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1.
Environ Monit Assess ; 192(4): 213, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32133548

RESUMO

Wet and dry extraction methods are two main methods used in toxicological in vitro and in vivo studies to recover particulate matter (PM) from filter papers. The aim of this study was to extract PM by wet and dry extraction methods and compare the elemental content and carcinogenic risks of extracts. PM10 samples were collected using fiberglass filters and a high-volume air sampler. For wet extraction, the method involved agitation in water, sonication in water bath, and agitation again. For dry extraction, the filters were sonicated and the PM was recovered using sweeping by a brush. Elemental composition of extracts was determined by inductively coupled plasma-optical emission spectrometry (ICP-OES). Excess lifetime cancer risks (ELCR) of As, Cd, Cr, Ni, and Pb in extracts were estimated. The average recovery efficiency (%) of dry and wet extraction methods were 36.8% and 58.5%, respectively. The average elemental concentration that resulted from dry and wet methods was calculated to be 2.27 and 1.26 µg/m3, respectively. The total ELCR of all heavy metals in both methods exceeds the 1 × 10-6 limit. However, the total ELCR of heavy metals that resulted from the dry method was higher than that from the wet method. In conclusion, the dry method showed to be more effective to recover a representative extract from the filter. This can ultimately lead to a realistic and robust response in toxicological studies. However, a toxicological comparison between the extracts of these two methods is required.


Assuntos
Poluentes Atmosféricos , Carcinógenos , Metais Pesados , Material Particulado , Carcinógenos/toxicidade , Exposição Ambiental , Monitoramento Ambiental , Humanos , Neoplasias/induzido quimicamente , Material Particulado/toxicidade , Medição de Risco
2.
Chem Biol Interact ; 317: 108937, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926150

RESUMO

The biotoxin okadaic acid (OA) is a lipophilic secondary metabolite of marine microalgae. Therefore, OA accumulates in the fatty tissue of various shellfish and may thus enter the food chain. The ingestion of OA via contaminated marine species can lead to the diarrhetic shellfish poisoning syndrome characterized by the occurrence of a series of acute gastrointestinal symptoms in humans. In addition, genotoxicity and tumor-promoting properties of OA might constitute a long-term threat to human health. In order to deepen our understanding of the molecular effects of OA, we compared long-term (14 d) and short-term (24 h and 48 h) apoptotic effects of the compound on human HepaRG hepatocarcinoma cells. Cells were treated either with single doses for 24 and 48 h, respectively, or seven times over a period of 14 d, so that the cumulated quantities of OA in the long-term approach were equal to the single doses upon short-term treatment. Both short-term treatment scenarios led to the induction of apoptosis. Specific caspase activation assays and transcriptional analysis of mRNAs encoding proteins involved in the regulation of apoptosis suggest that OA-induced apoptosis occurs presumably by activation of the intrinsic apoptotic pathway. In contrast, effects were much less pronounced in case of long-term treatment. This is possibly linked to cellular protective mechanisms against low amounts of toxins, e.g. transporter-mediated efflux. In conclusion, our results show a clear concentration- and time-dependency of OA-mediated apoptotic effects in HepaRG cells and contribute to the elucidation of molecular effects of OA.


Assuntos
Apoptose/efeitos dos fármacos , Carcinógenos/toxicidade , Hepatócitos/efeitos dos fármacos , Ácido Okadáico/toxicidade , Carcinógenos/administração & dosagem , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Ácido Okadáico/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
3.
Food Chem Toxicol ; 135: 110898, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31654706

RESUMO

Sucralose is widely used as a sugar substitute. Many studies and authoritative reviews have concluded that sucralose is non-carcinogenic, based primarily on animal cancer bioassays and genotoxicity data. To add to the body of knowledge on the potential carcinogenicity of sucralose, a systematic assessment of mechanistic data was conducted. This entailed using a framework developed for the quantitative integration of data related to the proposed key characteristics of carcinogens (KCCs). Data from peer-reviewed literature and the ToxCast/Tox21 database were evaluated using an algorithm that weights data for quality and relevance. The resulting integration demonstrated an overall lack of activity for sucralose across the KCCs, with no "strong" activity observed for any KCC. Almost all data collected demonstrated inactivity, including those conducted in human models. The overall lack of activity in mechanistic data is consistent with findings from animal cancer bioassays. The few instances of activity across the KCC were generally accompanied by limitations in study design in the context of either quality and/or dose and model relevance, highlighted upon integration of the totality of the evidence. The findings from this comprehensive and integrative evaluation of mechanistic data support prior conclusions that sucralose is unlikely to be carcinogenic in humans.


Assuntos
Carcinógenos/toxicidade , Sacarose/análogos & derivados , Edulcorantes/toxicidade , Animais , Testes de Carcinogenicidade , Qualidade de Produtos para o Consumidor , Determinação de Ponto Final , Feminino , Humanos , Masculino , Camundongos , Ratos , Medição de Risco , Sacarose/toxicidade
4.
Toxicol Lett ; 320: 103-108, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31816332

RESUMO

Acrylamide is included on the State of California's Proposition 65 list as a carcinogen. Acrylamide is found in cigarette smoke and in many types of foods, including breads, cereals, coffee, cookies, French fries, and potato chips. In 1990, California's Office of Environmental Health Hazard Assessment (OEHHA) established a no significant risk level (NSRL) of 0.2 µg/day for acrylamide. Since then, multiple cancer studies have been published. In this report, we developed an updated NSRL for acrylamide. Using benchmark dose modeling and a weight-of-evidence, non-threshold approach to identify the most sensitive species, cancer slope factors (CSFs) were derived based on combined incidences of statistically significant neoplastic lesions in the Harderian gland, lung, and stomach in male mice. We then used a toxicokinetic (TK)-based scaling approach to convert the animal CSF to a human equivalent CSF, which served as the basis for the NSRL of 1.1 µg/day at the cancer risk level of 1 in 100,000. This NSRL can be used in quantitative exposure assessments to assess compliance with Proposition 65 to ascertain either the need for or exemption from the Proposition 65 labeling requirement and drinking water discharge prohibition.


Assuntos
Acrilamida/toxicidade , Carcinógenos/toxicidade , Modelos Teóricos , Neoplasias/induzido quimicamente , Acrilamida/farmacocinética , Animais , Testes de Carcinogenicidade , Carcinógenos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Ratos Endogâmicos F344 , Medição de Risco , Toxicocinética
5.
Chemosphere ; 239: 124748, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31520971

RESUMO

A total of 100 samples were collected from the sediments of a typical copper mining area, south China. Leaching concentrations of selected heavy metals (Ni, Cd, Cu, Pb, Zn, Ba, As, and Hg) were measured to evaluate their distribution patterns and associated health risk. Leaching concentrations of Cu (3.58 ±â€¯1.49 mg/L), Pb (1.50 ±â€¯1.06 mg/L), and Zn (4.04 ±â€¯1.68 mg/L) were significantly higher than the other metals in the samples. By evaluating the spatial heterogeneity, it was found that leaching metal concentrations did not decrease with environmental gradients, mostly caused by diverse distribution in pollution sources. The hazard index and carcinogenic risk indices showed significant risks of human exposure. For public safety, priority governance should be given to the main pollutants (Cd, Cu, Pb, Zn, and As) in sediments. In future studies, the integrated data will be urgently required for local stakeholders to conduct environmental monitoring and remediation scenarios.


Assuntos
Sedimentos Geológicos/análise , Metais Pesados/análise , Mineração , Poluentes do Solo/análise , Poluentes Químicos da Água/toxicidade , Carcinógenos/toxicidade , China , Cobre , Exposição Ambiental/efeitos adversos , Monitoramento Ambiental , Humanos , Metais Pesados/toxicidade , Modelos Teóricos , Saúde Pública , Medição de Risco , Poluentes do Solo/toxicidade , Poluentes Químicos da Água/análise
6.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(10): 865-871, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31814561

RESUMO

Objective To construct a double transfected Flp-InTM CHO cell line stably expressing both cytochrome P450 family 2 subfamily A member 13(CYP2A13) and multidrug resistance-associated protein 2(MRP2). Methods We constructed the recombinant plasmids of pCMV6-NEO-CYP2A13 and pcDNA5-MRP2. The pCMV6-NEO-CYP2A13 recombinant plasmid was first transfected into Flp-InTM CHO cells, and CYP2A13-Flp-InTM CHO cells with higher CYP2A13 activity were screened using limiting dilution method and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) cytotoxicity assay. Thereafter, pcDNA5-MRP2 was transfected into CYP2A13-Flp-InTM CHO cells. The expression levels and activities of CYP2A13 and MRP2 in the double transfected cells and normal cells were detected by real-time quantitative PCR, Western blot analysis and NNK cytotoxicity assay in order to screen Flp-InTM CHO cells with stable expression of CYP2A13 and MRP2. Results Compared with non-transfected cells, the expression of CYP2A13 and the sensitivity of NNK toxicity in CYP2A13-Flp-InTM CHO cells increased. The expression of CYP2A13 and MRP2 in CYP2A13/MRP2-Flp-InTM CHO cells also increased significantly. Compared with CYP2A13-Flp-InTM CHO cells, CYP2A13/MRP2-Flp-InTM CHO cells showed no significant difference in CYP2A13 expression; the expression of MRP2 increased while the sensitivity of NNK toxicity decreased significantly. Conclusion The double transfected cell model of CYP2A13 and MRP2 has been successfully established, which lays the foundation for the study of in situ activation of respiratory carcinogens.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Células CHO , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Animais , Carcinógenos/toxicidade , Cricetinae , Cricetulus , Nitrosaminas/toxicidade , Plasmídeos , Transfecção
7.
Environ Health Perspect ; 127(12): 125003, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31854200

RESUMO

BACKGROUND: Due to the large number of chemicals not yet tested for carcinogenicity but to which people are exposed, the limited number of human and animal cancer studies conducted each year, and the frequent need for a timely response, mechanistic data are playing an increasingly important role in carcinogen hazard identification. OBJECTIVES: To provide a targeted approach to identify relevant mechanistic data in our cancer evaluation of haloacetic acids (HAAs), we used several approaches including systematic review, the 10 key characteristics of carcinogens (KCs), and read-across methods. Our objective in this commentary is to discuss the strengths, limitations, and challenges of these approaches in a cancer hazard assessment. METHODS: A cancer hazard assessment for 13 HAAs found as water disinfection by-products was conducted. Literature searches for mechanistic studies focused on the KCs and individual HAAs. Studies were screened for relevance and categorized by KCs and other relevant data, including chemical properties, toxicokinetics, and biological effects other than KCs. Mechanistic data were organized using the KCs, and strength of evidence was evaluated; this information informed potential modes of action (MOAs) and read-across-like approaches. Three read-across options were considered: evaluating HAAs as a class, as subclass(es), or as individual HAAs (analog approach). DISCUSSION: Because of data limitations and uncertainties, listing as a class or subclass(es) was ruled out, and an analog approach was used. Two brominated HAAs were identified as target (untested) chemicals based on their metabolism and similarity to source (tested) chemicals. In addition, four HAAs with animal cancer data had sufficient evidence for potential listing in the Report on Carcinogens (RoC). This is the first time that the KCs and other relevant data, in combination with read-across principles, were used to support a recommendation to list chemicals in the RoC that did not have animal cancer data. https://doi.org/10.1289/EHP5672.


Assuntos
Ácido Acético/toxicidade , Carcinógenos/toxicidade , Desinfetantes/toxicidade , Neoplasias/epidemiologia , Poluição Química da Água/estatística & dados numéricos , Medição de Risco
8.
Mutat Res ; 782: 108281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31843138

RESUMO

Cigarette smoking is a strong risk factor for bladder cancer. It has been shown that the duration of smoking is associated with a poor prognosis and a higher risk of recurrence. This is due to tobacco carcinogens forming adducts with DNA and proteins that participate in the DNA repair mechanisms. Additionally, polymorphisms of genes responsible for methyl group transfer in the methionine cycle and dosages of vitamins (from diet and supplements) can cause an increased risk of bladder cancer. Upregulated DNA methyltransferase 1 expression and activity results in a high level of methylated products of metabolism, as well as hypermethylation of tumor suppressor genes. The development of a market that provides new inhibitors of DNA methyltransferase or alternatives for current smokers is essential not only for patients but also for people who are under the danger of secondhand smoking and can experience its long-term exposure consequences.


Assuntos
Carcinógenos/toxicidade , Metionina/metabolismo , Tabaco/toxicidade , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Reparo do DNA/efeitos dos fármacos , Humanos , Fatores de Risco
9.
Mutat Res ; 782: 108276, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31843140

RESUMO

Bracken fern is carcinogenic when fed to domestic and laboratory animals inducing bladder and ileal tumours and is currently classified as a possible human carcinogen by IARC. The carcinogenic illudane, ptaquiloside (PTQ) was isolated from bracken fern and is widely assumed to be the major bracken carcinogen. However, several other structurally similar illudanes are found in bracken fern, in some cases at higher levels than PTQ and so may contribute to the overall toxicity and carcinogenicity of bracken fern. In this review, we critically evaluate the role of illudanes in bracken fern induced toxicity and carcinogenicity, the mechanistic basis of these effects including the role of DNA damage, and the potential for human exposure in order to highlight deficiencies in the current literature. Critical gaps remain in our understanding of bracken fern induced carcinogenesis, a better understanding of these processes is essential to establish whether bracken fern is also a human carcinogen.


Assuntos
Carcinógenos/toxicidade , Pteridium/toxicidade , Animais , Dano ao DNA/efeitos dos fármacos , Humanos , Indanos/toxicidade , Sesquiterpenos/toxicidade
10.
Life Sci ; 237: 116895, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610204

RESUMO

To evaluate the effect of a probiotic on the aggressiveness of a chemically induced colorectal tumor in rats. Twenty-five male Fisher 344 rats, 250 g, provided with feed and water ad libitum, were randomly divided into 5 groups (5 rats/group): GControl, no treatment; GTumor, tumor induction; GTumor+5FU, tumor induction, 5-Fluorouracil applied; GTumor+Prob, induction of the tumor, supplemented with probiotic; GTumor+5-FU+Prob, tumor induction, 5-Fluorouracil applied, supplemented with probiotic. For tumor induction 20 mg/kg of 1,2-dimethylhydrazine was applied intraperitoneally over 4 weeks, followed by an interval of 15 days, and then repeated for a further 4 weeks. Five weeks after the final dose of the carcinogen, treatment was initiated with 5-Fluorouracil (15 mg/kg, intraperitoneally/week) and a commercial probiotic (1 × 109 CFU, daily/gavage). Data were analyzed by One Way Variance Analysis and means compared by Dunnett's test. GraphPad Prism statistical software was used. The histopathological analyzes were evaluated by the chi-square test. A 5% type-I error was considered statistically significant. Compared with the GTumor, the GTumor+Prob (p < 0.0373) and GTumor+5-FU+Prob (p < 0.0003) demonstrated an attenuated effect on the aggressiveness of the colorectal tumor, with a reduction in the count of Aberrant Crypt foci; and a lower percentage of malignant neoplastic lesions in the GTumor+Prob (40% low grade tubular adenoma, 40% carcinoma in situ, 20% low grade adenocarcinoma) and GTumor+5-FU+Prob (40% low grade tubular adenoma and 60% carcinoma in situ). Probiotic supplementation has the potential to decrease the formation of aberrant crypts and ameliorate tumor malignancy, enhancing the antitumor effect of 5-Fluorouracil chemotherapy in colic segments.


Assuntos
Neoplasias Colorretais/prevenção & controle , Suplementos Nutricionais , Dimetilidrazinas/toxicidade , Probióticos/administração & dosagem , Animais , Carcinógenos/toxicidade , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/patologia , Masculino , Ratos , Ratos Endogâmicos F344
11.
J Toxicol Sci ; 44(10): 693-699, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588060

RESUMO

Cigarette smoking is a risk factor for the development of various cancers, such as lung, nasal, liver and bladder cancers. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, is implicated in human lung cancer. NNK-induced DNA adducts are found in target tissues for NNK carcinogenesis. NNK is activated by cytochrome P450 dependent α-hydroxylation at either the methylene carbon or methyl carbon adjacent to the N-nitroso group. The former leads to the formation of the methylating agent, and the latter produce the pyridyloxobutylating agent. NNK and some of its metabolites are further metabolized by UDP-glucuronosyltransferases (UGTs). Glucuronides generally are much less active than the parent aglycon therefore the glucuronides of NNK-related metabolites are thought to be inactive. However, 4-(hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide (HO-methyl NNK glucuronide) can be transported to the target organs of NNK carcinogenesis where subsequent hydrolysis causes the release of the reactive intermediate. Regeneration of HO-methyl NNK could play an important role in the tissue-specific carcinogenicity of NNK. In the present study, we investigated the reactivity of HO-methyl NNK glucuronide toward 2'-deoxyguanosine (dGuo) and N-acetylcysteine (NAC; used as a models for thiol groups on proteins). The reaction mixtures of HO-methyl NNK glucuronide and dGuo or NAC were analyzed by LCMS-IT-TOF-MS. We also employed 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone, a pyridyloxobutylating agent, to confirm the formation of pyridyloxobutylated adducts. Thus, we determined the production of pyridyloxobutylated dGuo and NAC adducts. Our results suggest HO-methyl NNK glucuronide could generate a reactive intermediate in the tissues and then form adducts with proteins and DNA.


Assuntos
Acetilcisteína/metabolismo , Carcinógenos/toxicidade , Adutos de DNA , Desoxiguanosina/metabolismo , Glucuronídeos/toxicidade , Nitrosaminas/toxicidade , Animais , Esterases/metabolismo , Fígado/metabolismo , Camundongos
12.
Environ Pollut ; 255(Pt 2): 113315, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31606661

RESUMO

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been detected in various environmental media and has been implicated as a weak mutagen or carcinogen, but whether TDCIPP can promote the progression of liver tumor remains unclear. In this study, krasV12 genetically modified zebrafish, Tg(fabp10:rtTA2s-M2; TRE2:EGFP-krasG12V), a model system in which liver tumors can be induced by doxycycline (DOX), was used to evaluate the liver tumor promotion potential of TDCIPP. Briefly, krasV12 transgenic females were exposed to 0.3 mg/L TDCIPP, 20 mg/L DOX or a binary mixture of 0.3 mg/L TDCIPP with 20 mg/L DOX, and liver size, histopathology, and transcriptional profiles of liver were determined. Treatment with TDCIPP resulted in increased liver size and caused more aggressive hepatocellular carcinoma (HCC). Compared with the exposure to DOX, TDCIPP in the presence of DOX up-regulated the expression of genes relevant with salmonella infection and the toll-like receptor signaling pathway. These results implied an occurrence of inflammatory reaction, which was sustained by the increase in the amount of infiltrated neutrophils in the liver of Tg(lyz:DsRed2) transgenic zebrafish larvae whose neutrophils were labelled by red fluorescent protein under the lysozyme C promoter. Furthermore, compared with the binary exposure of DOX and TDCIPP, treatment with a ternary mixture of TDCIPP, DOX and inflammatory response inhibitor (ketoprofen) significantly decrease the liver size and the amounts of neutrophils in the livers of kras and lyz double transgenic zebrafish larvae. Collectively, our results suggested that TDCIPP could promote the liver tumor progression by induction of hepatic inflammatory responses.


Assuntos
Carcinógenos/toxicidade , Organofosfatos/toxicidade , Animais , Animais Geneticamente Modificados , Carcinoma Hepatocelular , Transformação Celular Neoplásica , Feminino , Larva , Neoplasias Hepáticas , Proteínas Luminescentes , Fosfatos/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais , Peixe-Zebra/metabolismo
13.
Life Sci ; 238: 116969, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628912

RESUMO

AIMS: Glutamatergic dysfunction is posed as a main stage in neurodegenerative disorders such as Alzheimer's disease (AD). Glutamate-mediated excitotoxicity contributes to cognitive dysfunction and cell death in AD. Ceftriaxone (CFT), a well-known upregulator of GLT-1, selectively induces the expression of glutamate transporter-1 (GLT-1) in different brain regions and therefore can be posed as a potential candidate for elimination of glutamate-induced excitotoxicity which is an early prominent event in AD brains. This study was designed to investigate the electrophysiological and behavioral effects of the ß-lactam antibiotic ceftriaxone in okadaic acid (OKA)-induced model of AD. MATERIALS AND METHODS: Male Wistar rats divided into four control, ceftriaxone (CFT), OKA, and OKA plus ceftriaxone (OKA + CFT) groups. OKA was injected intracerebroventricularly (i.c.v., 200 ng/5 µl) into lateral ventricles and after two weeks the evoked field potential recorded from hippocampal perforant path-DG synapses in order to evaluate the effect of ceftriaxone treatment (200 mg/kg/day, i.p.) on long-term potentiation (LTP) and paired-pulse responses. KEY FINDINGS: Results of this study revealed that ceftriaxone treatment significantly ameliorates the OKA-induced attenuation of field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude following high-frequency stimulation and paired-pulse paradigm indicating its beneficial effects on both short-term and long-term plasticity in these neurons. Ceftriaxone also has an improving effect on OKA-induced impairment in short- and long-term memories evaluated by alternation behavior and passive avoidance tasks in rats. SIGNIFICANCE: Therefore, this study suggests that GLT-1 might be a promising therapeutic target for treatment of neurodegenerative disorders such as AD in the future.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ceftriaxona/farmacologia , Giro Denteado/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Animais , Antibacterianos/farmacologia , Carcinógenos/toxicidade , Giro Denteado/patologia , Hipocampo/patologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/patologia , Ácido Okadáico/toxicidade , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos
14.
Life Sci ; 238: 116968, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628914

RESUMO

AIMS: Colorectal cancer (CRC) is the third most common cancer worldwide. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of many cytoprotective genes, plays a protective role in carcinogenesis. Recent studies have identified a specific gene-expression signature regulated by the Nrf2 pathway in lung adenocarcinoma and head-and-neck squamous cell cancer. However, the roles of Nrf2 in the development of colitis-associated colorectal cancer (CACC) have not been well characterized. Nrf2 target genes as prognostic biomarkers in CACC remain to be explored. Thus, this work aimed to identify the molecular changes that occur during mouse CACC progression to facilitate the development of diagnostic and prognostic biomarkers. MAIN METHODS: The CACC model was established using azoxymethane (AOM) with dextran sulfate sodium salt (DSS) in BALB/c mice for 3 weeks to induce colitis-associated adenoma (CAA, early stage) and for 9 weeks to induce colitis-associated carcinoma (CAC, late stage). Using RNA-sequencing and bioinformatics analyses we examined the mRNA expression profiles of 6 groups: wild-type control (WT-C), WT-CAA, WT-CAC, Nrf2 knockout control (Nrf2KO-C), Nrf2KO-CAA, and Nrf2KO-CAC. KEY FINDINGS: In the AOM/DSS model of colitis-associated tumorigenesis, Nrf2-/- mice showed a phenotype similar to WT mice, but with significantly more tumors and a much higher percentage of adenocarcinomas. We identified 47 novel Nrf2 genes via gene expression profiling of tumor samples. Survival analysis showed that 23 of these genes were biomarkers of a poor prognosis in colon cancer patients. SIGNIFICANCE: Nrf2 target genes deserve exploration as prognostic and therapeutic targets for CRC.


Assuntos
Biomarcadores/metabolismo , Carcinogênese/patologia , Colite/complicações , Neoplasias Colorretais/diagnóstico , Regulação Neoplásica da Expressão Gênica , Fator 2 Relacionado a NF-E2/fisiologia , Animais , Azoximetano/toxicidade , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinógenos/toxicidade , Colite/induzido quimicamente , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
15.
Int J Nanomedicine ; 14: 6465-6480, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616140

RESUMO

Purpose: Multiwalled carbon nanotubes (MWCNTs) have been known to enter the circulatory system via the lungs from inhalation exposure; however, its carcinogenicity and subsequent accumulation in other organs have not been adequately reported in the literature. Moreover, the safety of MWCNTs as a biomaterial has remained a matter of debate, particularly when the material enters the circulatory system. To address these problems, we used carcinogenic rasH2 transgenic mice to intravenously administer highly dispersed MWCNTs and to evaluate their carcinogenicity and accumulation in the organs. Methods: Two types of MWCNTs (thin- and thick-MWCNTs) were intravenously administered at a high dose (approximately 0.7 mg per kg body weight) and low dose (approximately 0.07 mg per kg body weight). Results: MWCNTs showed pancreatic accumulation in 3.2% of mice administered with MWCNTs, but there was no accumulation in other organs. In addition, there was no significant difference in the incidence of tumor among the four MWCNTs-administered groups compared to the vehicle group without MWCNTs administration. Blood tests revealed elevated levels in mean red blood cell volume and mean red blood cell hemoglobin level for the MWCNTs-administered group, in addition to an increase in eotaxin. Conclusion: The present study demonstrated that the use of current technology to sufficiently disperse MWCNTs resulted in minimal organ accumulation with no evidence of carcinogenicity.


Assuntos
Carcinógenos/toxicidade , Nanotubos de Carbono/toxicidade , Administração Intravenosa , Animais , Peso Corporal , Carcinogênese/patologia , Citocinas/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos Transgênicos , Nanotubos de Carbono/ultraestrutura , Análise de Sobrevida , Distribuição Tecidual/efeitos dos fármacos
16.
Nat Med ; 25(9): 1428-1441, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501614

RESUMO

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.


Assuntos
Imunidade Celular , Neoplasias/imunologia , Estresse Psicológico/imunologia , Fatores de Transcrição/genética , Animais , Ansiedade/sangue , Ansiedade/induzido quimicamente , Ansiedade/imunologia , Ansiedade/psicologia , Comportamento Animal/fisiologia , Carcinógenos/toxicidade , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/psicologia , Corticosterona/sangue , Células Dendríticas/transplante , Regulação Neoplásica da Expressão Gênica , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/psicologia , Ativação Linfocitária/genética , Camundongos , Monitorização Imunológica/métodos , Neoplasias/induzido quimicamente , Neoplasias/genética , Neoplasias/psicologia , Receptores de Glucocorticoides/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/psicologia , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/genética , Estresse Psicológico/terapia , Fatores de Transcrição/imunologia
17.
Arch Oral Biol ; 108: 104547, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31525531

RESUMO

OBJECTIVE: This study investigated the risk and prognostic value of single nucleotide polymorphisms (SNP) inIL-8, MMP-1 and MMP-13 in oral and oropharyngeal squamous cell carcinomas (SCCs). DESIGN: SNPs rs2227532 and rs4073 inIL-8, rs2071230 and rs470558 in MMP-1, and rs2252070 in MMP-13 were genotyped in 125 oral and oropharyngeal SCC patients and 130 healthy controls, using TaqMan allelic discrimination assays. Multiple logistic regression models were used to explore the association between SNPs and cancer development, as well as SNP-SNP interaction and gene-environmental factor (GxE) interaction. Univariate and multivariate methods were applied for survival analyses. RESULTS: With exception of rs2227532, all the SNPs were in Hardy-Weinberg equilibrium in the control. No associations between rs4073 in IL-8 and rs2071230 and rs470558 in MMP-1 were observed, but rs2252070 in MMP-13, in the dominant model, was associated in a protective manner to oral and oropharyngeal SCC (OR: 0.20, 95% CI: 0.06-0.71, p = 0.007). All SNPs interact significantly with cigarette smoking and alcohol consumption on susceptibility to oral and oropharyngeal SCC, but they showed no influence on survival of the patients. CONCLUSIONS: Our results show that rs2252070 inMMP-13 may confer protection effect against oral and oropharyngeal SCC. In addition, the combined effects of IL-8 (rs4073), MMP-1 (rs2071230 and rs470558) and MMP-13 (rs2252070) with environmental carcinogens, such as tobacco and alcohol, are related to increased risk for oral and oropharyngeal SCC development.


Assuntos
Carcinoma de Células Escamosas , Interleucina-8 , Metaloproteinase 13 da Matriz , Metaloproteinase 1 da Matriz , Neoplasias Bucais , Carcinógenos/toxicidade , Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença , Humanos , Interleucina-8/genética , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 13 da Matriz/genética , Neoplasias Bucais/genética , Polimorfismo de Nucleotídeo Único , Prognóstico
18.
World J Gastroenterol ; 25(33): 4885-4891, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31543680

RESUMO

Portal hypertension, liver fibrosis, and angiosarcoma of the liver (ASL) have been reported among workers exposed to vinyl chloride monomer (VCM) since the 1970s. In 2007, the International Agency for Research on Cancer established the association of VCM with hepatocellular carcinoma (HCC), though only on the basis of the few cases available. Thereafter, recent reports from the United States cohort and a European sub-cohort of vinyl chloride workers provided compelling evidence of a strong association between cumulative VCM exposure and HCC risk. Further areas of research include the risk of liver cancer at lower levels of exposure and different patterns of risk of ASL and HCC with the time since exposure. The evidence of interaction between VCM exposure and other known liver carcinogens such as alcohol and chronic viral infection provides clues for the health surveillance of exposed workers. Notably, also the risk of VCM-associated chronic liver disease is modulated by alcohol consumption, viral infection, and genetic polymorphism. A counter-intuitive finding from cohort studies of exposed workers is the lower mortality from liver cirrhosis with respect to the general population; this can be attributed to the healthy worker effect and to the selection of liver cancer as the cause of death in the presence of concomitant chronic liver disease. Studies designed to overcome these intricacies confirmed an association between cumulative VCM exposure and the risk of liver cirrhosis.


Assuntos
Carcinógenos/toxicidade , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Cloreto de Vinil/toxicidade , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Causas de Morte , Doença Crônica/epidemiologia , Europa (Continente)/epidemiologia , Hemangiossarcoma/epidemiologia , Hemangiossarcoma/etiologia , Hemangiossarcoma/patologia , Humanos , Hipertensão Portal/epidemiologia , Hipertensão Portal/etiologia , Hipertensão Portal/patologia , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Doenças Profissionais/etiologia , Doenças Profissionais/patologia , Fatores de Risco , Análise de Sobrevida , Estados Unidos/epidemiologia , Viroses/complicações , Viroses/epidemiologia
19.
Part Fibre Toxicol ; 16(1): 34, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477126

RESUMO

BACKGROUND: Potassium octatitanate fibers (K2O•8TiO2, POT fibers) are used as an asbestos substitute. Their physical characteristics suggest that respirable POT fibers are likely to be carcinogenic in the lung and pleura. However, previous 2-year inhalation studies reported that respired POT fibers had little or no carcinogenic potential. In the present study ten-week old male F344 rats were left untreated or were administered vehicle, 0.25 or 0.5 mg rutile-type nano TiO2 (r-nTiO2), 0.25 or 0.5 mg POT fibers, or 0.5 mg MWCNT-7 by intra-tracheal intra-pulmonary spraying (TIPS), and then observed for 2 years. RESULTS: There were no differences between the r-nTiO2 and control groups. The incidence of bronchiolo-alveolar cell hyperplasia was significantly increased in the groups treated with 0.50 mg POT and 0.50 mg MWCNT-7. The overall incidence of lung tumors, however, was not increased in either the POT or MWCNT-7 treated groups. Notably, the carcinomas that developed in the POT and MWCNT-7 treated rats were accompanied by proliferative fibrous connective tissue while the carcinomas that developed in the untreated rats and the r-nTiO2 treated rats were not (carcinomas did not develop in the vehicle control rats). In addition, the carcinoma that developed in the rat treated with 0.25 mg POT was a squamous cell carcinoma, a tumor that develops spontaneously in about 1 per 1700 rats. The incidence of mesothelial cell hyperplasia was 4/17, 7/16, and 10/14 and the incidence of malignant mesothelioma was 3/17, 1/16, and 2/14 in the 0.25 mg POT, 0.5 mg POT, and MWCNT-7 treated groups, respectively. Neither mesothelial cell hyperplasia nor mesothelioma developed in control rats or the rats treated with r-nTiO2. Since the incidence of spontaneously occurring malignant mesothelioma in rats is extremely low, approximately 1 per 1000 animals (Japan Bioassay Research Center [JBRC] historical control data), the development of multiple malignant mesotheliomas in the POT and MWCNT-7 treated groups was biologically significant. CONCLUSION: The incidence of pleural mesotheliomas in male F344 rats administered POT fibers and MWCNT-7 was significantly higher than the JBRC historical control data, indicating that the incidence of pleural mesothelioma in the groups administered POT fibers and MWCNT-7 fibers via the airway using TIPS was biologically significant. The incidence of type II epithelial cell hyperplasia and the histology of the carcinomas that developed in the POT treated rats also indicates that respirable POT fibers are highly likely to be carcinogenic in the lungs of male F344 rats.


Assuntos
Carcinógenos/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Pulmão/efeitos dos fármacos , Mesotelioma/induzido quimicamente , Pleura/efeitos dos fármacos , Titânio/toxicidade , Animais , Carcinógenos/química , Carcinógenos/farmacocinética , Exposição por Inalação , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Fibras Minerais , Pleura/patologia , Ratos Endogâmicos F344 , Propriedades de Superfície , Distribuição Tecidual , Titânio/química , Titânio/farmacocinética
20.
BMC Complement Altern Med ; 19(1): 238, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481122

RESUMO

BACKGROUND: Annonacin, an annonaceous acetogenin isolated from Annona muricata has been reported to be strongly cytotoxic against various cell lines, in vitro. Nevertheless, its effect against in vivo tumor promoting activity has not been reported yet. Therefore, this study was aimed to investigate antitumor-promoting activity of annonacin via in vivo two-stage mouse skin tumorigenesis model and its molecular pathways involved. METHODS: Mice were initiated with single dose of 7,12-dimethylbenz[α]anthracene (DMBA) (390 nmol/100 µL) followed by, in subsequent week, repeated promotion (twice weekly; 22 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 µL). Annonacin (85 nM) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application for 22 weeks. Upon termination, histopathological examination of skin, liver and kidney as well as genes and proteins expression analysis were conducted to elucidate the potential mechanism of annonacin. RESULTS: With comparison to the carcinogen control, Annonacin significantly increased the tumor latency period and reduced the tumor incidence, tumor burden and tumor volume, respectively. In addition, it also suppressed tumorigenesis manifested by significant reduction of hyperkeratosis, dermal papillae and number of keratin pearls on skin tissues. Annonacin also appeared to be non-toxic to liver and kidney. Significant modulation of both AKT, ERK, mTOR, p38, PTEN and Src genes and proteins were also observed in annonacin-targeted signaling pathway(s) against tumorigenesis. CONCLUSIONS: Collectively, results of this study indicate that annonacin is a potential therapeutic compound targeting tumor promoting stage in skin tumorigenesis by modulating multiple gene and protein in cancer signaling pathways without apparent toxicity.


Assuntos
Anticarcinógenos/farmacologia , Carcinogênese/efeitos dos fármacos , Furanos/farmacologia , Lactonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Carcinógenos/toxicidade , Feminino , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Pele/efeitos dos fármacos , Pele/patologia , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/metabolismo , Acetato de Tetradecanoilforbol/toxicidade
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