Assuntos
Detergentes/toxicidade , Hidróxidos/toxicidade , Doenças Labiais/induzido quimicamente , Doenças da Boca/induzido quimicamente , Úlceras Orais/induzido quimicamente , Compostos de Potássio/toxicidade , Doenças da Língua/induzido quimicamente , Adulto , Humanos , Masculino , Ilustração MédicaRESUMO
One of the major mechanisms of heavy metal toxicity is the induction of oxidative stress. Redox-active heavy metals, like chromium, can induce it directly, whereas redox-inactive metals, like cadmium, play an indirect role in the generation of reactive oxygen species (ROS). Living organisms defend themselves against oxidative stress taking advantage of low-molecular-weight antioxidants and ROS-detoxifying enzymes. Tocopherols and plastoquinol are important plastid prenyllipid antioxidants, playing a role during acclimation of Chlamydomonas reinhardtii to heavy metal-induced stress. However, partial inhibition of synthesis of these prenyllipids by pyrazolate did not decrease the tolerance of C. reinhardtii to Cr- and Cd-induced stress, suggesting redundancy between antioxidant mechanisms. To verify this hypothesis we have performed comparative analyses of growth, photosynthetic pigments, low-molecular-weight antioxidants (tocopherols, plastoquinol, plastochromanol, ascorbate, soluble thiols, proline), activities of the ascorbate peroxidase (APX), catalase and superoxide dismutase (SOD) and cumulative superoxide production in C. reinhardtii exposed to Cd2+ and Cr2O72- ions in the presence or absence of pyrazolate. The decreased α-tocopherol and plastoquinol content resulted in the increase in superoxide generation and APX activity in pyrazolate-treated algae. The application of heavy metal ions and pyrazolate had a pronounced impact on Asc and total thiol content, as well as SOD and APX activities (the latter only in Cd-exposed cultures), when compared with algae grown in the presence of heavy metal ions or pyrazolate alone. The superoxide production in cultures exposed to heavy metal ions and pyrazolate decreased when compared to the cultures exposed to either heavy metal ions or an inhibitor alone.
Assuntos
Antioxidantes/metabolismo , Cloreto de Cádmio/toxicidade , Cromatos/toxicidade , Plastoquinona/análogos & derivados , Compostos de Potássio/toxicidade , Tocoferóis/metabolismo , Chlamydomonas reinhardtii/metabolismo , Relação Dose-Resposta a Droga , Íons , Estresse Oxidativo/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Plastoquinona/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
The aim of this study was to investigate the effect of the cell differentiation status on the sensitivity to genotoxic insults. For this, we utilized the comet assay to test the DNA damage after treatment with 5 different substances with different mechanism of action in human promyelocytic HL60 cells with or without cell differentiation. A 4-hour MMS treatment induced a significant and concentration-dependent increase in DNA damage for both differentiated and undifferentiated cells, but the difference in sensitivity was only significant at the highest concentration. A 4-hour doxorubicin treatment did not induce DNA damage in differentiated HL60 cells, while it did in undifferentiated cells with its highest tested concentration. A one-hour etoposide treatment caused significant increase in DNA damage concentration dependently in both cell variants. This DNA damage was significantly higher in undifferentiated HL60 cells with several tested concentrations of etoposide. The treatment with the oxidizing substances hydrogen peroxide and potassium bromate yielded significant DNA damage induction in both undifferentiated and differentiated cells with no difference according to the differentiation status. Doxorubicin and etoposide are known to inhibit topoisomerase II. The activity of this enzyme has been shown to be higher in undifferentiated actively proliferating cells than in differentiated cells. This may be of relevance when exposures to topoisomerase-inhibiting compounds or the genotoxicity of compounds with unknown mechanism of action are assessed in routine testing.
Assuntos
Ensaio Cometa , Células HL-60/efeitos dos fármacos , Mutagênicos/toxicidade , Brometos/toxicidade , Diferenciação Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/ultraestrutura , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , DNA Topoisomerases Tipo II , DNA de Neoplasias/efeitos dos fármacos , Dimetil Sulfóxido/farmacologia , Doxorrubicina/toxicidade , Resistência a Medicamentos , Etoposídeo/toxicidade , Células HL-60/citologia , Humanos , Peróxido de Hidrogênio/toxicidade , Metanossulfonato de Metila/toxicidade , Proteínas de Neoplasias/antagonistas & inibidores , Estresse Oxidativo , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Compostos de Potássio/toxicidade , Inibidores da Topoisomerase II/toxicidadeRESUMO
Hexavalent chromium [Cr(VI)] compounds that are generated during industrial processes are widely recognized as highly toxic and carcinogenic. It has been reported that exposure to Cr(VI) can produce some chromium intermediates and reactive oxygen species (ROS), which causes DNA damages, genetic instability, and eventually leads to the elevated risk of various diseases including cancers. In recent years, it has been proposed that epigenetic-based mechanisms may involve in the toxic heavy metals-induced cytotoxicity and mutagenicity besides the genetic-based mechanisms. However, whether Cr(VI) could impose its cytotoxic effect through dysregulating the RNA epigenetic modifications remains poorly defined. We systematically investigated the effects of Cr(VI) exposure on 14 kinds of modifications in mRNA of HEK293T cells. We found that Cr(VI) exposure can induce an obvious decrease of inosine in mRNA. In addition, we observed that the expression level of the adenosine deaminase acting on RNA (ADAR1) was significantly decreased upon Cr(VI) exposure, which could be responsible for the induced decrease of inosine in mRNA by Cr(VI) exposure. Together, we demonstrated that Cr(VI) could interrupt A-to-I RNA editing in mRNA, which may eventually lead to the cytotoxicity and mutagenicity.
Assuntos
Cromatos/toxicidade , Compostos de Potássio/toxicidade , RNA Mensageiro/química , RNA Mensageiro/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Células HEK293 , Humanos , RNA Mensageiro/isolamento & purificação , RNA Mensageiro/metabolismo , Espectrometria de Massas em TandemRESUMO
PURPOSE: To determine whether Toll-like receptor 4 knockout protects mice from corneal neovascularization following chemical injury compared to wild-type (WT) mice. METHODS: A chemical burn (75% silver nitrate, 25% potassium nitrate) was created under anesthesia in the central right cornea of 32 WT and 31 Toll-like receptor 4 knockout mice. Corneal neovascularization was evaluated at 3, 4, 6, 8, 10, and 35 days after injury using digital photography, fluorescein angiography, gelatin perfusion with fluorescence vascular imaging, immunofluorescence staining, and molecular analysis. RESULTS: There was no significant between-group difference in relative corneal burn area at 10 days after injury (39.0 ± 2.4% vs. 38.8 ± 9.8%, respectively). Neovascularization was detected in all corneas in vivo and perfusion was detected by fluorescence vascular imaging, reaching maximum area on day 10. The relative area of neovascularization was significantly smaller in the knockout than the WT mice on days 6 (33.3 ± 4.2% vs. 46.8 ± 7.4%, respectively, p = 0.005) and 8 (36.6 ± 1.1% vs. 52.2 ± 6.4%, respectively, p = 0.027), although neovascularization was intensive in both groups. In line with the immunostaining findings of angiogenesis and inflammatory infiltration of damaged corneas, molecular analysis (performed on day 3) revealed elevated expression levels of angiogenesis-related genes (vascular endothelial growth factor, VEGFR2, VEGFR1) and inflammation-related genes (CD45 and TGFß1) in the WT mice. The knockout mice had higher TNF-α expression than the WT mice. CONCLUSION: In a mouse corneal chemical burn model, lack of Toll-like receptor 4 expression did not completely inhibit angiogenesis, but did have a relative effect to reduce neovascularization as compared to the WT.
Assuntos
Queimaduras Químicas/prevenção & controle , Neovascularização da Córnea/prevenção & controle , Modelos Animais de Doenças , Queimaduras Oculares/induzido quimicamente , Regulação da Expressão Gênica/fisiologia , Receptor 4 Toll-Like/genética , Animais , Queimaduras Químicas/etiologia , Queimaduras Químicas/metabolismo , Córnea/irrigação sanguínea , Neovascularização da Córnea/etiologia , Neovascularização da Córnea/metabolismo , Combinação de Medicamentos , Angiofluoresceinografia , Técnica Indireta de Fluorescência para Anticorpo , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitratos/toxicidade , Fotografação , Compostos de Potássio/toxicidade , Reação em Cadeia da Polimerase em Tempo Real , Nitrato de Prata/toxicidade , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
AIM: The aim of the present study was to evaluate the genotoxicity of non-alcoholic mouth rinses on buccal epithelial cells using a micronucleus test. METHODS: A total of 105 patients were selected and randomly divided into five groups. Four different mouth rinses and normal saline were given for 2 weeks' duration, and cytological smears were collected before and after exposure. These smears were subjected to micronucleus (MN) and other nuclear abnormalities (ONA) tests using acridine orange stain, and their frequencies were obtained in 500 buccal epithelial cells. The statistical analysis included mean, χ2 -test, analysis of variance, and post-hoc analysis by Bonferroni test. RESULTS: Micronucleated cells (P < .00) and MN (P < .00) were higher in individuals exposed to chlorhexidine (CHX), followed by chlorine dioxide (ClO2 ), potassium nitrate (KNO3 ), and sodium fluoride (NaF), amine fluoride (AmF), and normal saline. ONA were greater (P < .00) in individuals exposed to CHX, followed by ClO2 , AmF, KNO3 , and NaF and normal saline. Overall, the results showed that genotoxic damage was greater in the case of CHX, followed by ClO2 , KNO3 , and NaF, AmF, and normal saline. CONCLUSION: Chronic exposure to mouth rinses can cause genotoxic damage to buccal epithelial cells. Long-term injudicious and inadvertent use of mouth rinses should be discouraged.
Assuntos
Células Epiteliais/efeitos dos fármacos , Testes para Micronúcleos , Mucosa Bucal/efeitos dos fármacos , Antissépticos Bucais/toxicidade , Adulto , Anti-Infecciosos Locais/toxicidade , Clorexidina/toxicidade , Compostos Clorados/toxicidade , Feminino , Fluoretos Tópicos/toxicidade , Humanos , Índia , Masculino , Microscopia de Fluorescência , Mucosa Bucal/citologia , Antissépticos Bucais/química , Nitratos/toxicidade , Óxidos/toxicidade , Compostos de Potássio/toxicidade , Fluoreto de Sódio/toxicidadeRESUMO
This study investigated the potential toxic effects of environmentally relevant nitrate concentrations on development, growth, and mortality of early life stages of common hour-glass tree frog, Polypedates cruciger. Tadpoles from hatchlings through pre-adult were exposed to environmentally relevant nitrate concentrations detected in Mirissa, Sri Lanka. Newly hatched, external gill stage, and internal gill stage tadpoles were exposed to potassium nitrate for bioassay tests. No behavioral changes or abnormalities were observed in control and nitrate-induced group. However, detected environmental nitrate concentration significantly increased (p < 0.05) the growth of the tadpoles up to 25 days old. Results revealed that newly hatched and external gill stage was more susceptible to the nitrate pollution than internal gill stage. The results suggest that environmentally relevant nitrate can cause mortality on the amphibian population in ecosystems associated with agro-pastoral activities through altering the growth and direct toxicological effects on the survivorship.
Assuntos
Anuros/fisiologia , Larva/efeitos dos fármacos , Nitratos/toxicidade , Compostos de Potássio/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Poluição Ambiental , Brânquias , Testes de Toxicidade AgudaRESUMO
Potassium nitrate (E252) is widely used as a food preservative and has applications in the treatment of high blood pressure however high doses are carcinogenic. Larvae of Galleria mellonella were administered potassium nitrate to establish whether the acute effects in larvae correlated with those evident in mammals. Intra-haemocoel injection of potassium nitrate resulted in a significant increase in the density of circulating haemocytes and a small change in the relative proportions of haemocytes but haemocytes showed a reduced fungicidal ability. Potassium nitrate administration resulted in increased superoxide dismutase activity and in the abundance of a range of proteins associated with mitochondrial function (e.g. mitochondrial aldehyde dehydrogenase, putative mitochondrial Mn superoxide dismutase), metabolism (e.g. triosephosphate isomerase, glyceraldehyde 3 phosphate dehydrogenase) and nitrate metabolism (e.g. aliphatic nitrilase, glutathione S-transferase). A strong correlation exists between the toxicity of a range of food preservatives when tested in G. mellonella larvae and rats. In this work a correlation between the effect of potassium nitrate in larvae and mammals is shown and opens the way to the utilization of insects for studying the in vivo acute and chronic toxicity of xenobiotics.
Assuntos
Hemócitos/efeitos dos fármacos , Proteínas de Insetos/metabolismo , Mariposas/metabolismo , Nitratos/farmacologia , Compostos de Potássio/farmacologia , Proteoma/metabolismo , Aldeído Desidrogenase/metabolismo , Aminoidrolases/metabolismo , Animais , Catalase/metabolismo , Glutationa Transferase/metabolismo , Gliceraldeído 3-Fosfato Desidrogenase (NADP+)/metabolismo , Hemócitos/metabolismo , Larva/efeitos dos fármacos , Larva/metabolismo , Proteínas Mitocondriais/metabolismo , Nitratos/metabolismo , Nitratos/toxicidade , Oxirredução/efeitos dos fármacos , Compostos de Potássio/toxicidade , Proteômica , Superóxido Dismutase/metabolismo , Testes de Toxicidade Aguda/métodos , Triose-Fosfato Isomerase/metabolismoRESUMO
Hexavalent chromium reportedly induces reproductive toxicity and further inhibits male fertility in mammals. In this study, we investigated the molecular mechanism by which hexavalent chromium affects motility signaling in boar spermatozoa in vitro. The results indicated that Cr(VI) decreased sperm motility, protein phosphorylation, mitochondrial membrane potential (ΔΨm) and metabolic enzyme activity starting at 4µmol/mL following incubation for 1.5h. Notably, all parameters were potently inhibited by 10µmol/mL Cr, while supplementation with the dibutyryl-cAMP (dbcAMP) and the 3-isobutyl-1-methylxanthine (IBMX) prevented the inhibition of protein phosphorylation. Interestingly, high concentrations of Cr (>10µmol/mL) increased the tyrosine phosphorylation of some high-molecular-weight proteins in the principle piece but decreased that in the middle piece associated with an extreme reduction of sperm motility. These results suggest that chromium affects boar sperm motility by impairing tyrosine phosphorylation in the midpiece of sperm by blocking the cAMP/PKA pathway in boar sperm in vitro.
Assuntos
Cromatos/toxicidade , Cromo/toxicidade , Poluentes Ambientais/toxicidade , Compostos de Potássio/toxicidade , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Peça Intermédia do Espermatozoide/efeitos dos fármacos , Motilidade dos Espermatozoides/efeitos dos fármacos , Animais , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Peça Intermédia do Espermatozoide/metabolismo , Peça Intermédia do Espermatozoide/patologia , Suínos , TirosinaRESUMO
Hexavalent chromium is a human respiratory carcinogen that undergoes intracellular activation in vivo primarily via reduction with ascorbate. Replication of Cr-adducted DNA triggers mismatch repair that generates toxic DNA double-strand breaks (DSBs) as secondary lesions. Here, we examined the intranuclear distribution of chromate-induced breaks and a central DSB signaling branch targeting histone H2AX. Using ascorbate-restored cells (H460 human lung epithelial cells, normal human lung and normal mouse embryonic fibroblasts (MEFs)), we found that Cr(VI) produced a typical DSB-associated spectrum of H2AX modifications, including its Ser139-phosphorylated (known as γH2AX) and mono- and diubiquitinated forms. However, whereas canonical DSB signaling relies on ATM, the formation of γH2AX and its ubiquitinated products by Cr(VI) was dependent on ATR kinase. Based on the established mode of ATR activation, this suggests that Cr-induced DSB are not blunt-ended and likely contain single-stranded tails. Confocal imaging with markers of active and inactive chromatin revealed a selective formation of Cr-induced DSB in euchromatin of mouse and human cells. In contrast to DSB, Cr-DNA adducts were produced in both types of chromatin. The euchromatin targeting of Cr-induced DSB makes these lesions particularly dangerous by increasing the probability of deleting active tumor suppressors and producing oncogenic translocations. Accumulation of transcription-inhibiting ubiquitinated forms of γH2AX in euchromatin is expected to contribute to the ability of Cr(VI) to suppress upregulation of inducible genes.
Assuntos
Núcleo Celular/efeitos dos fármacos , Cromatos/toxicidade , Cromo/toxicidade , Quebras de DNA de Cadeia Dupla , Eucromatina/efeitos dos fármacos , Histonas/metabolismo , Compostos de Potássio/toxicidade , Animais , Ácido Ascórbico/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/enzimologia , Núcleo Celular/patologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eucromatina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Microscopia Confocal , Oxirredução , Fosforilação , Transdução de Sinais/efeitos dos fármacos , UbiquitinaçãoRESUMO
Repeated intraperitoneal injections of nickel and chromium (VI) into rats appeared to demonstrate that the combined subchronic toxicity can be additive or vary (mostly to subadditivity) in accordance with effect on which they are evaluated. With moderate general toxic effects, the studied combination has marked genotoxicity with additive effect. The studies demonstrated reciprocal influence of nickel and chromium on accumulation of the second metal in some organs (especially, in spleen), but not on its renal excretion.
Assuntos
Cromatos/farmacocinética , Cromatos/toxicidade , Níquel/farmacocinética , Níquel/toxicidade , Compostos de Potássio/farmacocinética , Compostos de Potássio/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Cromatos/sangue , Cromatos/urina , Fragmentação do DNA/efeitos dos fármacos , Sinergismo Farmacológico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Níquel/sangue , Níquel/urina , Especificidade de Órgãos , Compostos de Potássio/sangue , Compostos de Potássio/urina , Ratos , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Testes de Toxicidade SubcrônicaRESUMO
Chromium is a potent human mutagen and carcinogen. The capability of chromium to cause cancers has been known for more than a century, and numerous epidemiological studies have been performed to determine its carcinogenicity. In the post-genome era, cancer has been found to relate to epigenetic mutations. However, very few researches have focused on hexavalent chromium (Cr(VI))-induced epigenetic alterations. The present study was designed to investigate whether Cr(VI) would affect the level of a newfound epigenetic modification: histone biotinylation. Histone acetylation and histone biotinylation were studied in detail using human bronchial epithelial (16HBE) cells as an in vitro model after Cr(VI) treatment. Our study showed that Cr(VI) treatment decreased histone acetylation level in 16HBE cells. In addition, low doses of Cr(VI) (≤0.6µM) elevated the level of histone biotinylation. Furthermore, immunoblot analysis of biotinidase (BTD), a major protein which maintains homeostasis of histone biotinylation, showed that the distribution of BTD became less even and more concentrated at the nuclear periphery in cells exposed to Cr(VI). Moreover, Cr(VI)-induced histone deacetylation may take part in the regulation of histone biotinylation. Together, our study provides new insight into the mechanisms of Cr(VI)-induced epigenetic regulation that may contribute to the chemoprevention of Cr(VI)-induced cancers and may have important implications for epigenetic therapy.
Assuntos
Brônquios/efeitos dos fármacos , Cromatos/toxicidade , Cromo/toxicidade , Epigênese Genética/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Histonas/metabolismo , Compostos de Potássio/toxicidade , Acetilação , Biotinidase/metabolismo , Biotinilação , Brônquios/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Humanos , Fatores de TempoRESUMO
Our previous epidemiological study revealed that co-exposure of [Cr(VI)] with small amount of heavy metals could induce peripheral blood element imbalance, but little was known about the contribution of Cr(VI) itself and the multi-element distribution profile in other target tissues. We explored element homeostasis in the blood, RBC, serum and lung after Cr(VI) exposure and Zn intervention. 60 Sprague-Dawley male rats received intratracheal instillation of Cr(VI) (0, 0.063, 0.630mgCr/kg) weekly and/or intragastric administration of zinc sulfate (0, 10mgZn/kg) daily for one month. Element contents and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations were determined. Dose-response relationship was observed among rats exposed to Cr(VI). Ca, Mg, Mn in the blood, Fe, Mg, Se in the serum, and Mg and Zn in lung tissue decreased significantly, while Ca, Co, Cr, Mg, Mn, Se in RBC, and Ca, Co, Mo in the lung increased after Cr(VI) exposure. The alteration trends manifested differently, with RBC the most sensitive. Cr induced increase of urinary 8-OHdG, which decreased after Zn intervention. Zn intervention could help to restore element homeostasis after Cr(VI) exposure, especially for Ca, Fe, Mg and Se.
Assuntos
Antioxidantes/farmacologia , Carcinógenos/toxicidade , Cromatos/toxicidade , Cromo/toxicidade , Eritrócitos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Compostos de Potássio/toxicidade , Oligoelementos/metabolismo , Sulfato de Zinco/farmacologia , 8-Hidroxi-2'-Desoxiguanosina , Administração por Inalação , Administração Oral , Animais , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Biomarcadores/sangue , Biomarcadores/urina , Carcinógenos/administração & dosagem , Carcinógenos/metabolismo , Cromatos/administração & dosagem , Cromatos/metabolismo , Cromo/administração & dosagem , Cromo/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/urina , Relação Dose-Resposta a Droga , Esquema de Medicação , Eritrócitos/metabolismo , Pulmão/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Compostos de Potássio/administração & dosagem , Compostos de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Distribuição Tecidual , Oligoelementos/sangue , Sulfato de Zinco/administração & dosagem , Sulfato de Zinco/metabolismoRESUMO
INTRODUCTION: A study was conducted on histological patterns and biomolecular changes in Goitrogen-induced experimental rat thyroid tumors. The link between the histological types observed and N-ras, B-raf, and PI3KCA gene mutations widely reported in human thyroid cancers was explored. MATERIAL AND METHODS: An analysis was done on paraffin-embedded tumor tissue sections from Wistar rats receiving 1% potassium perchlorate (KClO(4)) added to the ad libitum drinking-water supply over an 18-month period. Three experimental subgroups were formed, each comprising 10 thyroids: subgroup I (control) consisted of thyroids from untreated controls; subgroups II and III (experimental) consisted of thyroids from KClO(4)-treated rats, displaying capsular, vascular, or both invasion but no metastasis (II), or distant metastasis (III). DNA was extracted from paraffin-embedded tissues. To test for the genetic mutations most widely reported in human thyroid cancers, exon 1 of the N-ras gene, exons 9 and 20 of the PI3KCA gene, and exon 15 of the B-raf gene were amplified and sequenced. RESULTS: All tumors were of the follicular type. None of the 20 experimental rat thyroids displayed the expected gene mutations reported in humans. However, 90% of them contained four new B-raf gene mutations and all were silent and did not cause an amino acid substitution in the protein chain. CONCLUSIONS: Biomolecular analysis suggested that N-ras, PI3KCA, and B-raf gene mutations may not be involved in thyroid tumor formation using the experimental procedure applied in this study. But the four mutations in B-raf, though without functional repercussions, may be a specific marker for this tumor type.
Assuntos
Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patologia , Transdução de Sinais/genética , Neoplasias da Glândula Tireoide/genética , Adenocarcinoma Folicular/induzido quimicamente , Animais , Sequência de Bases , Éxons , Feminino , Genes ras , Humanos , Dados de Sequência Molecular , Mutação , Percloratos/toxicidade , Compostos de Potássio/toxicidade , Proteínas Proto-Oncogênicas B-raf/genética , Ratos , Ratos Wistar , Análise de Sequência de DNA , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/induzido quimicamente , Neoplasias da Glândula Tireoide/patologiaRESUMO
The increasing pollution of aquatic habitats with anthropogenic compounds has led to various test strategies to detect hazardous chemicals. However, information on effects of pollutants in the thyroid system in fish, which is essential for growth, development and parts of reproduction, is still scarce. Other vertebrate groups such as amphibians or mammals are well-studied; so the need for further knowledge especially in fish as a favored vertebrate model test organism is evident. Modified early life-stage tests were carried out with zebrafish exposed to the known thyroid inhibitor potassium perchlorate (0, 62.5, 125, 250, 500 and 5000 µg/L) to identify adverse effects on the hypothalamic-pituitary-thyroid axis. Especially higher perchlorate concentrations led to conspicuous alterations in thyroidal tissue architecture and to effects in the pituitary. In the thyroid, severe hyperplasia at concentrations ≥ 500 µg/L together with an increase in follicle number could be detected. The most sensitive endpoint was the colloid, which showed alterations at ≥ 250 µg/L. The tinctorial properties and the texture of the colloid changed dramatically. Interestingly, effects on epithelial cell height were minor. The pituitary revealed significant proliferations of TSH-producing cells resulting in alterations in the ratio of adeno- to neurohypophysis. The liver as the main site of T4 deiodination showed severe glycogen depletion at concentrations ≥ 250 µg/L. In summary, the thyroid system in zebrafish showed effects by perchlorate from concentrations ≥ 250 µg/L, thus documenting a high sensitivity of the zebrafish thyroid gland for goitrogens. In the future, such distinct alterations could lead to a better understanding and identification of potential thyroid-disrupting chemicals.
Assuntos
Antitireóideos/toxicidade , Percloratos/toxicidade , Compostos de Potássio/toxicidade , Glândula Tireoide/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/fisiologia , Animais , Constituição Corporal/efeitos dos fármacos , Tamanho Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Gônadas/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Tiroxina/análiseRESUMO
INTRODUCTION: Patients receiving radiation therapy due to oral cancer develop complications such as hyposalivation, mucositis, oral infections, dental hypersensitivity and caries. Mouthrinses can alleviate some of these problems. AIMS AND OBJECTIVES: To investigate the in vitro antimicrobial properties and cytotoxicity of an experimental mouthrinse. METHODS: The mouthrinse contained 30% hexylene glycol (glycerine), 7% potassium nitrate and 0.025% sodium fluoride. The minimal inhibitory concentration (MIC) of these ingredients and the mixture was determined for C. albicans, S. aureus and S. mutans over 24 hours at different concentrations. The MICs of two commercial mouthrinses, Corsodyl and Plax, were also determined using the same organisms. All mouthrinses were then tested to determine the percentage kill over 1, 2, and 3 minutes. RESULTS: The MICs for hexylene glycol were 10%, 30% and 10% for C. albicans, S. aureus and S. mutons respectively. Potassium nitrate and sodium fluoride had no antimicrobial effects. The MIC of Corsodyl was 0.016 mg/ml for all the test organisms. The MIC for Plax varied from 0.0002 mg/ml to 0.001 mg/ml. The kill rates for all mouthrinses were acceptable, with no statistical differences between them. The experimental mouthrinse was not toxic to human oesophageal SCC cells after 1 minute exposure. At the time of the experiment, the costs of a similar quantity of the experimental mouthrinse, Corsodyl and Plax were R5.24, R30.00 and R10.00 respectively. CONCLUSIONS: The experimental mouthrinse was cost-effective and proved to have an antimicrobial effect and could be used safely to alleviate oral infections, desensitize teeth, improve oral hygiene and control dental caries in cancer patients after radiation therapy.
Assuntos
Anti-Infecciosos Locais/farmacologia , Antissépticos Bucais/farmacologia , Radioterapia , Anti-Infecciosos Locais/economia , Anti-Infecciosos Locais/toxicidade , Benzoatos/farmacologia , Candida albicans/efeitos dos fármacos , Carcinoma de Células Escamosas/patologia , Cariostáticos/farmacologia , Cariostáticos/toxicidade , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Clorexidina/análogos & derivados , Clorexidina/farmacologia , Dessensibilizantes Dentinários/farmacologia , Dessensibilizantes Dentinários/toxicidade , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/patologia , Glicóis/farmacologia , Glicóis/toxicidade , Humanos , Lubrificantes/farmacologia , Lubrificantes/toxicidade , Teste de Materiais , Testes de Sensibilidade Microbiana , Antissépticos Bucais/economia , Antissépticos Bucais/toxicidade , Nitratos/farmacologia , Nitratos/toxicidade , Compostos de Potássio/farmacologia , Compostos de Potássio/toxicidade , Radioterapia/efeitos adversos , Dodecilsulfato de Sódio/farmacologia , Fluoreto de Sódio/farmacologia , Fluoreto de Sódio/toxicidade , Staphylococcus aureus/efeitos dos fármacos , Streptococcus mutans/efeitos dos fármacos , Fatores de Tempo , Triclosan/farmacologiaAssuntos
Resistência a Medicamentos/genética , Fluoretos/toxicidade , Nicotiana/genética , Proteínas de Plantas/genética , Compostos de Potássio/toxicidade , Fatores de Transcrição/genética , Células Cultivadas , Fluoretos/farmacologia , Proteínas de Choque Térmico/genética , Plantas Geneticamente Modificadas , Compostos de Potássio/farmacologia , Nicotiana/efeitos dos fármacos , Nicotiana/metabolismoAssuntos
Doença de Bowen/diagnóstico , Carcinoma Basocelular/diagnóstico , Lesões Pré-Cancerosas/diagnóstico , Psoríase/diagnóstico , Neoplasias Cutâneas/diagnóstico , Idoso , Intoxicação por Arsênico/complicações , Intoxicação por Arsênico/patologia , Arsenitos/administração & dosagem , Arsenitos/toxicidade , Doença de Bowen/induzido quimicamente , Doença de Bowen/patologia , Carcinoma Basocelular/induzido quimicamente , Carcinoma Basocelular/patologia , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/patologia , Diagnóstico Diferencial , Feminino , Humanos , Compostos de Potássio/administração & dosagem , Compostos de Potássio/toxicidade , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Psoríase/tratamento farmacológico , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/patologia , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/patologiaRESUMO
As a consequence of human activity, various toxicants - especially metal ions - enter aquatic ecosystems and many fish are exposed to considerable levels. As the free ion and in some complexes, there is no doubt that copper promotes damage to cellular molecules and structures through radical formation. Therefore, we have investigated the influence of copper uptake by the red blood of the sea bass (Dicentrarchus labrax), and its oxidative action and effects on cells in the presence of complexed and uncomplexed Fe3+ ions. Erythrocytes were exposed to various concentrations of CuSO4, Fe(NO3)3, and K3Fe(CN)6 for up to 5h, and the effects of copper ions alone and in the combination with iron determined. The results show that inside the cells cupric ion interacts with hemoglobin, causing methemoglobin formation by direct electron transfer from heme Fe2+ to Cu2+. Potassium ferricyanide as a source of complexed iron decreases Met-Hb formation induced by copper ions unlike Fe(NO3)3. We also found that incubation of fish erythrocytes with copper increased hemolysis of cells. But complexed and uncomplexed iron protected the effect of copper. CuSO4 increased the level of lipid peroxidation and a protective effect on complexed iron was observed. Incubation of erythrocytes with copper ions resulted in the loss of a considerable part of thiol content at 10 and 20 microM. This effect was decreased by potassium ferricyanide and Fe(NO3)3 only after 1 and 3h of incubation. The level of nuclear DNA damage assayed by comet assay showed that 20 microM CuSO4 as well as 20 microM Fe(NO3)3 and 10 mM K3Fe(CN)6 induce single- and double-strand breaks. The lower changes were observed after the exposure of cells to K3Fe(CN)6. The data suggest that complexed iron can act protectively against copper ions in contrast to Fe(NO3)3.
Assuntos
Bass/metabolismo , Cobre/metabolismo , Eritrócitos/metabolismo , Ferro/metabolismo , Animais , Cátions Bivalentes/metabolismo , Cátions Bivalentes/farmacologia , Cobre/toxicidade , Sulfato de Cobre/metabolismo , Sulfato de Cobre/toxicidade , Eritrócitos/efeitos dos fármacos , Feminino , Ferrocianetos/metabolismo , Ferrocianetos/toxicidade , Ferro/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Nitratos/metabolismo , Nitratos/toxicidade , Compostos de Potássio/metabolismo , Compostos de Potássio/toxicidadeRESUMO
Occupational exposure to nickel (Ni), chromium (Cr), and arsenic (As) containing compounds has been associated with lung cancer and other adverse health effects. Their carcinogenic properties may be attributable in part, to activation and/or repression of gene expression induced by changes in the DNA methylation status and histone tail post-translational modifications. Here we show that individual treatment with nickel, chromate, and arsenite all affect the gene activating mark H3K4 methylation. We found that nickel (1 mM), chromate (10 microM), and arsenite (1 microM) significantly increase tri-methyl H3K4 after 24 h exposure in human lung carcinoma A549 cells. Seven days of exposure to lower levels of nickel (50 and 100 microM), chromate (0.5 and 1 microM) or arsenite (0.1, 0.5 and 1 microM) also increased tri-methylated H3K4 in A549 cells. This mark still remained elevated and inherited through cell division 7 days following removal of 1 microM arsenite. We also demonstrate by dual staining immunofluorescence microscopy that both H3K4 tri-methyl and H3K9 di-methyl marks increase globally after 24 h exposure to each metal treatment in A549 cells. However, the tri-methyl H3K4 and di-methyl H3K9 marks localize in different regions in the nucleus of the cell. Thus, our study provides further evidence that a mechanism(s) of carcinogenicity of nickel, chromate, and arsenite metal compounds may involve alterations of various histone tail modifications that may in turn affect the expression of genes that may cause transformation.