 1 mg/L (a.i.), and cat and cox1 genes were differently transcribed from controls. DNA damage was detected by the Fpg-modified comet assay in RTL-W1 cell line exposed to the technical-grade glyphosate and Roundup formulation. The results suggest that chronic exposure to glyphosate, at environmental concentrations, could represent a potential risk for early life stages of fish.


Assuntos
Glicina/análogos & derivados , Herbicidas/toxicidade , Estágios do Ciclo de Vida/efeitos dos fármacos , Fígado/citologia , Oncorhynchus mykiss/crescimento & desenvolvimento , Animais , Células Sanguíneas/metabolismo , Gatos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Ensaio Cometa , Dano ao DNA , Embrião não Mamífero/efeitos dos fármacos , Exposição Ambiental , Regulação da Expressão Gênica/efeitos dos fármacos , Glicina/toxicidade , Larva/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Mutagênicos/toxicidade , Oncorhynchus mykiss/sangue , Oncorhynchus mykiss/embriologia , Carbonilação Proteica/efeitos dos fármacos , Natação , Poluentes Químicos da Água/toxicidade
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