Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.628
Filtrar
1.
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
2.
Cancer Sci ; 110(9): 2748-2759, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301081

RESUMO

In hepatocarcinogenesis induced by diethylnitrosamine (DEN) in B6C3F1 mice, the BrafV637E mutation, corresponding to the human BRAFV600E mutation, plays a pivotal role. The livers of transgenic mice with a hepatocyte-specific human BRAFV600E mutation weighed 4.5 times more than that of normal mice and consisted entirely of hepatocytes, resembling DEN-induced preneoplastic hepatocytes. However, these transgenic mice spontaneously died 7 wk after birth, therefore this study aimed to clarify the causes of death. In the transgenic mice, the liver showed thrombopoietin (TPO) overexpression, which is associated with eventual megakaryocytosis and thrombocytosis, and activated platelets were deposited in hepatic sinusoids. TPO was also overexpressed in the DEN-induced hepatic tumors, and sinusoidal platelet deposition was observed in the hepatic tumors of humans and mice. Podoplanin was expressed in some of the Kupffer cells in the liver of the transgenic mice, indicating that platelet activation occurred via the interaction of podoplanin with C-type lectin receptor 2 (CLEC-2) on the platelet membrane. Additionally, erythrocyte dyscrasia and glomerulonephropathy/interstitial pneumonia associated with platelet deposition were observed. In the transgenic mice, aspirin (Asp) administration prevented platelet activation, reduced the liver/body weight ratio, decreased the platelet deposition in the liver, kidney, and lung, and prevented erythrocyte dyscrasia and ameliorated the renal/pulmonary changes. Thrombopoietin overproduction by BRAFV600E-mutated hepatocytes may contribute to hepatocyte proliferation via thrombocytosis, platelet activation, and the interaction of platelets with hepatic sinusoidal cells, while hematologic, renal, and pulmonary disorders due to aberrant platelet activation may lead to spontaneous death in the transgenic mice.


Assuntos
Carcinogênese/genética , Neoplasias Hepáticas Experimentais/patologia , Fígado/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Trombopoetina/metabolismo , Animais , Biópsia , Plaquetas/patologia , Medula Óssea/patologia , Capilares/patologia , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Proliferação de Células/genética , Dietilnitrosamina/administração & dosagem , Dietilnitrosamina/toxicidade , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatectomia , Hepatócitos/patologia , Humanos , Fígado/irrigação sanguínea , Fígado/citologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Ativação Plaquetária/genética , Cultura Primária de Células , Proteínas Proto-Oncogênicas B-raf/metabolismo , Células Tumorais Cultivadas
3.
Nat Commun ; 10(1): 3071, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296856

RESUMO

The formation of new blood vessels is essential for normal development, tissue repair and tumor growth. Here we show that inhibition of the kinase p38α enhances angiogenesis in human and mouse colon tumors. Mesenchymal cells can contribute to tumor angiogenesis by regulating proliferation and migration of endothelial cells. We show that p38α negatively regulates an angiogenic program in mesenchymal stem/stromal cells (MSCs), multipotent progenitors found in perivascular locations. This program includes the acquisition of an endothelial phenotype by MSCs mediated by both TGF-ß and JNK, and negatively regulated by p38α. Abrogation of p38α in mesenchymal cells increases tumorigenesis, which correlates with enhanced angiogenesis. Using genetic models, we show that p38α regulates the acquisition of an endothelial-like phenotype by mesenchymal cells in colon tumors and damage tissue. Taken together, our results indicate that p38α in mesenchymal cells restrains a TGF-ß-induced angiogenesis program including their ability to transdifferentiate into endothelial cells.


Assuntos
Neoplasias do Colo/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Azoximetano/administração & dosagem , Azoximetano/toxicidade , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Proliferação de Células , Transdiferenciação Celular , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Transição Epitelial-Mesenquimal , Técnicas de Silenciamento de Genes , Células HT29 , Humanos , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína Quinase 14 Ativada por Mitógeno/genética , Neoplasias Experimentais/induzido quimicamente , RNA Interferente Pequeno/metabolismo
4.
Zhonghua Zhong Liu Za Zhi ; 41(5): 346-350, 2019 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-31137167

RESUMO

Objective: To explore the feasibility of 7, 12-dimethylbenz[a] anthracene (DMBA) induced tree shrew breast cancer model, and compare the effects of two administration modes by gavage and mammary gland injection. Methods: A total of 40 tree shrews were randomly divided into two groups (20 animals per group): DMBA gavage group and mammary gland injection group. DMBA was dissolved in edible vegetable oil. For gavage group, tree shrews were administered with DMBA solutions (15 mg/kg) by gavage once a day. For mammary gland injection group, DMBA solution (10 mg/kg) was injected into the mammary fat pad of tree shrews, and the injection was performed for a total of 3 times. From the first administration of DMBA, medroxyprogesterone acetate (MPA, 100 mg/kg) was intramuscularly injected into the muscles of the lateral thighs of tree shrews at the same time, for a total of 5 times. The tumorigenesis and survival of tree shrews were monitored. The tumor histological morphology was observed by HE staining. The expression of estrogen receptor (ER), progesterone receptor (PR), cytokeratin5/6 (CK5/6) and human epidermal factor receptor-2 (HER-2) was detected by immunohistochemical staining. Results: In the gavage group, there were 10 deaths, and 4 tree shrews developed mammary tumors with 20.0% (4/20) tumor formation rate. The success rate of mammary cancer modeling was 10.0% (2/20), and the tumor formation time was 197.3±15.1 days. In the mammary gland injection group, there were 8 tree shrews died, and 9 tree shrews formed tumors with 45.0% (9/20) tumor formation rate. The success rate of mammary cancer modeling was 40.0% (8/20), and the tumor formation time was 71.8±19.0 days. There was no significant difference in mortality and tumor formation rate (P>0.05) between the two groups (all P>0.05). However, in the mammary gland injection group, the success rate of mammary cancer modeling was significantly higher than that in the gavage group (P<0.05), whereas the tumor formation time was markedly shorter than that in the gavage group (P<0.01). The pathological types in the gavage group included ductal hyperplasia, intraductal papilloma and ductal carcinoma in situ, while those in the breast injection group included intraductal papilloma and ductal carcinoma in situ. In both groups, immunohistochemical staining showed the negative expression of HER-2 but positive expression of ER, PR and CK5/6 with varying degrees. Conclusion: Both the DMBA gavage and mammary gland injection can successfully establish the tree shrew breast cancer model, and the modeling effect of mammary gland injection is better than gavage.


Assuntos
9,10-Dimetil-1,2-benzantraceno/toxicidade , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Neoplasias Mamárias Experimentais/induzido quimicamente , 9,10-Dimetil-1,2-benzantraceno/administração & dosagem , Administração Oral , Animais , Neoplasias da Mama/induzido quimicamente , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Feminino , Injeções , Distribuição Aleatória , Tupaiidae
5.
Elife ; 82019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30990169

RESUMO

Hepatocellular carcinoma (HCC) is a deadly human cancer associated with chronic inflammation. The cytosolic pathogen sensor NLRP12 has emerged as a negative regulator of inflammation, but its role in HCC is unknown. Here we investigated the role of NLRP12 in HCC using mouse models of HCC induced by carcinogen diethylnitrosamine (DEN). Nlrp12-/- mice were highly susceptible to DEN-induced HCC with increased inflammation, hepatocyte proliferation, and tumor burden. Consistently, Nlrp12-/- tumors showed higher expression of proto-oncogenes cJun and cMyc and downregulation of tumor suppressor p21. Interestingly, antibiotics treatment dramatically diminished tumorigenesis in Nlrp12-/- mouse livers. Signaling analyses demonstrated higher JNK activation in Nlrp12-/- HCC and cultured hepatocytes during stimulation with microbial pattern molecules. JNK inhibition or NLRP12 overexpression reduced proliferative and inflammatory responses of Nlrp12-/- hepatocytes. In summary, NLRP12 negatively regulates HCC pathogenesis via downregulation of JNK-dependent inflammation and proliferation of hepatocytes.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Regulação para Baixo , Hepatócitos/enzimologia , Hepatócitos/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Neoplasias Hepáticas/fisiopatologia , Animais , Carcinógenos/administração & dosagem , Carcinoma Hepatocelular/induzido quimicamente , Proliferação de Células , Dietilnitrosamina/administração & dosagem , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Neoplasias Hepáticas/induzido quimicamente , Camundongos Knockout , Proteínas Proto-Oncogênicas c-myc/metabolismo
6.
Food Chem Toxicol ; 128: 54-60, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30914355

RESUMO

Here we evaluate a multiplicative (relative) risk model for improved cancer risk estimation of genotoxic compounds. According to this model, cancer risk is proportional to the background tumor incidence and to the internal dose of the genotoxic compound. Furthermore, the relative risk coefficient per internal dose is considered to be approximately the same across tumor sites, sex, and species. In the present study, we demonstrate that the relative risk model is valid for cancer risk estimation of glycidol, a common food contaminant. Published tumor data from glycidol carcinogenicity studies in mice and rats were evaluated in combination with internal dose estimates from hemoglobin adduct measurements in blood from mice and rats treated with glycidol in short-term studies. A good agreement between predicted and observed tumor incidence in responding sites was demonstrated in the animals, supporting a relative risk coefficient that is independent of tumor site, sex, and species. There was no significant difference between the risk coefficients for mice (5.1% per mMh) and rats (5.4% per mMh) when considering internal doses of glycidol. Altogether, this mechanism-based risk model gives a reliable risk coefficient, which then was extrapolated to humans considering internal dose, and background cancer incidence.


Assuntos
Carcinógenos/toxicidade , Compostos de Epóxi/toxicidade , Modelos Teóricos , Neoplasias Experimentais/induzido quimicamente , Propanóis/toxicidade , Animais , Área Sob a Curva , Carcinógenos/administração & dosagem , Carcinógenos/farmacocinética , Relação Dose-Resposta a Droga , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacocinética , Feminino , Hemoglobinas/metabolismo , Masculino , Camundongos , Propanóis/administração & dosagem , Propanóis/farmacocinética , Ratos , Ratos Sprague-Dawley , Medição de Risco
7.
Chem Res Toxicol ; 32(5): 869-877, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-30807115

RESUMO

Acrylamide has been classified as a "Group 2A carcinogen" (probably carcinogenic to humans) by the International Agency for Research on Cancer. The carcinogenicity of acrylamide is attributed to its well-recognized genotoxicity. In the present study, we investigated the effect of acrylamide on epigenetic alterations in mice. Female B6C3F1 mice received acrylamide in drinking water for 28 days, at doses previously used in a 2 year cancer bioassay (0, 0.0875, 0.175, 0.35, and 0.70 mM), and the genotoxic and epigenetic effects were investigated in lungs, a target organ for acrylamide carcinogenicity, and livers, a nontarget organ. Acrylamide exposure resulted in a dose-dependent formation of N7-(2-carbamoyl-2-hydroxyethyl)guanine and N3-(2-carbamoyl-2-hydroxyethyl)adenine in liver and lung DNA. In contrast, the profiles of global epigenetic alterations differed between the two tissues. In the lungs, acrylamide exposure resulted in a decrease of histone H4 lysine 20 trimethylation (H4K20me3), a common epigenetic feature of human cancer, while in the livers, there was increased acetylation of histone H3 lysine 27 (H3K27ac), a gene transcription activating mark. Treatment with 0.70 mM acrylamide also resulted in substantial alterations in the DNA methylation and whole transcriptome in the lungs and livers; however, there were substantial differences in the trends of DNA methylation and gene expression changes between the two tissues. Analysis of differentially expressed genes showed a marked up-regulation of genes and activation of the gene transcription regulation pathway in livers, but not lungs. This corresponded to increased histone H3K27ac and DNA hypomethylation in livers, in contrast to hypermethylation and transcription silencing in lungs. Our results demonstrate that acrylamide induced global epigenetic alterations independent of its genotoxic effects, suggesting that epigenetic events may determine the organ-specific carcinogenicity of acrylamide. Additionally this study provides strong support for the importance of epigenetic alterations, in addition to genotoxic events, in the mechanism of carcinogenesis induced by genotoxic chemical carcinogens.


Assuntos
Acrilamida/toxicidade , Adutos de DNA/metabolismo , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Mutagênicos/toxicidade , Poluentes Químicos da Água/toxicidade , Acrilamida/administração & dosagem , Adenina/análogos & derivados , Adenina/química , Administração Oral , Animais , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Adutos de DNA/química , Adutos de DNA/genética , Epigênese Genética/efeitos dos fármacos , Feminino , Guanina/análogos & derivados , Guanina/química , Histonas/química , Histonas/genética , Histonas/metabolismo , Metilação/efeitos dos fármacos , Camundongos , Mutagênicos/administração & dosagem , Poluentes Químicos da Água/administração & dosagem
8.
Regul Toxicol Pharmacol ; 104: 1-7, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30779931

RESUMO

A 2-year inhalation rat and mouse cancer study by the National Toxicology Program (NTP) on 1-bromopropane, a brominated solvent most commonly used as a vapor degreaser, showed significant increase in tumors in the lung of female mice and in the large intestine of male and female rats. The most sensitive endpoint was lung tumors in female mice. Mice of both sexes had hyperplasia and inflammation of the nose and showed regeneration of lung tissue. The NTP assumed that these tumors were due to genotoxic effects and that a linear dose-response relationship was appropriate. It is plausible that, similar to chloroform, hyperplasia and inflammation are required as initial events for tumor development. If true, then a threshold-based model may be more appropriate for 1-bromopropane. To test this hypothesis, a 28-day repeat dose inhalation Big Blue® Assay was conducted using female transgenic B6C3F1 mice. The target exposure concentrations and the exposure regimen were identical to those used by the NTP. Results demonstrated no elevation in mutant frequency of the cII transgene in lung, colon, or liver. Positive controls produced statistically significant increases in mutant frequencies across all tested tissues. These results demonstrate that 1-bromopropane does not induce cII mutants in lungs, colon, or liver under the testing conditions. These data have important ramifications in the quantitative evaluation of tumor results for this chemical and support a mechanism of action where a threshold for carcinogenicity is plausible.


Assuntos
Carcinogênese/efeitos dos fármacos , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Exposição por Inalação , Mutação/efeitos dos fármacos , Animais , Testes de Carcinogenicidade , Colo , Feminino , Hidrocarbonetos Bromados/administração & dosagem , Hidrocarbonetos Bromados/toxicidade , Fígado , Pulmão , Camundongos , Camundongos Transgênicos
9.
Int J Mol Sci ; 20(2)2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30669675

RESUMO

Acute myeloid leukaemia (AML) is a rare but severe form of human cancer that results from a limited number of functionally cooperating genetic abnormalities leading to uncontrolled proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Before the identification of genetic driver lesions, chemically, irradiation or viral infection-induced mouse leukaemia models provided platforms to test novel chemotherapeutics. Later, transgenic mouse models were established to test the in vivo transforming potential of newly cloned fusion genes and genetic aberrations detected in patients' genomes. Hereby researchers constitutively or conditionally expressed the respective gene in the germline of the mouse or reconstituted the hematopoietic system of lethally irradiated mice with bone marrow virally expressing the mutation of interest. More recently, immune deficient mice have been explored to study patient-derived human AML cells in vivo. Unfortunately, although complementary to each other, none of the currently available strategies faithfully model the initiation and progression of the human disease. Nevertheless, fast advances in the fields of next generation sequencing, molecular technology and bioengineering are continuously contributing to the generation of better mouse models. Here we review the most important AML mouse models of each category, briefly describe their advantages and limitations and show how they have contributed to our understanding of the biology and to the development of novel therapies.


Assuntos
Modelos Animais de Doenças , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Animais , Transplante de Medula Óssea , Carcinógenos/administração & dosagem , Transformação Celular Viral , Edição de Genes , Xenoenxertos , Humanos , Hospedeiro Imunocomprometido , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Transgênicos , Radiação Ionizante
10.
BMC Genomics ; 20(1): 17, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621584

RESUMO

BACKGROUND: Spalax, the blind mole rat, developed an extraordinary cancer resistance during 40 million years of evolution in a subterranean, hypoxic, thus DNA damaging, habitat. In 50 years of Spalax research, no spontaneous cancer development has been observed. The mechanisms underlying this resistance are still not clarified. We investigated the genetic difference between Spalax and mice that might enable the Spalax relative resistance to cancer development. We compared Spalax and mice responses to a treatment with the carcinogen 3-Methylcholantrene, as a model to assess Spalax' cancer-resistance. RESULTS: We compared RNA-Seq data of untreated Spalax to Spalax with a tumor and identified a high number of differentially expressed genes. We filtered these genes by their expression in tolerant Spalax that resisted the 3MCA, and in mice, and found 25 genes with a consistent expression pattern in the samples susceptible to cancer among species. Contrasting the expressed genes in Spalax with benign granulomas to those in Spalax with malignant fibrosarcomas elucidated significant differences in several pathways, mainly related to the extracellular matrix and the immune system. We found a central cluster of ECM genes that differ greatly between conditions. Further analysis of these genes revealed potential microRNA targets. We also found higher levels of gene expression of some DNA repair pathways in Spalax than in other murines, like the majority of Fanconi Anemia pathway. CONCLUSION: The comparison of the treated with the untreated tissue revealed a regulatory complex that might give an answer how Spalax is able to restrict the tumor growth. By remodeling the extracellular matrix, the possible growth is limited, and the proliferation of cancer cells was potentially prevented. We hypothesize that this regulatory cluster plays a major role in the cancer resistance of Spalax. Furthermore, we identified 25 additional candidate genes that showed a distinct expression pattern in untreated or tolerant Spalax compared to animals that developed a developed either a benign or malignant tumor. While further study is necessary, we believe that these genes may serve as candidate markers in cancer detection.


Assuntos
Carcinogênese/efeitos dos fármacos , Resistência à Doença/genética , Neoplasias/genética , Spalax/genética , Sequência de Aminoácidos/genética , Animais , Carcinógenos/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Neoplasias/patologia , Alinhamento de Sequência , Especificidade da Espécie , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
11.
Food Addit Contam Part B Surveill ; 12(1): 38-44, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30277127

RESUMO

The aim of this study was to determine the heavy metals content of milk from cows fed with forage irrigated with waste water from industrial sources and the health risk to children. Milk samples were taken from milk collection tanks of eight localities in the state of Puebla. On average, the heavy metals in the milk had the following order Zn> As> Pb > Cr> Cu > Ni. Pb (0.03 mg kg-1) exceeded the Codex limits. For As the hazard index was 8.0 ± 0.4, which is far above 1. On the other hand, the individual risk of cancer showed a descending order Cr> As > Pb, while the risk of total cancer (0.004 ± 0.002) indicated that the combined effect of heavy metals created a serious risk for girls and children.


Assuntos
Irrigação Agrícola/métodos , Carcinógenos , Metais Pesados/efeitos adversos , Metais Pesados/análise , Leite/química , Águas Residuárias/química , Adolescente , Fatores Etários , Ração Animal , Animais , Carcinógenos/administração & dosagem , Carcinógenos/farmacocinética , Bovinos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Concentração Máxima Permitida , Metais Pesados/administração & dosagem , México , Neoplasias/induzido quimicamente , Medição de Risco , Fatores de Risco , Fatores Sexuais , Poluentes Químicos da Água/análise
12.
J Food Sci ; 84(1): 192-200, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30561018

RESUMO

Heterocyclic amines (HCAs) have been identified as highly mutagenic and are risk factors for human cancer. In recent years, the intake of fast-food meat products has increased exponentially due to their convenience. Therefore, it is important to assess the health risks of HCAs and provide useful public dietary guidelines. Eight fast-food meat products were selected from the Chinese market, including chicken, beef, and fish, to evaluate their health risk in conjunction with HCAs. Crispy chicken drumsticks contained the maximum level of total HCAs (24.18 ± 3.57 ng/g), followed by crispy fried chicken burgers (19.99 ± 1.41 ng/g) and traditional Chinese nuggets (19.17 ± 1.23 ng/g), whereas shrimp cake burgers had the lowest levels (13.17 ± 1.77 ng/g). Crispy chicken drumsticks (men: 169.12 ng/day, women: 108.70 ng/day), hot chicken wings (men: 126.32 ng/day, women: 142.11 ng/day), and crispy fried chicken burgers (men: 129.78 ng/day, women: 59.91 ng/day) were found to provide the highest dietary intake of HCAs in both genders, which may lead to an increase in colorectal and breast cancers. PRACTICAL APPLICATIONS: The rapid expansion of the Chinese fast-food industry has promoted serious health problems, such as colorectal cancer and some cardiovascular diseases. Several epidemiological studies revealed that a high intake of processed meats may increase the risk of cancer in humans because cooking food proteins, such as meat, at high temperatures could produce high levels of carcinogenic compounds, such as HCAs. Because of the vast variation in eating habits, preparation methods and the frequency of meat consumption, it is important to evaluate the accurate level of HCAs in commercially available fast-food meat products with the aim to clarify the association between processed meats and the health risk.


Assuntos
Aminas/administração & dosagem , Fast Foods/análise , Compostos Heterocíclicos/administração & dosagem , Produtos da Carne/análise , Neoplasias/epidemiologia , Aminas/toxicidade , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , China/epidemiologia , Cor , Culinária , Dieta , Feminino , Compostos Heterocíclicos/toxicidade , Temperatura Alta , Humanos , Concentração de Íons de Hidrogênio , Masculino , Neoplasias/etiologia , Fatores de Risco
13.
Toxicol Appl Pharmacol ; 364: 97-105, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30582946

RESUMO

Benzo[a]pyrene (BaP), is a known human carcinogen (International Agency for Research on Cancer (IARC) class 1). The remarkable sensitivity (zepto-attomole 14C in biological samples) of accelerator mass spectrometry (AMS) makes possible, with de minimus risk, pharmacokinetic (PK) analysis following [14C]-BaP micro-dosing of humans. A 46 ng (5 nCi) dose was given thrice to 5 volunteers with minimum 2 weeks between dosing and plasma collected over 72 h. [14C]-BaPeq PK analysis gave plasma Tmax and Cmax values of 1.25 h and 29-82 fg/mL, respectively. PK parameters were assessed by non- compartment and compartment models. Intervals between dosing ranged from 20 to 420 days and had little impact on intra-individual variation. DNA, extracted from peripheral blood mononuclear cells (PBMCs) of 4 volunteers, showed measurable levels (LOD ~ 0.5 adducts/1011 nucleotides) in two individuals 2-3 h post-dose, approximately three orders of magnitude lower than smokers or occupationally-exposed individuals. Little or no DNA binding was detectable at 48-72 h. In volunteers the allelic variants CYP1B1*1/*⁎1, *1/*3 or *3/*3 and GSTM1*0/0 or *1 had no impact on [14C]-BaPeq PK or DNA adduction with this very limited sample. Plasma metabolites over 72 h from two individuals (one CYP1B1*1/*1 and one CYP1B1*3/*3) were analyzed by UPLC-AMS. In both individuals, parent [14C]-BaP was a minor constituent even at the earliest time points and metabolite profiles markedly distinct. AMS, coupled with UPLC, could be used in humans to enhance the accuracy of pharmacokinetics, toxicokinetics and risk assessment of environmental carcinogens.


Assuntos
Benzo(a)pireno/farmacocinética , Carcinógenos/farmacocinética , Cromatografia Líquida/métodos , Espectrometria de Massas , Administração Oral , Adulto , Idoso , Benzo(a)pireno/administração & dosagem , Benzo(a)pireno/efeitos adversos , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Adutos de DNA/metabolismo , Feminino , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Variantes Farmacogenômicos , Medição de Risco , Adulto Jovem
14.
Adv Exp Med Biol ; 1210: 29-55, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31900903

RESUMO

Prostate cancer (PC) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of cancer-related to death in men. The major risk factors for PC are age, family history, and African American ethnicity. Epidemiological studies have reported large geographical variations in PC incidence and mortality, and thus lifestyle and dietary factors influence PC risk. High fat diet, dairy products, alcohol and red meats, are considered as risk factors for PC. This book chapter provides a comprehensive, literature-based review on dietary factors and their molecular mechanisms of prostate carcinogenesis. A large portion of our knowledge is based on epidemiological studies where dietary factors such as cancer promoting agents, including high-fat, dairy products, alcohol, and cancer-initiating genotoxicants formed in cooked meats have been evaluated for PC risk. However, the precise mechanisms in the etiology of PC development remain uncertain. Additional animal and human cell-based studies are required to further our understandings of risk factors involved in PC etiology. Specific biomarkers of chemical exposures and DNA damage in the prostate can provide evidence of cancer-causing agents in the prostate. Collectively, these studies can improve public health research, nutritional education and chemoprevention strategies.


Assuntos
Carcinógenos/administração & dosagem , Carcinógenos/farmacologia , Adutos de DNA/efeitos dos fármacos , Neoplasias da Próstata/genética , Animais , Dieta/efeitos adversos , Humanos , Masculino , Carne/efeitos adversos , Fatores de Risco
15.
Int J Mol Sci ; 19(10)2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30314274

RESUMO

Platelet-activating factor-receptor (PAF-R) agonists are pleiotropic lipid factors that influence multiple biological processes, including the induction and resolution of inflammation as well as immunosuppression. PAF-R agonists have been shown to modulate tumorigenesis and/or tumor growth in various skin cancer models by suppressing either cutaneous inflammation and/or anti-tumoral adaptive immunity. We have previously shown that a chronic systemic PAF-R agonist administration of mice enhances the growth of subcutaneously implanted melanoma tumors. Conversely, chronic topical applications of a PAF-R agonist suppressed non-melanoma skin cancer (NMSC) in a topical chemical carcinogenesis model (dimethylbenz[a]anthracene/phorbol 12-myristate 13-acetate (DMBA/PMA)) in-part via anti-inflammatory effects. These results indicate that the context of PAF-R agonist exposure via either chronic cutaneous or systemic administration, result in seemingly disparate effects on tumor promotion. To further dissect the contextual role of PAF-R agonism on tumorigenesis, we chronically administered systemic PAF-R agonist, carbamoyl-PAF (CPAF) to mice under a cutaneous chemical carcinogenesis protocol, recently characterized to initiate both NMSC and melanocytic nevus formation that can progress to malignant melanoma. Our results showed that while systemic CPAF did not modulate melanocytic nevus formation, it enhanced the growth of NMSC tumors.


Assuntos
Glicoproteínas da Membrana de Plaquetas/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Animais , Carcinógenos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Humanos , Camundongos , Neoplasias Cutâneas/etiologia , Carga Tumoral
16.
Biochem Biophys Res Commun ; 506(1): 12-19, 2018 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-30333090

RESUMO

Although the regeneration of the adult liver depends on hepatic progenitor cells (HPCs), many uncertainties regarding hepatic regeneration in the injured liver remain. Trefoil factor family 1 (TFF1), a secretory protein predominantly expressed in the gastrointestinal tract, is responsible for mucosal restitution. Here, we investigated the role of TFF1 in liver regeneration using a mouse model of hepatic injury (choline-deficient ethionine-supplemented diet and carbon tetrachloride administration) and genetically engineered mice (TFF1 knockout (TFF1-/-)). Immunohistochemistry analysis of human liver samples revealed TFF1 expression in the hepatocytes close to ductular reaction and the regenerating biliary epithelium in injured liver. The number of cytokeratin 19 (CK19)-positive bile ducts was significantly decreased in the TFF1-/- mice after liver injury. Notch pathway in the TFF1-/- mice was also downregulated. HPCs in the control mice differentiated into biliary cells (CK19+/SRY HMG box 9 (SOX9)+) more frequently. In contrast, HPCs in the TFF1-/- mice more frequently differentiated into a hepatic lineage (alpha fetoprotein+/SOX9+) after acute liver damage. Hepatocyte proliferation was upregulated, and the liver weight was increased in TFF1-/- mice in response to chronic liver damage. Thus, TFF1 is responsible for liver regeneration after liver injury by promoting HPC differentiation into a biliary lineage and inhibiting HPC differentiation into a hepatic lineage.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Hepatócitos/metabolismo , Regeneração Hepática/genética , Células-Tronco/metabolismo , Fator Trefoil-1/genética , Animais , Ductos Biliares/citologia , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/metabolismo , Tetracloreto de Carbono/administração & dosagem , Carcinógenos/administração & dosagem , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundário , Diferenciação Celular , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Deficiência de Colina/genética , Deficiência de Colina/metabolismo , Deficiência de Colina/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Dieta/efeitos adversos , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Etionina/administração & dosagem , Regulação da Expressão Gênica , Hepatite Crônica/genética , Hepatite Crônica/metabolismo , Hepatite Crônica/patologia , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , Queratina-19/genética , Queratina-19/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Regeneração Hepática/efeitos dos fármacos , Camundongos , Camundongos Knockout , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Fator Trefoil-1/deficiência
17.
Arch Toxicol ; 92(12): 3459-3469, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30259071

RESUMO

Cooking food at high temperatures produces genotoxic chemicals and there is concern about their impact on human health. DNA damage caused by individual chemicals has been investigated but few studies have examined the consequences of exposure to mixtures as found in food. The current study examined the mutagenic response to binary mixtures of benzo[a]pyrene (BaP) with glycidamide (GA), BaP with acrylamide (AC), or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) with GA at human-relevant concentrations (sub-nM). The metabolically competent human MCL-5 cells were exposed to these chemicals individually or in mixtures and mutagenicity was assessed at the thymidine kinase (TK) locus. Mixture exposures gave dose-responses that differed from those for the individual chemicals; for the BaP-containing mixtures, an increased mutation frequency (MF) at low concentration combinations that were not mutagenic individually, and decreased MF at higher concentration combinations, compared to the calculated predicted additive MF of the individual chemicals. In contrast, the mixture of PhIP with GA did not increase MF above background levels. These data suggest BaP is driving the mutation response and that metabolic activation plays a role; in mixtures with BaP the increased/decreased MF above/below the expected additive MF the order is PhIP > AC > GA. The increase in MF at some low concentration combinations that include BaP is interesting and supports our previous work showing a similar response for BaP with PhIP, confirming this response is not limited to the BaP/PhIP combination. Moreover, the lack of a mutation response for PhIP with GA relative to the response of the individual chemicals at equivalent doses is interesting and may represent a potential avenue for reducing the risk of exposure to environmental carcinogens; specifically, removal of BaP from the mixture may reduce the mutation effect, although in the context of food this would be significantly challenging.


Assuntos
Acrilamida/toxicidade , Benzo(a)pireno/toxicidade , Compostos de Epóxi/toxicidade , Imidazóis/toxicidade , Acrilamida/administração & dosagem , Benzo(a)pireno/administração & dosagem , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Carcinógenos Ambientais/administração & dosagem , Carcinógenos Ambientais/toxicidade , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Compostos de Epóxi/administração & dosagem , Alimentos/toxicidade , Humanos , Imidazóis/administração & dosagem , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade , Mutagênicos/administração & dosagem , Mutagênicos/toxicidade , Mutação/efeitos dos fármacos
18.
Am J Physiol Lung Cell Mol Physiol ; 315(5): L752-L764, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30091382

RESUMO

The function and cell surface phenotype of lung macrophages vary within the respiratory tract. Alterations in the bioenergetic profile of macrophages may also be influenced by their location within the respiratory tract. This study sought to characterize the bioenergetic profile of macrophages sampled from different locations within the respiratory tract at baseline and in response to ex vivo xenobiotic challenge. Surface macrophages recovered from healthy volunteers by induced sputum and by bronchial and bronchoalveolar lavage were profiled using extracellular flux analyses. Oxygen consumption and extracellular acidification rates were measured at rest and after stimulation with lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate (PMA), or 1,2-naphthoquinone (1,2-NQ). Oxygen consumption and extracellular acidification rates were highly correlated for all macrophage samples. Induced sputum macrophages had relatively higher oxygen consumption and extracellular acidification rates and were largely reliant on glycolysis. In contrast, bronchial fraction and bronchoalveolar macrophages depended more heavily on mitochondrial respiration. Bronchoalveolar macrophages showed elevated LPS-induced cytokine responses. Unlike their autologous peripheral blood monocytes, lung macrophages from any source did not display bioenergetic changes following LPS stimulation. The protein kinase C activator PMA did not affect mitochondrial respiration, whereas the air pollutant 1,2-NQ induced marked mitochondrial dysfunction in bronchoalveolar and bronchial fraction macrophages. The bioenergetic characteristics of macrophages from healthy individuals are dependent on their location within the respiratory tract. These findings establish a regional bioenergetic profile for macrophages from healthy human airways that serves as a reference for changes that occur in disease.


Assuntos
Brônquios/metabolismo , Lavagem Broncoalveolar , Mediadores da Inflamação/metabolismo , Macrófagos Alveolares/metabolismo , Escarro/metabolismo , Brônquios/efeitos dos fármacos , Carcinógenos/administração & dosagem , Células Cultivadas , Metabolismo Energético , Feminino , Glicólise , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos Alveolares/citologia , Macrófagos Alveolares/efeitos dos fármacos , Masculino , Escarro/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia
19.
Anal Chem ; 90(20): 11863-11872, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30086646

RESUMO

The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent lung carcinogen that exerts its carcinogenic effects upon metabolic activation. The identification and quantitation of NNK metabolites could identify potential biomarkers of bioactivation and detoxification of this potent carcinogen and may be used to predict lung cancer susceptibility among smokers. Here, we used in vivo isotope-labeling and high-resolution-mass-spectrometry-based methods for the comprehensive profiling of all known and unknown NNK metabolites. The sample-enrichment, LC-MS, and data-analysis workflow, including a custom script for automated d0- d4- m/ z-pair-peak detection, enabled unbiased identification of numerous NNK metabolites. The structures of the metabolites were confirmed using targeted LC-MS2 with retention-time ( tR) and MS2-fragmentation comparisons to those of standards when possible. Eleven known metabolites and unchanged NNK were identified simultaneously. More importantly, our workflow revealed novel NNK metabolites, including 1,3-Diol (13), α-OH-methyl-NNAL-Gluc (14), nitro-NK- N-oxide (15), nitro-NAL- N-oxide (16), γ-OH NNAL (17), and three N-acetylcysteine (NAC) metabolites (18a-c). We measured the differences in the relative distributions of a panel of nitroso-containing NNK-specific metabolites in rats before and after phenobarbital (PB) treatment, and this served as a demonstration of a general strategy for the detection of metabolic differences in animal and cell systems. Lastly, we generated a d4-labeled NNK-metabolite mixture to be used as internal standards ( d4-rat urine) for the relative quantitation of NNK metabolites in humans, and this new strategy will be used to assess carcinogen exposure and ultimately to evaluate lung-cancer risk and susceptibility in smokers.


Assuntos
Carcinógenos/análise , Carcinógenos/metabolismo , Metabolômica , Animais , Carcinógenos/administração & dosagem , Cromatografia Líquida , Injeções Intraperitoneais , Marcação por Isótopo , Espectrometria de Massas , Estrutura Molecular , Nitrosaminas/administração & dosagem , Nitrosaminas/metabolismo , Nitrosaminas/urina , Ratos , Ratos Endogâmicos F344
20.
Cell Mol Biol (Noisy-le-grand) ; 64(10): 34-39, 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30084793

RESUMO

 Arsenic is carcinogenic to human beings, and environmental exposure to arsenic is a public health issue that affects large populations around the world. Thus, studies are needed to determine the mode of action of arsenic and to prevent harmful effects that arise from arsenic intake. In particular, knowledge of the effects of arsenic exposure in individuals who are undergoing a carcinogenesis process is lacking. The present study was performed in mice to evaluate the effect of chronic As3+ administration on peritoneal and alveolar macrophages; the As3+ was administered in drinking water over 9 months and there was a two-stage carcinogenesis process. At the end of the experiment, the number of tumors stabilized to below the control values, but the tumors showed increased malignancy. Our objective was to evaluate the systemic effects of chronic As3+ingestion in a population of macrophages that was derived from the peritoneal cavity and the broncho-alveolar trunk of cancerized mice since they are the first line of defense in the immune system. The results showed that the macrophages under all conditions retained their ability to self-regulate their metabolic reactivity. This feature was more evident in peritoneal macrophages than in alveolar macrophages. Furthermore, an increase in the number of macrophages from animals receiving higher doses of As3+ compared to untreated animals was observed. These findings indicate that certain parameters associated with two-stage skin carcinogenesis are modified by the presence of As3+ in drinking water.


Assuntos
Arsenitos/toxicidade , Carcinogênese/induzido quimicamente , Carcinógenos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Compostos de Sódio/toxicidade , Animais , Arsenitos/administração & dosagem , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinógenos/administração & dosagem , Células Cultivadas , Ingestão de Líquidos , Feminino , Macrófagos/patologia , Camundongos , Compostos de Sódio/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA