Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 711
Filtrar
1.
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
2.
Environ Mol Mutagen ; 60(9): 837-844, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31490579

RESUMO

Caffeic acid is found in variety of fruits and vegetables. It is considered as possible human carcinogen (Group 2B). It is negative in Ames and mouse micronucleus (MN), but positive in mouse lymphoma and chromosomal aberration assays. The objective of this study was to evaluate the in vivo genotoxicity of caffeic acid using three different endpoints: in vivo MN, Pig-a, and comet assay. Two sets of six rats per group were administered vehicle (0.5% hydroxypropyl methylcellulose), 500, 1,000, or 2,000 mg/kg/day of caffeic acid for three consecutive days via oral gavage. One set of animals was used for the Pig-a and MN assay and the other set was used for the comet assay. N-Ethyl N-Nitrosourea was used as positive control for the Pig-a and MN assay, and ethyl methanesulfonate for the comet assay. From one set of animals, peripheral blood was collected on Days -1, 14, and 30 for the Pig-a assay and on Day 4 for the MN assay. The other set of animals was euthanized 3 hr after the last dose; liver and blood were collected for the comet assay. A statistically significant increase in the MN frequency was observed at 2,000 mg/kg/day. No increase in the red blood cells (RBCCD59- ) or reticulocytes (RETCD59- ) Pig-a mutant frequencies was observed on Days 14 or 30. No increase in DNA strand breaks was observed in the peripheral blood or liver in the comet assay. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.


Assuntos
Ácidos Cafeicos/efeitos adversos , Animais , Antígenos CD59/metabolismo , Aberrações Cromossômicas/efeitos dos fármacos , Ensaio Cometa/métodos , Quebras de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Metanossulfonato de Etila/efeitos adversos , Etilnitrosoureia/efeitos adversos , Masculino , Testes para Micronúcleos/métodos , Testes de Mutagenicidade/métodos , Mutagênicos/efeitos adversos , Ratos , Ratos Sprague-Dawley , Reticulócitos/efeitos dos fármacos
3.
Environ Mol Mutagen ; 60(9): 816-829, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31415110

RESUMO

Iron oxide nanoparticles (ION) are gaining importance as diagnostic and therapeutic tool of central nervous system diseases. Although oleic acid-coated ION (O-ION) have been described as stable and biocompatible, their potential neurotoxicity was scarcely evaluated in human nervous cells so far. The primary aim of this work was to assess the molecular and cellular effects of O-ION on human astrocytes (A172 cells) under different experimental conditions. An extensive set of cyto- and genotoxicity tests was carried out, including lactate dehydrogenase release assay, cell cycle alterations, and cell death production, as well as comet assay, γH2AX assay, and micronucleus (MN) test, considering also iron ion release capacity and alterations in DNA repair ability. Results showed a moderate cytotoxicity related to cell cycle arrest and cell death promotion, regardless of serum presence. O-ION induced genotoxic effects, namely primary DNA damage, as detected by the comet assay and H2AX phosphorylation, but A172 cells were able to repair this particular damage because no chromosome alterations were found (confirmed by MN test results). Accordingly, no effects on the DNA repair ability were observed. The presence of serum proteins did not influence O-ION toxicity. Iron ions released from the O-ION surface seemed not to be responsible for the cytotoxic and genotoxic effects observed. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.


Assuntos
Astrócitos/efeitos dos fármacos , Compostos Férricos/efeitos adversos , Nanopartículas Metálicas/efeitos adversos , Ácido Oleico/efeitos adversos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Aberrações Cromossômicas/efeitos dos fármacos , Ensaio Cometa/métodos , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Humanos , Testes para Micronúcleos/métodos , Testes de Mutagenicidade/métodos , Mutagênicos/efeitos adversos
4.
Artigo em Inglês | MEDLINE | ID: mdl-31373329

RESUMO

E-cigarette aerosol contains lower levels of most known carcinogens than tobacco smoke, but many users of e-cigarettes are also smokers, and these individuals may be vulnerable to possible promoting and/or cocarcinogenic effects of e-cigarettes. We investigated the possibility that a condensate of e-cigarette aerosol (EAC) enhances the metabolism of the tobacco carcinogen, benzo(a)pyrene (BaP), to genotoxic products in a human oral keratinocyte cell line. Cells were pretreated with EAC from two popular e-cigs and then with BaP. Metabolism to its ultimate carcinogenic metabolite, anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro B[a]P (BPDE), was assayed by measuring isomers of its spontaneous hydrolysis products, BaP tetrols. The pretreatment of cells with EAC enhanced the rate of BaP tetrol formation several fold. Pretreatment with the e-liquid resulted in a smaller enhancement. The treatment of cells with EAC induced CYP1A1/1B1 mRNA and protein. The enhancement of BaP tetrol formation was inhibited by the aryl hydrocarbon receptor (AhR) inhibitor, α-napthoflavone, indicating EAC likely induces CYP1A1/1B1 and enhances BaP metabolism by activating the AhR. To our knowledge, this is first report demonstrating that e-cigarettes can potentiate the genotoxic effects of a tobacco smoke carcinogen.


Assuntos
Aerossóis/efeitos adversos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Benzo(a)pireno/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Mutagênicos/efeitos adversos , Receptores de Hidrocarboneto Arílico/genética , Fumaça/efeitos adversos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinógenos/toxicidade , Linhagem Celular Tumoral , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/metabolismo , Sistemas Eletrônicos de Liberação de Nicotina , Humanos , Receptores de Hidrocarboneto Arílico/metabolismo
5.
Environ Mol Mutagen ; 60(7): 607-616, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30968449

RESUMO

Atmospheric particulate matter (PM) organic fractions from urban centers are frequently mutagenic for the Salmonella/microsome assay. This mutagenicity is related to both primary and secondary pollutants, and meteorological conditions have great influence on the secondary pollutant's formation. Our objective was to compare the mutagenicity of atmospheric total suspended particulates (TSP) from three cities with marked different meteorological conditions and TSP concentrations: Limeira (Brazil) with 99.0 µg/m3 , Stockholm (Sweden) with 6.2 µg/m3 , and Kyoto (Japan) with 28.0 µg/m3 . For comparison, we used the same batch of filters, sample extraction method, and Salmonella/microsome testing protocol with 11 strains of Salmonella with and without metabolic activation. Samples were collected during winter and pooled into one single extract representing each city. All samples were mutagenic for all tested strains, except for TA102. Based on the strain's selectivity, nitroarenes, polycyclic aromatic hydrocarbons, and aromatic amines play a predominant role in the mutagenicity of these samples. The mutagenic potencies expressed by mass of extracted organic material (EOM; revertants/µg EOM) were similar (~twofold difference) among the cities, despite differences in meteorological conditions and pollution sources. In contrast, the mutagenic potencies expressed by air volume (rev/m3 ) varied ~20-fold, with Limeira > Kyoto ≈ Stockholm. These results are the first systematic assessment of air mutagenicity from cities on three continents using the same protocols. The results confirm that the mutagenic potency expressed by EOM mass is similar regardless of continent of origin, whereas the mutagenic potency expressed by air volume can vary by orders of magnitude. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.


Assuntos
Mutagênese/efeitos dos fármacos , Mutagênicos/efeitos adversos , Material Particulado/efeitos adversos , Poluentes Atmosféricos/efeitos adversos , Aminas/efeitos adversos , Bioensaio/métodos , Brasil , Cidades , Japão , Microssomos/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Hidrocarbonetos Policíclicos Aromáticos , Salmonella/efeitos dos fármacos , Suécia
6.
Environ Mol Mutagen ; 60(7): 588-593, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31001845

RESUMO

2-Hydroxypyridine N-oxide (HOPO) is an important coupling reagent used in pharmaceutical synthesis. Our laboratory previously reported HOPO as equivocal in the Ames assay following extensive testing of multiple lots of material. Given the lack of reproducibility between lots of material and the weak increase in revertants observed, it was concluded that it would be highly unlikely that HOPO would pose a mutagenic risk in vivo. The purpose of the current investigation was to assess experimentally in rats the mutagenic (Pig-a mutation induction) and more broadly genotoxic (micronucleus and comet induction) potential of HOPO. Rats were administered HOPO (0, 50, 150, 300, and 500 mg/kg/day) by oral gavage for 28 days. At the end of study, the following parameters were assessed: frequency of Pig-a mutant red blood cells and reticulocytes, frequency of peripheral blood micronuclei, and the incidence of comet formation in liver. Toxicokinetic data collected on study Days 1 and 28 demonstrated systemic exposure to HOPO. Although there were no overt clinical signs, animals treated with HOPO showed a dose-related decrease in body weight gain. There were no increases observed in any of the genotoxicity endpoints assessed. The results from this study further support the conclusion that in the context of pharmaceutical synthesis, HOPO should not be considered a mutagenic impurity but rather controlled as a normal process-related impurity. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.


Assuntos
Óxidos N-Cíclicos/efeitos adversos , Mutagênese/efeitos dos fármacos , Mutagênicos/efeitos adversos , Piridinas/efeitos adversos , Animais , Eritrócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Testes de Mutagenicidade/métodos , Mutação/efeitos dos fármacos , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Reticulócitos/efeitos dos fármacos
7.
Mini Rev Med Chem ; 19(15): 1196-1203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30887924

RESUMO

Cancer is the second leading factor of human death in the world. Long-term consumption of cooked red meat brings about various types of cancers like colorectal cancer due to the formation of Heterocyclic Aromatic Amines (HAAs) during the heating process of meat. There are various solutions for the reduction of these toxicants. The aim of this article is to describe probiotic as one of the possible strategies for bioremoval of these carcinogenic and mutagenic substances and change food to functional one as well. The mechanism of biodetoxification is binding by probiotics, which depends on some variables including the probiotic characteristics, kind and content of the mutagens, as well as some properties of media. In this article, after introducing detoxification ability of probiotics and listing of all reported probiotics in this field, the influencing variables are surveyed and finally, opportunities and problems of HAA bioremoval by probiotics are described.


Assuntos
Aminas/química , Carcinógenos/química , Compostos Heterocíclicos/química , Mutagênicos/química , Neoplasias/prevenção & controle , Probióticos/farmacologia , Desintoxicação por Sorção/métodos , Aminas/efeitos adversos , Aminas/síntese química , Aminas/isolamento & purificação , Carcinógenos/síntese química , Carcinógenos/isolamento & purificação , Compostos Heterocíclicos/efeitos adversos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/isolamento & purificação , Humanos , Carne/efeitos adversos , Mutagênicos/efeitos adversos , Mutagênicos/síntese química , Mutagênicos/isolamento & purificação , Neoplasias/dietoterapia , Neoplasias/etiologia , Probióticos/química
8.
Environ Mol Mutagen ; 60(6): 470-493, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30848503

RESUMO

During the First Gulf War (1991) over 100 servicemen sustained depleted uranium (DU) exposure through wound contamination, inhalation, and shrapnel. The Department of Veterans Affairs has a surveillance program for these Veterans which has included genotoxicity assays. The frequencies of glycosylphosphatidylinositol anchor (GPIa) negative (aerolysin resistant) cells determined by cloning assays for these Veterans are reported in Albertini RJ et al. (2019: Environ Mol Mutagen). Molecular analyses of the GPIa biosynthesis class A (PIGA) gene was performed on 862 aerolysin-resistant T-lymphocyte recovered isolates. The frequencies of different types of PIGA mutations were compared between high and low DU exposure groups. Additional molecular studies were performed on mutants that produced no PIGA mRNA or with deletions of all or part of the PIGA gene to determine deletion size and breakpoint sequence. One mutant appeared to be the result of a chromothriptic event. A significant percentage (>30%) of the aerolysin resistant isolates, which varied by sample year and Veteran, had wild-type PIGA cDNA (no mutation). As described in Albertini RJ et al. (2019: Environ Mol Mutagen), TCR gene rearrangement analysis of these isolates indicated most arose from multiple T-cell progenitors (hence the inability to find a mutation). It is likely that these isolates were the result of failure of complete selection against nonmutant cells in the cloning assays. Real-time studies of GPIa resistant isolates with no PIGA mutation but with a single TCR gene rearrangement found one clone with a PIGV deletion and several others with decreased levels of GPIa pathway gene mRNAs implying mutation in other GPIa pathway genes. Environ. Mol. Mutagen. 60:470-493, 2019. © 2019 Wiley Periodicals, Inc.


Assuntos
Toxinas Bacterianas/metabolismo , Glicosilfosfatidilinositóis/deficiência , Glicosilfosfatidilinositóis/metabolismo , Mutagênicos/efeitos adversos , Exposição Ocupacional/efeitos adversos , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Convulsões/metabolismo , Urânio/efeitos adversos , Guerra do Golfo , Humanos , Militares , Mutação/efeitos dos fármacos , Estados Unidos , Veteranos
9.
Environ Mol Mutagen ; 60(6): 494-504, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30848527

RESUMO

Fifty Veterans of the first Gulf War in 1991 exposed to depleted uranium (DU) were studied for glycosylphosphatidylinositol-anchor (GPIa) deficient T-cell mutants on three occasions during the years 2009, 2011, and 2013. GPIa deficiency was determined in two ways: cloning assays employing aerolysin selection and cytometry using the FLAER reagent for positive staining of GPIa cell surface proteins. Subsequent molecular analyses of deficient isolates recovered from cloning assays (Nicklas JA et al. [2019]: Environ Mol Mutagen) revealed apparent incomplete selection in some cloning assays, necessitating correction of original data to afford a more realistic estimate of GPIa deficient mutant frequency (MF) values. GPIa deficient variant frequencies (VFs) determined by cytometry were determined in the years 2011 and 2013. A positive but nonsignificant association was observed between MF and VF values determined on the same blood samples during 2013. Exposure to DU had no effect on either GPIa deficient MF or VFs. Environ. Mol. Mutagen. 60:494-504, 2019. © 2019 Wiley Periodicals, Inc.


Assuntos
Glicosilfosfatidilinositóis/deficiência , Mutagênicos/efeitos adversos , Mutação/efeitos dos fármacos , Exposição Ocupacional/efeitos adversos , Convulsões/metabolismo , Linfócitos T/efeitos dos fármacos , Urânio/efeitos adversos , Estudos de Coortes , Glicosilfosfatidilinositóis/metabolismo , Guerra do Golfo , Humanos , Estudos Longitudinais , Militares , Veteranos
10.
Artigo em Inglês | MEDLINE | ID: mdl-30744813

RESUMO

Genotoxicity assays are characterized by a method, an in vitro or in vivo target, and an endpoint. Many cell types have been used as targets, including bacterial cells, cultured mammalian cells, and rodent cells in vivo. Human cells are the most important target for evaluating the risk to humans associated with exposure to chemicals. Almost exclusively, the human cells used in genotoxicity tests have been cultured cells. Here, we have tested human hepatocytes in PXB-mice®, chimeric mice in which the liver has been repopulated with human hepatocytes, as a source of target cells for in vivo genotoxicity assays. We applied the single-cell gel electrophoresis (comet) assay to detect DNA damage and the micronucleus assay to evaluate chromosomal aberrations. These chimeric mice can serve as a valuable model system for genotoxicity assays.


Assuntos
Quimera/fisiologia , Aberrações Cromossômicas , Dano ao DNA , Hepatócitos/patologia , Testes de Mutagenicidade/métodos , Mutagênicos/efeitos adversos , Animais , Ensaio Cometa , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Testes para Micronúcleos
11.
Chem Pharm Bull (Tokyo) ; 67(5): 433-438, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30787216

RESUMO

Oxaliplatin is a third generation platinum based anti-cancer drug used against various human malignancies but displays genotoxic properties against normal cells. Naringenin is a naturally occurring bioflavonoid that possesses anti-oxidant properties and has protective effects against DNA damage. The aim of this study is to examine the protective effects of naringenin on oxaliplatin-induced DNA damage in mice. A total of 50, male BALB/c mice were randomly divided equally into five groups. Oxaliplatin toxicity was induced by a single dose (7 mg/kg body weight (b.w.)) injection (intraperitoneally (i.p.)) of oxaliplatin. Naringenin was given orally for ten consecutive days at two doses, 20 mg/kg b.w. (dose I) and 40 mg/kg b.w. (dose II), to group I and group II, respectively. On the tenth day of the experiment, animals in groups III, IV, and V were given a single i.p. injection of oxaliplatin (7 mg/kg b.w.). All the animals were sacrificed 24 h after oxaliplatin treatment. The extent of genotoxicity was assessed by multiple genotoxicity assays (8-hydroxydeoxy-guanosine marker, comet, micronucleus and chromosomal aberration assays, oxidative stress-marker Glutathione evaluation) in order to determine diverse kinds of DNA damage. The results indicated that naringenin administration significantly reduced the DNA damage induced by oxaliplatin possibly due to its strong anti-oxidant properties. The results suggest that naringenin is a potential candidate for future development as a chemoprotective agent against chemotherapy associated complications.


Assuntos
Antineoplásicos/efeitos adversos , Antioxidantes/farmacologia , Dano ao DNA/efeitos dos fármacos , Flavanonas/farmacologia , Mutagênicos/efeitos adversos , Oxaliplatina/efeitos adversos , Animais , Antioxidantes/administração & dosagem , Aberrações Cromossômicas/efeitos dos fármacos , Flavanonas/administração & dosagem , Masculino , Camundongos Endogâmicos BALB C , Testes para Micronúcleos , Estresse Oxidativo/efeitos dos fármacos
12.
Sci Total Environ ; 660: 459-467, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30640113

RESUMO

The use of silver nanoparticles (AgNPs) in commercial products has increased significantly in recent years. However, findings on the toxic effects of the AgNPs are still limited. This paper reports an investigation on the cytotoxic and genotoxic potential of the AgNPs on root cells of Allium cepa. Germination (GI), root elongation (REI), mitotic (MI), nuclear abnormality (NAI), and micronucleus index (MNI) were determined for seeds exposed to various AgNPs diameters (10, 20, 51, and 73 nm) as well as to the silver bulk (AgBulk) (micrometer-size particles) at the concentration of 100 mg·L-1. Transmission electron microscopy (TEM) provided the particle size distribution, while dynamic light scattering (DLS) was used to get the hydrodynamic size, polydispersity index, and zeta potential of the AgNPs. Laser-induced breakdown spectroscopy (LIBS) and inductively coupled plasma/optical emission spectrometry (ICP OES) were applied for quantifying the AgNPs content uptake by roots. Silver dissolution was determined by dialysis experiment. Results showed that the AgNPs penetrated the roots, affecting MI, GI, NAI, and MNI in meristematic cells. Changes in these indicators were AgNPs diameter-dependent so that cytotoxic and genotoxic effects in Allium cepa increased with the reduction of the particle diameter. The results also revealed that the AgNPs were the main responsible for the cytotoxicity and genotoxicity since negligible silver dissolution was observed.


Assuntos
Allium/efeitos dos fármacos , Citotoxinas/efeitos adversos , Meristema/efeitos dos fármacos , Nanopartículas Metálicas/efeitos adversos , Mutagênicos/efeitos adversos , Prata/efeitos adversos , Testes de Mutagenicidade , Tamanho da Partícula , Raízes de Plantas/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos
13.
Artigo em Inglês | MEDLINE | ID: mdl-30696096

RESUMO

In 2015, the International Federation of Gynecology and Obstetrics established the prevention of exposures to environmental reprotoxic substances as a priority for health professionals. However, available information about reproductive hazards is voluminous, dispersed, and complex, and this is a severe limitation for physicians to incorporate the prevention of environmental exposure into standard preventive care. One difficulty frequently cited by physicians is the lack of evidence-based information. The objective of our study was to identify a list of environmental chemical hazards to reproduction. We used lists present in relevant regulations or included in scientific reports or databases to identify reproductive hazards. The reproductive hazards were prioritized according to the strength of evidence concerning their impact on fertility or development of the offspring. We identified 1251 reproductive hazards. Our prioritization approach resulted in a high-priority classification for 462 risk factors belonging to the following eight classes: drugs (n = 206), metals (n = 116), pesticides (n = 38), organic solvents (n = 27), synthesizing and/or processing agents in industrial processes (n = 23), phthalates (n = 13), perfluorinated compounds (n = 13), and other compounds (n = 26). Despite the limitations of this work, the generated lists constitute a useful working basis to put in place innovative environmental preventive measures according to the principle of evidence-based medicine.


Assuntos
Exposição Ambiental/efeitos adversos , Fertilidade/efeitos dos fármacos , Substâncias Perigosas/efeitos adversos , Mutagênicos/efeitos adversos , Assistência Perinatal/normas , Complicações na Gravidez/prevenção & controle , Reprodução/efeitos dos fármacos , Adulto , Feminino , Guias como Assunto , Humanos , Gravidez , Fatores de Risco
14.
Environ Mol Mutagen ; 60(3): 302-304, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30525240

RESUMO

Sickle cell anemia (SCA) is a hereditary hematological disease that is characterized by a point mutation in the beta globin S gene and has no specific treatment; hydroxyurea (HU) is the only therapeutic agent used in clinical practice. In the present study, we evaluated the deoxyribonucleic acid (DNA) damage index (DI) and chromosomal damage in leukocytes of adult patients with SCA with and without HU. The DI was assessed by the comet assay and chromosomal damage by the leukocyte micronucleus test of adult patients treated with HU (SCA-HU) and without the use of HU (SCA-NoHU). This is a cross-sectional study with 77 patients with SCA who attended a referral hospital in Fortaleza, Brazil. The control group (CG) consisted of 58 reportedly healthy individuals. The comparisons of means were performed by analysis of variance and Tukey's post-test. Values of P < 0.05 were considered statistically significant. SCA-NoHU patients had statistically higher DI values and a statistically significantly higher frequency of micronuclei compared to the CG. In addition, HU treatment accentuated DNA lesions by significantly increasing both parameters in treated patients (SCA-HU). HU potentiates DNA damage and the occurrence of chromosomal damage, which may promote genomic instability, mutation occurrence, and carcinogenesis. Studies are needed to evaluate the involved pathways, repair mechanisms, and the clinical impact that such damage can cause. Environ. Mol. Mutagen. 60:302-304, 2019. © 2018 Wiley Periodicals, Inc.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/efeitos adversos , Antidrepanocíticos/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Adolescente , Adulto , Brasil , Estudos Transversais , Dano ao DNA/genética , Feminino , Humanos , Leucócitos/citologia , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Mutagênicos/efeitos adversos , Mutagênicos/uso terapêutico , Adulto Jovem
15.
Food Chem Toxicol ; 124: 374-384, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30572064

RESUMO

Dietary carcinogens, such as benzo[a]pyrene (BaP), are suspected to contribute to colorectal cancer development. n-3 Polyunsaturated fatty acids (PUFAs) decrease colorectal cancer risk in individuals consuming diets rich in PUFAs. Here, we investigated the impact of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid on metabolism and genotoxicity of BaP in human cell models derived from the colon: HT-29 and HCT-116 cell lines. Both PUFAs reduced levels of excreted BaP metabolites, in particular BaP-tetrols and hydroxylated BaP metabolites, as well as formation of DNA adducts in HT-29 and HCT-116 cells. However, EPA appeared to be a more potent inhibitor of formation of some intracellular BaP metabolites, including BaP-7,8-dihydrodiol. EPA also reduced phosphorylation of histone H2AX (Ser139) in HT-29 cells, which indicated that it may reduce further forms of DNA damage, including DNA double strand breaks. Both PUFAs inhibited induction of CYP1 activity in colon cells determined as 7-ethoxyresorufin-O-deethylase (EROD); this was at least partly linked with inhibition of induction of CYP1A1, 1A2 and 1B1 mRNAs. The downregulation and/or inhibition of CYP1 enzymes by PUFAs could thus alter metabolism and reduce genotoxicity of BaP in human colon cells, which might contribute to known chemopreventive effects of PUFAs in colon epithelium.


Assuntos
Anticarcinógenos/farmacologia , Benzo(a)pireno/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Células Epiteliais/efeitos dos fármacos , Mutagênicos/metabolismo , Benzo(a)pireno/efeitos adversos , Linhagem Celular Tumoral , Família 1 do Citocromo P450/metabolismo , Adutos de DNA/metabolismo , Dano ao DNA/efeitos dos fármacos , Histonas/metabolismo , Humanos , Mutagênicos/efeitos adversos , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos
16.
Bull Exp Biol Med ; 166(1): 43-45, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30417284

RESUMO

We studied the mutagenic effect of X-ray irradiation in doses of 0.5, 1, and 1.5 Gy on female (CBA×C57Bl/6)F1 mice. The mutagenic effect (assessed by the parameter "frequency of bone marrow polychromatophilic erythrocytes with micronuclei") linearly depended on the dose of X-ray irradiation in the range of up to 1 Gy and reached the plateau at 1.5 Gy. The fraction of polychromatophilic erythrocytes was 45, 45, and 46% under control conditions (without exposure) and exposure to the irradiation in the doses of 0.5 and 1 Gy, respectively. Irradiation in a dose of 1.5 Gy induced a slight inhibition of erythropoiesis. These data confirm the hypothesis on possible death of highly aberrant erythrocyte precursors after irradiation in high doses.


Assuntos
Eritrócitos/efeitos da radiação , Mutagênicos/efeitos adversos , Radiação Ionizante , Raios X , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Testes para Micronúcleos
17.
Mutat Res Genet Toxicol Environ Mutagen ; 836(Pt A): 47-52, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30389162

RESUMO

Recently fourteen systematic reviews applying the same selection and evaluation criteria analyzed the induction of micronuclei in lymphocytes as biomarker for DNA damage induced by human exposure to a given chemical or chemical mixture. The results obtained in the individual reviews were summarized to evaluate the validity of the Cytokinesis-Block-Micronucleus assay in lymphocytes (L-CBMN) and propose recommendations for its use in occupational and environmental exposure studies. All systematic reviews found consistent increases of MN frequencies in exposed subjects versus controls in all genotoxic compounds or group of chemicals investigated, in the following decreasing order: As/Cr/Ni, vinyl chloride, formaldehyde, Hg/Pb/Cd, "miscellaneous", pesticides, cytostatics/antineoplastics, anaesthetic gasses, dust/asbestos/other fibers, polycyclic aromatic hydrocarbons, ethylene oxide, butadiene, styrene and petroleum/derivatives. Two reviews compared the results with the recommended exposure limits. For styrene, MN was found not to be induced under the recommended threshold limit. For vinyl chloride the safe exposure limit based on the L-CBMN data is lower than the current one. The L-CBMN thus appears to be a valid biomarker to assess DNA damage in populations exposed to genotoxic chemicals. Many shortcomings have been reported in assessment of confounding factors, such as lifestyle patterns, in particular diet and the major one the exposure assessment. All these factors together with methodological variables may contribute to the large variability in MN frequencies, also in controls. Information on frequency and origin of MN in more than one tissue (e.g. lymphocytes and buccal cells) in parallel, may provide better understanding of the mechanisms involved. Use of automated MN scoring systems to increase numbers of cells scored and facilitate screening more individuals would increase data reliability and provide information on the link between mutagenicity and carcinogenicity, if the studies are done prospectively. Efforts should be made to unravel the genotoxic effects induced when chronic and/or mixed exposures are involved.


Assuntos
Biomarcadores/análise , Citocinese , Dano ao DNA , Exposição Ambiental/efeitos adversos , Linfócitos/efeitos dos fármacos , Mutagênicos/efeitos adversos , Exposição Ocupacional/efeitos adversos , Humanos , Testes para Micronúcleos , Revisão Sistemática como Assunto
18.
Mutat Res Genet Toxicol Environ Mutagen ; 836(Pt A): 53-64, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30389163

RESUMO

The lymphocyte Cytokinesis-Block Micronucleus (CBMN) assay was originally developed for the measurement of micronuclei (MN) exclusively in binucleated (BN) cells, which represent the population of cells that can express MN because they completed nuclear division. Recently the assay has evolved into a comprehensive cytome method to include biomarkers that measure chromosomal instability and cytotoxicity by quantification of nuclear buds (NBUDs), nucleoplasmic bridges (NPBs) and apoptotic/necrotic cells. Furthermore, enumeration of mono- and polynucleated cells allows for computation of the nuclear division index (NDI) to assess mitotic activity. Typically performed by manual microscopy, the CBMN cytome assay is laborious and subject to scorer bias and fatigue, leading to inter- and intra-scorer variability. Automated microscopy and conventional flow cytometry methods have been developed to automate scoring of the traditional and cytome versions of the assay. However, these methods have several limitations including the requirement to create high-quality microscope slides, lack of staining consistency and sub-optimal nuclear/cytoplasmic visualization. In the case of flow cytometry, stripping of the cytoplasmic membrane makes it impossible to measure MN in BN cells, calculate the NDI or to quantify apoptotic or necrotic cells. Moreover, the absence of cellular visualization using conventional flow cytometry, makes it impossible to quantify NBUDs and NPBs. In this review, we propose that imaging flow cytometry (IFC), which combines high resolution microscopy with flow cytometry, may overcome these limitations. We demonstrate that by using IFC, images from cells in suspension can be captured, removing the need for microscope slides and allowing visualization of intact cytoplasmic membranes and DNA content. Thus, mono-, bi- and polynucleated cells with and without MN can be rapidly and automatically identified and quantified. Finally, we present high-resolution cell images containing NBUDs and NPBs, illustrating that IFC possesses the potential for completely automated scoring of all components of the CBMN cytome assay.


Assuntos
Citocinese , Dano ao DNA , Exposição Ambiental/efeitos adversos , Citometria de Fluxo/métodos , Linfócitos/efeitos dos fármacos , Testes para Micronúcleos/métodos , Mutagênicos/efeitos adversos , Apoptose , Biomarcadores/análise , Núcleo Celular , Exposição Ambiental/análise , Humanos
19.
Regul Toxicol Pharmacol ; 99: 274-288, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30278198

RESUMO

In drug development, genetic toxicology studies are conducted using in vitro and in vivo assays to identify potential mutagenic and clastogenic effects, as outlined in the International Council for Harmonisation (ICH) S2 regulatory guideline. (Quantitative) structure-activity relationship ((Q)SAR) models that predict assay outcomes can be used as an early screen to prioritize pharmaceutical candidates, or later during product development to evaluate safety when experimental data are unavailable or inconclusive. In the current study, two commercial QSAR platforms were used to build models for in vitro chromosomal aberrations in Chinese hamster lung (CHL) and Chinese hamster ovary (CHO) cells. Cross-validated CHL model predictive performance showed sensitivity of 80 and 82%, and negative predictivity of 75 and 76% based on 875 training set compounds. For CHO, sensitivity of 61 and 67% and negative predictivity of 68 and 74% was achieved based on 817 training set compounds. The predictive performance of structural alerts in a commercial expert rule-based SAR software was also investigated and showed positive predictivity of 48-100% for selected alerts. Case studies examining incorrectly-predicted compounds, non-DNA-reactive clastogens, and recently-approved pharmaceuticals are presented, exploring how an investigational approach using similarity searching and expert knowledge can improve upon individual (Q)SAR predictions of the clastogenicity of drugs.


Assuntos
Aberrações Cromossômicas/induzido quimicamente , Mutagênicos/efeitos adversos , Mutagênicos/química , Animais , Células CHO , Linhagem Celular , Simulação por Computador , Cricetinae , Cricetulus , Contaminação de Medicamentos , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Relação Quantitativa Estrutura-Atividade , Ratos , Software
20.
Artigo em Inglês | MEDLINE | ID: mdl-30200545

RESUMO

Ultraviolet absorbing chemicals (UV filters) are widely used in personal care products for protecting human skin and hair from damage by UV radiation. Although these substances are released into the environment during production and consumption processes, little is known about their genotoxicity effects. Our previous studies have shown that benzophenone-type UV filters exhibited acute toxicity on three species of aquatic organisms. Mutagenesis by benzophenone (BP) and benzophenone-1(BP-1) was tested in the present study by the Salmonella typhimurium/reverse mutation assay (Ames assay). All the positive reverse mutations occurred in the absence of the S9 liver extract system for both chemicals. From BP, positive mutation effects on the TA102 strain at doses of 0.05 µg/plate and 0.5 µg/plate were detected. From BP-1, positive mutation effects on the TA97 strain at doses of 0.05 µg/plate and 0.5 µg/plate, and on the TA100 strain at a dose of 0.5 µg/plate, were detected. A mixture of BP and BP-1 exhibited mutagenicity on the TA97 and TA100 strains. For the TA97 strain, the positive mutation results were detected at 10% and 50% of the mixture. For the TA100 strain, the results were detected when the mixture was at 5% and 10%. In the mixture at 5%, the concentrations of BP and BP-1 were 3.5 µg/plate and 14 µg/plate, respectively. In the 10% mixture, the doses of BP and BP-1 were 7 µg/plate and 28 µg/plate, respectively. In the 50% mixture, the doses of BP and BP-1 were 35 µg/plate and 140 µg/plate, respectively. The mixture test results suggested that there was antagonism in mutagenicity between BP and BP-1.


Assuntos
Benzofenonas/efeitos adversos , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Mutagênicos/efeitos adversos , Salmonella typhimurium/efeitos dos fármacos , Protetores Solares/efeitos adversos , Raios Ultravioleta/efeitos adversos , Bioensaio , Monitoramento Ambiental/métodos , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA