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1.
Sci Total Environ ; 779: 146514, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34030253

RESUMO

The toxicity of carbon-based nanomaterials (CNs) has been observed in different organisms; however, little is known about the impact of water polluted with carbon nanofibers (CNFs) on reptiles. Thus, the aim of the current study was to assess the chronic effects (7.5 months) of 1 and 10 mg/L of CNF on Podocnemis expansa (Amazon turtle) juveniles (4 months old) based on different biomarkers. Increased total organic carbon (TOC) concentrations observed in the liver and brain (which suggests CNF uptake) were closely correlated to changes in REDOX systems of turtles exposed to CNFs, mainly to higher nitrite, hydrogen peroxide and lipid peroxidation levels. Increased levels of antioxidants such as total glutathione, catalase and superoxide dismutase in the exposed animals were also observed. The uptake of CNFs and the observed biochemical changes were associated with higher frequency of erythrocyte nuclear abnormalities (assessed through micronucleus assays), as well as with both damage in erythrocyte DNA (assessed through comet assays) and higher apoptosis and necrosis rates in erythrocytes of exposed turtles. Cerebral and hepatic acetylcholinesterase (AChE) increased in turtles exposed to CNFs, and this finding suggested the neurotoxic effect of these nanomaterials. Data in the current study reinforced the toxic potential of CNFs and evidenced the biochemical, mutagenic, genotoxic, cytotoxic, and neurotoxic effects of CNFs on P. expansa.


Assuntos
Nanofibras , Tartarugas , Animais , Carbono , Testes para Micronúcleos , Mutagênicos , Nanofibras/toxicidade
2.
Environ Res ; 197: 111209, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33895109

RESUMO

Workers in marble processing plants are at high risk of exposure to high levels of marble dust containing silica, but there are limited studies evaluating the genotoxicity and oxidative stress parameters of workers occupationally exposed to marble dust. In this study, we aimed to clarify how marble dust affects genotoxicity and immunotoxicity mechanisms alongside oxidative stress in the workers in the marble processing plants of Iscehisar, Turkey. The oxidative stress and immune system parameters were determined spectrophotometrically using commercial kits. Genotoxicity was evaluated by Comet and micronucleus (MN) assays in the lymphocytes and buccal cells, respectively. The enzyme activities of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and the levels of glutathione, and Clara cell secretory protein CC16 in workers (n = 48) were significantly lower than in controls (n = 41), whereas the levels of malondialdehyde, 8-oxo-7,8-dihydro-2'-deoxyguanosine, tumor necrosis factor-alpha, interleukin-1beta were significantly higher in workers. DNA damage in workers were significantly higher than in controls and there was a clear correlation between the increase in DNA damage and the duration of exposure. Marble workers had significantly higher MN frequencies when compared to controls. The results indicate the possibility of immunotoxic and genotoxic risks to workers in marble industry.


Assuntos
Exposição Ocupacional , Carbonato de Cálcio , Ensaio Cometa , Dano ao DNA , Humanos , Testes para Micronúcleos , Mucosa Bucal , Exposição Ocupacional/efeitos adversos , Estresse Oxidativo , Turquia
3.
Mutat Res ; 865: 503314, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33865536

RESUMO

The reconstructed skin micronucleus (RSMN) assay was developed in 2006, as an in vitro alternative for genotoxicity evaluation of dermally applied chemicals or products. In the years since, significant progress has been made in the optimization of the assay, including publication of a standard protocol and extensive validation. However, the diverse morphology of skin cells makes cell preparation and scoring of micronuclei (MN) tedious and subjective, thus requiring a high level of technical expertise for evaluation. This ultimately has a negative impact on throughput and the assay would benefit by the development of an automated method which could reduce scoring subjectivity while also improving the robustness of the assay by increasing the number of cells that can be scored. Imaging flow cytometry (IFC) with the ImageStream®X Mk II can capture high-resolution transmission and fluorescent imagery of cells in suspension. This proof-of-principle study describes protocol modifications that enable such automated measurement in 3D skin cells following exposure to mitomycin C and colchicine. IFC was then used for automated image capture and the Amnis® Artificial Intelligence (AAI) software permitted identification of binucleated (BN) cells with 91% precision. On average, three times as many BN cells from control samples were evaluated using IFC compared to the standard manual analysis. When IFC MNBN cells were visually scored from within the BN cell images, their frequency compared well with manual slide scoring, showing that IFC technology can be applied to the RSMN assay. This method enables faster time to result than microscope-based scoring and the initial studies presented here demonstrate its capability for the detection of statistically significant increases in MNBN frequencies. This work therefore demonstrates the feasibility of combining IFC and AAI to automate scoring for the RSMN assay and to improve its throughput and statistical robustness.


Assuntos
Aprendizado Profundo , Citometria de Fluxo/métodos , Processamento de Imagem Assistida por Computador/métodos , Pele/patologia , Inteligência Artificial , Automação Laboratorial/instrumentação , Automação Laboratorial/métodos , Reações Falso-Positivas , Estudos de Viabilidade , Citometria de Fluxo/instrumentação , Humanos , Processamento de Imagem Assistida por Computador/instrumentação , Testes para Micronúcleos/instrumentação , Testes para Micronúcleos/métodos , Mitomicina/toxicidade , Modelos Biológicos , Testes de Mutagenicidade/instrumentação , Testes de Mutagenicidade/métodos , Valor Preditivo dos Testes , Estudo de Prova de Conceito , Pele/diagnóstico por imagem , Pele Artificial , Software , Tecidos Suporte
4.
Mutat Res ; 865: 503322, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33865537

RESUMO

Chronic exposure to benzene is a risk factor for hematological malignancies. Gasoline-station workers are exposed to benzene in gasoline, via both inhalation and dermal contact (attendants and managers) or inhalation (workers in the on-site convenience stores and offices). We have studied the exposure of these workers to benzene and the resulting genotoxic and immunotoxic effects. Levels of urinary trans, trans-muconic acid were higher among gasoline-station workers than among office workers with no known exposure to benzene (comparison group). Among the exposed workers, we observed statistically significant biological effects, including elevated DNA damage (comet assay); higher frequencies of micronuclei and nuclear buds (CBMN assay); lower levels of T-helper lymphocytes and naive Th lymphocytes; lower CD4 / CD8 ratio; and higher levels of NK cells and memory Th lymphocytes. Both groups of exposed workers (inhalation and inhalation + dermal routes) showed similar genotoxic and immunotoxic effects.


Assuntos
Benzeno/toxicidade , Gasolina/toxicidade , Sistema Imunitário/efeitos dos fármacos , Exposição Ocupacional , Adulto , Idoso , Poluentes Ocupacionais do Ar/toxicidade , Brasil/epidemiologia , Ensaio Cometa , Estudos Transversais , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/imunologia , Feminino , Humanos , Sistema Imunitário/metabolismo , Imunomodulação/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Exposição por Inalação/análise , Contagem de Linfócitos , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Testes de Mutagenicidade , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Exposição Ocupacional/estatística & dados numéricos , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia , Adulto Jovem
5.
Mutat Res ; 865: 503338, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33865544

RESUMO

Quantum Dots (QDs), are considered as promising tools for biomedical applications. They have potential applications in agricultural industries, novel pesticide formulations, use in bio-labels and devices to aid genetic manipulation and post-harvest management. Since interactions with higher plants are of important environmental and ecological concern we investigated the cytotoxicity and genotoxicity of CdSe QDs in a model plant (Allium cepa) and established relationships between QDs genotoxic activity and oxidative stress. Allium cepa bulbs with intact roots were exposed to three concentrations of CdSe QDs (12.5, 25 and 50 nM). Cell viability and mitotic frequencies was measured for cytotoxicity, and to assess the genotoxicity DNA lesions, chromosome aberrations and micronuclei were evaluated. We report that QDs exerted significant genotoxic effects, associated with oxidative stress. This could be correlated with the retention of Cd in Allium roots as a dose-dependent increase with the highest uptake at 50 nM of CdSe QD. Oxidative stress induced by CdSe QD treatment activated both, antioxidant (SOD, CAT) scavengers and antioxidant (GPOD, GSH) enzymes. Concentrations as low as 25 nM CdSe QDs were cytotoxic and 50 nM CdSe QDs was found to be genotoxic to the plant. These findings enable to determine the concentrations to be used when practical applications using nanodevices of this type on plants are being considered.


Assuntos
Compostos de Cádmio/toxicidade , Cebolas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pontos Quânticos/toxicidade , Compostos de Selênio/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Ensaio Cometa , Dano ao DNA , Peroxidação de Lipídeos/efeitos dos fármacos , Testes para Micronúcleos , Testes de Mutagenicidade , Cebolas/genética , Cebolas/crescimento & desenvolvimento , Cebolas/metabolismo , Estresse Oxidativo/genética , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo
6.
Mutat Res ; 865: 503334, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33865545

RESUMO

Prednisone (PD) is one of the most commonly used corticosteroids in immunosuppressive therapy for patients with autoimmune diseases and transplants. Chronic use of corticosteroids is associated with several side effects and an increase in neoplasia. Since genotoxic effects are associated with an increased risk of cancer development, this study evaluated the genotoxic and cytotoxic activities of PD using the SMART/wing assay in Drosophila melanogaster and the micronucleus test and comet assay in mouse bone marrow cells. Further, the toxic effects of PD on mouse organ tissues were assessed using histopathological analyses. In the SMART/wing assay, PD showed a significant genotoxic activity at all concentrations tested (0.375, 0.75, 1.5, and 2.0 mg/mL) compared to the negative control (p < 0.05). The micronucleus test and comet assay also showed an elevated genotoxicity of PD at all treatment conditions (24, 48, and 120 h with doses ranging from 0.5 to 1.5 mg/kg) compared to the negative control (p < 0.05). The histopathological analyses did not show toxicity of PD in mouse cells and tissues. Therefore, our results demonstrate that PD is a potent genotoxic immunosuppressant in mice and D. melanogaster cells. Somatic recombination was the primary contributor (46%-82%) to the induced genotoxicity observed in the SMART test.


Assuntos
Dano ao DNA/efeitos dos fármacos , Prednisona/efeitos adversos , Animais , Animais Geneticamente Modificados , Animais não Endogâmicos , Ensaio Cometa , Drosophila melanogaster , Feminino , Masculino , Camundongos , Testes para Micronúcleos , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade
7.
Ann Work Expo Health ; 65(3): 307-318, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33886965

RESUMO

INTRODUCTION: Although useful in the treatment of malignant cells, antineoplastic drugs (ANPDs) as chemical genotoxic agents, can interfere with normal cell physiology causing genetic damage and unfavourable health effects, especially in occupationally exposed persons. The Cytokinesis-block Micronucleus (CBMN) Cytome assay has been widely used in human biomonitoring studies as a reliable biomarker of chemical genotoxic exposure. OBJECTIVES: Our comprehensive research was conducted in order to evaluate micronuclei as a marker for preventive medical screening purposes for persons occupationally exposed to ANPDs. METHODS: Using the CBMN Cytome test, peripheral blood lymphocytes of 201 control and 222 exposed subjects were screened for genetic damage. RESULTS: Age and gender influenced micronucleus (MN) frequency, but smoking habit did not. The mean micronuclei frequencies and other parameters of the CBMN Cytome test [numbers of binuclear lymphocytes with one (MN1) or two (MN2) micronuclei] were significantly higher in the group of exposed persons. Positive correlation between duration of occupational exposure and MN frequency was revealed. CONCLUSIONS: The results of our study performed on a large sample confirmed the capacity of the CBMN Cytome assay to serve as a reliable biomarker of long-term ANPD exposure.


Assuntos
Antineoplásicos , Exposição Ocupacional , Antineoplásicos/efeitos adversos , Citocinese , Hospitais , Humanos , Testes para Micronúcleos , Exposição Ocupacional/efeitos adversos
8.
Anticancer Res ; 41(4): 1849-1858, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813390

RESUMO

BACKGROUND/AIM: Epidemiological studies showed an increased risk of developing laryngeal head and neck squamous cell carcinoma (HNSCC) for employees working in the construction business. This suggested a causal link between exposure to cement particles and development of HNSCC but data were missing. MATERIALS AND METHODS: We established an Organisation for Economic Co-operation and Development (OECD) guideline 487-conform micronucleus assay (MNA) using oropharyngeal mucosa-derived primary epithelial cells (OPCs) ex vivo. OPCs from healthy mucosa of 52 donors were cultured in vitro and incubated with serial concentrations of two common cement particles. Mitomycin C was used as a soluble positive control, and TiO2 and DQ12 were used as negative and positive particle controls. Bi-nucleated cells were counted and the mitotic index (MI) was determined. Subsequently, micronuclei-containing bi-nucleated cells (MN+) were counted. RESULTS: Cement particles, in concentrations not significantly reducing ex vivo proliferation according to mitotic index, dose-dependently increased micronuclei formation. CONCLUSION: Through the establishment of an OECD guideline 487 conform MNA, we demonstrate the mutagenic effects of cement on human OPCs.


Assuntos
Materiais de Construção/toxicidade , Poeira , Células Epiteliais/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Mucosa Bucal/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células Epiteliais/patologia , Feminino , Humanos , Neoplasias Laríngeas/induzido quimicamente , Neoplasias Laríngeas/patologia , Masculino , Testes para Micronúcleos , Mucosa Bucal/patologia , Cultura Primária de Células , Medição de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/induzido quimicamente , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
9.
Ocul Surf ; 20: 195-198, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33677062

RESUMO

PURPOSE: To assess whether the micronucleus cytome assay (MCyt) reliably detects DNA damage occurring in control and pathological superficial epithelial cells from human conjunctiva. METHODS: Impression cytology samples from the bulbar conjunctiva of 33 healthy controls, eight patients with conjunctival intraepithelial neoplasia (CIN) and eight with mucous membrane pemphigoid (MMP) were examined using the MCyt modified for the ocular surface. RESULTS: The mean number of micronuclei (MNi) in control samples was 0.94 MNi/1000 epithelial cells, with no significant difference between conjunctival quadrants and independent of sex and age. The MCyt assay applied to CIN-affected eyes showed a significantly higher frequency of MNi (18.63/1000 cells), apoptotic cells, nuclear enlargement, multinucleated cells, and keratolysis compared with the corresponding unaffected paired eyes and with the control value. Although the mean MNi frequency in MMP eyes was also higher (1.73 MNi/1000 cells), it did not prove to be statistically different from the control samples. On the other hand, the MMP-affected eyes revealed significantly elevated percentages of cells with snake-like chromatin, multinucleated cells, apoptotic cells, and nuclear buds compared with controls. CONCLUSIONS: Micronucleus cytome assay was adapted as a rapid screening test for genomic instability on the ocular surface. We have determined reference levels for MNi and other nuclear alterations on healthy conjunctiva and demonstrated that particularly frequencies of MNi are significantly elevated in conjunctiva affected by CIN. We demonstrate that MNi are more specific than other nuclear abnormalities and thus can be used for screening of ocular surface neoplasia.


Assuntos
Dano ao DNA , Células Epiteliais , Núcleo Celular , Túnica Conjuntiva , Humanos , Testes para Micronúcleos
10.
Biomed Pharmacother ; 137: 111385, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33761606

RESUMO

A large body of evidence suggests that supplementation of butyric acid exerts beneficial intestinal and extra-intestinal effects. Unfortunately, unpleasant sensorial properties and unfavourable physico-chemical properties strongly limit its use in food supplements and foods for medicinal purposes. N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA) is a new butyric acid releaser in solid form with neutral sensorial properties. The aim of this investigation is to provide preliminary information on its pharmacokinetic and toxicological properties through the study of a) in vivo bioavailability of FBA administered by oral gavage to male and female Swiss CD1 mice in comparison with sodium butyrate, b) the influence of digestion on FBA stability through an in vitro simulated oro-gastro-duodenal digestion process, and c) in vitro toxicological profile by means of the Ames Test and Micronucleus Test. The results reveal that FBA is a good butyric acid releaser, being able to increase butyrate serum concentration in a dose and time dependent manner in both male and female mice with a pharmacokinetic profile similar to that obtained from sodium butyrate as such. These data are confirmed by investigating the influence of digestion on FBA, which undergoes extensive hydrolysis following oro-gastro-duodenal digestion, especially in duodenal conditions, with a residual concentration of less than 10% of the initial FBA concentration. Finally, in the Ames and Micronucleus Tests, FBA does not show any in vitro genotoxicity as it is non mutagenic in the Ames Test and results to be unable to induce chromosome breaks in the Micronucleus Test. In conclusion, FBA is a new butyric acid releaser that can overcome the disadvantages of butyric acid while maintaining the same pharmacokinetic properties and safety profile, as shown by the results of the preliminary in vitro toxicological studies performed in this investigation.


Assuntos
Butiratos/farmacologia , Ácido Butírico/metabolismo , Animais , Disponibilidade Biológica , Ácido Butírico/sangue , Quebra Cromossômica/efeitos dos fármacos , Suplementos Nutricionais , Digestão , Relação Dose-Resposta a Droga , Duodeno/metabolismo , Feminino , Mucosa Gástrica/metabolismo , Masculino , Camundongos , Testes para Micronúcleos , Testes de Mutagenicidade
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 255: 119680, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33744838

RESUMO

It is critical to develop new methods to assess genotoxic effects in human biomonitoring since the conventional methods are usually laborious, time-consuming, and expensive. It is aimed to evaluate if the analysis of a drop of serum by Fourier Transform Infrared spectroscopy, allow to assess genotoxic effects in occupational exposure to cytostatic drugs in hospital professionals, as obtained by the lymphocyte cytokinesis-block micronucleus assay. It was considered peripheral blood from hospital professionals exposed to cytostatic drugs (n = 22) and from a non-exposed group (n = 36). It was observed that workers occupationally exposed presented a higher number of micronuclei (p < 0.05) in lymphocytes, in relation to the non-exposed group. The serum Fourier Transform Infrared spectra from exposed workers presented diverse different peaks (p < 0.01) in relation to the non-exposed group. The hierarchical cluster analysis of serum spectra separated serum samples of the exposed group from the non-exposed group with 61% sensitivity and 88% specificity. A support vector machine model of serum spectra enables to predict exposure with high accuracy (0.91), precision (0.89), sensitivity (0.86), F1 score (0.87) and AUC (0.96). Therefore, Fourier Transform Infrared spectroscopic analysis of a drop of serum enabled to predict in a rapid and simple mode the genotoxic effects of cytostatic drugs. The method presents therefore potential for high-dimension screening of exposure of genotoxic substances, due to its simplicity and rapid setup mode.


Assuntos
Dano ao DNA , Exposição Ocupacional , Citocinese , Humanos , Linfócitos , Testes para Micronúcleos , Exposição Ocupacional/efeitos adversos
12.
Mutat Res ; 863-864: 503304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33678241

RESUMO

Presently, over 135 thousand barrels of crude oil are extracted daily from the Al-ahdeb oil fields (situated at 180 km south east of Baghdad, Iraq). Millions of gallons of untreated toxic wastes, gas and crude oil are released into the environment. Oil mining mediated pollution may cause damage to humans and the environment. To investigate potential health risks for children living in this area, we recruited a sample of 6-8 year old school children residing within a 5 km radius around the oil field, and a control sample of children of the same age from a school 40 km away from the oil-field. Exfoliated buccal mucosa cells obtained from these children were analyzed applying the micronucleus (MN) cytome assay. Possible confounding variables such as x-rays performed during three weeks preceding sampling were obtained by a questionnaire. Nuclear anomalies were significantly elevated in children living near the oil-field. Micronucleated cells 1.3-fold, nuclear buds 3-folds, binucleated cells 3-folds, karyorrhetic cells 4-folds and karyolysis more than 10 folds with a significant difference (P < 0.05). Hence, children living in the proximity of Iraqi oil-fields are at elevated risk of genetic damage, which can cause detrimental health effects in the future.


Assuntos
Poluentes Atmosféricos/toxicidade , Núcleo Celular , Dano ao DNA , Mucosa Bucal , Campos de Petróleo e Gás , Criança , Feminino , Humanos , Masculino , Testes para Micronúcleos , Instituições Acadêmicas
13.
Mutat Res ; 863-864: 503311, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33678247

RESUMO

In 2015, the International Agency for Research on Cancer classified the consumption of processed meat as carcinogenic to humans (Group 1) and red meat as probably carcinogenic to humans (Group 2A) based on sufficient data from animal models and epidemiological studies. However, research characterising the mechanisms underlying this carcinogenic process in humans are limited, particularly with respect to measures of direct DNA damage. The current review sought to evaluate and summarize the recent literature, published since 2000, regarding the associations of meat consumption and three biomarkers of genotoxicity in humans: DNA strand breaks (measured using the comet assay), DNA adducts, and micronucleus formation. After screening 230 potential articles, 35 were included, and then were classified as experimental or observational in design, the latter of which were further categorized according to their dietary assessment approach. Among the 30 observational studies, 4 of which used two different assays, 3 of 5 comet assay studies, 13 of 20 DNA adduct studies, and 7 of 9 micronucleus studies reported a positive association between meat consumption and DNA damage. Among the 5 experimental studies, 1 of 1 using the comet assay, 3 of 3 measuring DNA adducts and 0 of 1 measuring micronuclei reported significant positive associations with meat consumption. Nevertheless, common limitations among the selected publications included small sample size, and poor methodological reporting of both exposure and outcome measures. Moreover, the vast majority of studies only measured DNA damage in one biological sample using a single assay and we cannot exclude the possibility of publication bias. Ultimately, our review of the literature, published since 2000, revealed a preponderance of studies that support mechanisms of genotoxicity in playing an important role in the meat-cancer association.


Assuntos
Adutos de DNA , Dano ao DNA , Preferências Alimentares , Carne Vermelha/efeitos adversos , Ensaio Cometa , Humanos , Testes para Micronúcleos
14.
Mutat Res ; 863-864: 503321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33678246

RESUMO

Previous studies showed that the yield of cobalt-60 γ-rays-induced nucleoplasmic bridges (NPB) in human peripheral blood lymphocytes is dose dependent. However, the influence of the radiation quality and dose rates on NPB frequencies has not been investigated. The present study aimed to investigate NPB frequencies in human peripheral blood lymphocytes induced by carbon ions and explore the dose rate effect on cobalt-60 γ-rays-induced NPB. To establish dose-response curves, human peripheral blood samples were irradiated with 0, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0 and 8.0 Gy of carbon ions at a dose rate of 3.0 Gy/min in vitro. To explore the dose rate effect, human peripheral blood samples were irradiated with 2.0 and 5.0 Gy of cobalt-60 γ-rays at dose rates of 0.2, 0.5, 1.0, 3.0, 5.0 and 10.0 Gy/min in vitro. NPB and micronuclei (MN) in binucleated cells were analyzed with the cytokinesis-block micronucleus cytome assay. Results showed that the dose-response curve of carbon ion-induced NPB frequencies follow a linear-quadratic model (R2 = 0.934). The relative biological effectiveness (RBE) values of carbon ions to cobalt-60 γ-rays decreased with increased NPB frequencies (ranging from 2.47 to 5.86). Compared with group 1.0 Gy/min, the NPB frequencies in groups 10.0 Gy/min (2.0 Gy), 5.0 and 10.0 Gy/min (5.0 Gy) were decreased significantly (P < 0.05). Carbon ion-induced NPB in human peripheral blood lymphocytes have a good dose-response relationship. Cobalt-60 γ-rays-induced NPB frequencies are affected by the specific dose rate.


Assuntos
Radioisótopos de Cobalto , Dano ao DNA , Raios gama/efeitos adversos , Linfócitos/metabolismo , Adulto , Relação Dose-Resposta à Radiação , Humanos , Linfócitos/patologia , Masculino , Testes para Micronúcleos
15.
Toxicon ; 195: 20-23, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33689791

RESUMO

3-nitropropionic acid (3-NP) is a toxin that causes neural damage in the striatum and can lead to the development of Huntington's disease manifestations in animal models. Several studies have shown genotoxicity related to the 3-NP treatment. This study investigated potential genotoxicity and mutagenicity that was induced by a low dose (6.25 mg/kg i. p.) 3-NP subacute treatment (daily, over 6 days) in a rat model. The arterial blood and the frontal cortex were analyzed by the comet assay and the bone marrow by micronucleus. Surprisingly, the 3-NP subacute treatment with the low dose did not show genotoxic or mutagenic effects.


Assuntos
Dano ao DNA , Mutagênicos , Nitrocompostos/toxicidade , Propionatos/toxicidade , Animais , Ensaio Cometa , Relação Dose-Resposta a Droga , Testes para Micronúcleos , Testes de Mutagenicidade , Mutagênicos/toxicidade , Ratos
16.
BMC Cancer ; 21(1): 219, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663399

RESUMO

BACKGROUND: The question whether lymphocyte radiosensitivity is representative of patients' response to radiotherapy (RT) remains unsolved. We analyzed lymphocyte cytogenetic damage in patients who were homogeneously treated with preoperative radiochemotherapy (RCT) for rectal cancer within clinical trials. We tested for interindividual variation and consistent radiosensitivity after in-vivo and in-vitro irradiation, analyzed the effect of patients' and RCT characteristics on cytogenetic damage, and tested for correlations with patients' outcome in terms of tumor response, survival and treatment-related toxicity. METHODS: The cytokinesis-block micronucleus cytome (CBMNcyt) assay was performed on the peripheral blood lymphocytes (PBLCs) of 134 patients obtained before, during, at the end of RCT, and during the 2-year follow-up. A subset of PBLCs obtained before RCT was irradiated in-vitro with 3 Gy. RCT included 50.4 Gy of pelvic RT with 5-fluorouracil (5-FU) alone (n = 78) or 5-FU plus oxaliplatin (n = 56). The analyzed variables included patients' age, gender, RT characteristics (planning target volume size [PTV size], RT technique), and chemotherapy characteristics (5-FU plasma levels, addition of oxaliplatin). Outcome was analyzed as tumor regression, patient survival, and acute and late toxicity. RESULTS: Cytogenetic damage increased significantly with the radiation dose and varied substantially between individuals. Women were more sensitive than men; no significant age-dependent differences were observed. There was a significant correlation between the cytogenetic damage after in-vitro irradiation and in-vivo RCT. We found a significant effect of the PTV size on the yields of cytogenetic damage after RCT, while the RT technique had no effect. Neither the addition of oxaliplatin nor the 5-FU levels influenced cytogenetic damage. We found no correlation between patient outcome and the cytogenetic damage. CONCLUSIONS: We found consistent cytogenetic damage in lymphocytes after in-vivo RCT and in-vitro irradiation. Gender was confirmed as a well-known, and the PTV size was identified as a less well-known influencing variable on lymphocyte cytogenetic damage after partial-body irradiation. A consistent level of cytogenetic damage after in-vivo and in-vitro irradiation may indicate the importance of genetic factors for individual radiosensitivity. However, we found no evidence that in-vivo or in-vitro irradiation-induced cytogenetic damage is an adequate biomarker for the response to RCT in rectal cancer patients.


Assuntos
Quimiorradioterapia/métodos , Micronúcleos com Defeito Cromossômico , Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Neoplasias Retais/genética , Neoplasias Retais/mortalidade
17.
Toxins (Basel) ; 13(2)2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540511

RESUMO

In the last decade, it has become evident that complex mixtures of cyanobacterial bioactive substances, simultaneously present in blooms, often exert adverse effects that are different from those of pure cyanotoxins, and awareness has been raised on the importance of studying complex mixtures and chemical interactions. We aimed to investigate cytotoxic and genotoxic effects of complex extracts from laboratory cultures of cyanobacterial species from different orders (Cylindrospermopsis raciborskii, Aphanizomenon gracile, Microcystis aeruginosa, M. viridis, M. ichtyoblabe, Planktothrix agardhii, Limnothrix redekei) and algae (Desmodesmus quadricauda), and examine possible relationships between the observed effects and toxin and retinoic acid (RA) content in the extracts. The cytotoxic and genotoxic effects of the extracts were studied in the human hepatocellular carcinoma HepG2 cell line, using the MTT assay, and the comet and cytokinesis-block micronucleus (cytome) assays, respectively. Liquid chromatography electrospray ionization mass spectrometry (LC/ESI-MS) was used to detect toxins (microcystins (MC-LR, MC-RR, MC-YR) and cylindrospermopsin) and RAs (ATRA and 9cis-RA) in the extracts. Six out of eight extracts were cytotoxic (0.04-2 mgDM/mL), and five induced DNA strand breaks at non-cytotoxic concentrations (0.2-2 mgDM/mL). The extracts with genotoxic activity also had the highest content of RAs and there was a linear association between RA content and genotoxicity, indicating their possible involvement; however further research is needed to identify and confirm the compounds involved and to elucidate possible genotoxic effects of RAs.


Assuntos
Alcaloides/toxicidade , Clorófitas/metabolismo , Cianobactérias/metabolismo , Dano ao DNA , Microcistinas/toxicidade , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Tretinoína/toxicidade , Alcaloides/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Ensaio Cometa , Células Hep G2 , Humanos , Microcistinas/isolamento & purificação , Testes para Micronúcleos , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Tretinoína/isolamento & purificação
18.
Ecotoxicol Environ Saf ; 212: 111935, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33578128

RESUMO

During the welding activities many compounds are released, several of these cause oxidative stress and inflammation and some are considered carcinogenic, in fact the International Agency for Research on Cancer established that welding fumes are carcinogenic to humans. The aim of the present study was to analyze the cytotoxic and genotoxic potential of exposure to welding fumes and to determine concentrations of metals in blood and urine of occupationally exposed workers. We included 98 welders and 100 non-exposed individuals. Our results show significant increase in the frequency of micronuclei (MN), nucleoplasmic bridges (NPB), nuclear buds (NBUD) and necrotic cells (NECR) in cytokinesis-block micronucleus cytome (CBMN-Cyt) assay, as well as in the telomere length (TL) of the exposed individuals with respect to the non-exposed group. In the analysis of the concentrations of inorganic elements using PIXE method, were found higher concentrations of Cr, Fe and Cu in the urine, and Cr, Fe, Mg, Al, S, and Mn in the blood in the exposed group compared to the non-exposed group. A significant correlation was observed between MN and age and between NPB and years of exposure. Additionally, we found a significant correlation for TL in relation to MN, NPB, age and years of exposure in the exposed group. Interestingly, a significant correlation between MN and the increase in the concentration of Mg, S, Fe and Cu in blood samples of the exposed group, and between MN and Cr, Fe, Ni and Cu in urine. Thus, our findings may be associated with oxidative and inflammatory damage processes generated by the components contained in welding fumes, suggesting a high occupational risk in welding workers.


Assuntos
Poluentes Ocupacionais do Ar/análise , Bioensaio , Testes para Micronúcleos/métodos , Exposição Ocupacional/análise , Telômero , Biomarcadores/análise , Citocinese , Dano ao DNA , Humanos , Linfócitos , Estresse Oxidativo , Soldagem
19.
Environ Int ; 151: 106448, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33618327

RESUMO

BACKGROUND: Lead (Pb) is known to induce detrimental health effects in exposed populations, including hematotoxicity and genotoxicity. Complete blood count (CBC) is a cost-effective and easy way to determine toxicity, and variations in proportion of different types of leukocytes: neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) are further evidence of hematotoxicity. However, few studies have been conducted to systematically evaluate effects of occupational Pb exposure on NLR and LMR, and their associations with genotoxicity. OBJECTIVES: Our study was aimed to systematically assess the effects of current occupational Pb exposure on NLR and LMR, and their associations with genotoxicity. METHODS: Our investigation was performed on 1176 workers from a newly built battery factory in North China. The workers had just entered their current job position in recent years and most of them had no previous history of occupational exposure to Pb. Blood lead levels (BLLs) and leukocytes indices were detected for all participants. Cytokinesis-blocked micronucleus assay (MN; n = 675) and alkaline comet assay (% tail DNA; n = 869) were used to assess genotoxicity. Multivariate linear and Poisson regression analyses were conducted to examine associations between leukocytes indices, genotoxic biomarkers and BLLs with adjustment for covariates. Spearman correlation and mediation analyses were used to investigate relationships between NLR and genotoxicity. RESULTS: Among all the exposed workers, NLR increased with increasing BLLs. However, WBC and LMR did not change significantly. Significant and dose-dependent increases in both MN frequencies and % tail DNA were observed among groups with different exposure doses. Compared with the normal NLR group (1.48 ≤ NLR < 4.58), the high NLR group (NLR ≥ 4.58) had higher % tail DNA. In addition, there was a significant and positive association between NLR and % tail DNA among all the workers, and % tail DNA mediated 15% of the effect of Pb on increasing NLR. CONCLUSION: Our large-scale population study shows that Pb exposure increased NLR and induced genotoxicity. There was an association between elevated NLR and DNA damage. In addition, the mediation effect of % tail DNA on the relationship between BLLs and NLR provided mechanistic evidence that certain mechanisms, e.g. inflammation, may be involved in elevation of NLR from Pb exposure. Therefore, NLR may be a convenient and sensitive biomarker for indication of Pb toxicity. Further studies are needed to validate the proposed mechanism and NLR as a biomarker.


Assuntos
Chumbo , Exposição Ocupacional , China , Dano ao DNA , Humanos , Chumbo/toxicidade , Linfócitos , Testes para Micronúcleos , Neutrófilos , Exposição Ocupacional/efeitos adversos
20.
Mutat Res ; 861-862: 503294, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33551097

RESUMO

The pharmacological potential of drugs must be evaluated to establish their potential therapeutic benefits and side effects. This evaluation includes assessment of the effects of hepatic enzymes that catalyse their metabolic activation. Previously, our research group synthesized and characterized a set of synthetic 3-alkyl pyridine alkaloid (3-APA) analogues that cause in vitro cytotoxic, genotoxic, and mutagenic effects in various human cancer cell lines. The present study aimed to evaluate these activities with the two most promising synthetic 3-APAs (3-APA 1 and 3-APA 2) against cell lines derived from breast cancer (MDA-MB-231), ovarian cancer (TOV-21 G) and lung fibroblasts (WI-26-VA4) with and without metabolic activation (S9 fraction). The cytotoxicity of the compounds was evaluated employing MTT and clonogenic assays. In addition, comet assays, γH2AX immunocytochemistry labelling assays and cytokinesis-block micronucleus tests were carried out to evaluate the potential of these compounds to induce chromosomal damage. The results obtained in the MTT assay showed that compound 3-APA 2 exhibited high selectivity index (SI) values (ranging between 21.0 and 92.6). In addition, the cytotoxicity of the compounds was clearly enhanced by metabolic activation. Moreover, both compounds were genotoxic and induced double-strand breaks in DNA and chromosomal lesions with and without S9. The cancer cell lines tested showed higher genotoxic sensitivity to the compounds than did the non-tumour cell line used as a reference. The genotoxic and mutagenic effects of the compounds were potentiated in experiments with metabolic activation. The data obtained in this study indicate that compound 3-APA 2 is more active against the human cancer cell lines tested, both with and without metabolic activation, and can therefore be considered a candidate drug to treat human ovarian and breast cancer.


Assuntos
Ativação Metabólica , Alcaloides/farmacologia , Antineoplásicos/farmacologia , Citocinese/efeitos dos fármacos , Dano ao DNA , Mutagênicos/farmacologia , Neoplasias/patologia , Ensaio Cometa , Humanos , Testes para Micronúcleos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Células Tumorais Cultivadas
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