RESUMEN
The fungal toxin fumonisin B1 (FB1) is a potential human carcinogen based on evidence of renal carcinogenicity in rats and hepatocarcinogenicity in mice. The toxicity and carcinogenicity of FB1 is linked to ceramide synthase inhibition. Based on this mechanism of action and on lack of evidence of genotoxicity, FB1 is considered a non-genotoxic carcinogen. The p53 heterozygous (p53+/-) mouse is a cancer-prone model used for carcinogenesis. The effects of chronic dietary FB1 exposure were characterized in p53+/- mice to confirm non-genotoxicity using a model which is more sensitive to genotoxic than non-genotoxic carcinogens and to clarify the relationship between p53 expression, altered sphingolipid metabolism, and FB1-induced carcinogenesis. Responses to FB1 were similar in p53+/- and p53+/+ mice after 26 weeks exposure to 0, 5, 50 or 150 mg FB1/kg diet, supporting a non-genotoxic mechanism of action. Hepatic adenomas and cholangiomas were observed in mice exposed to 150 mg/kg FB1. For a 10% increase in hepatic megalocytosis, the estimated 95% lower confidence limit of the benchmark dose (BMDL10) ranged from 0.15 and 1.11 mg FB1/kg bw/day. Based on similar responses in p53+/- and p53+/+ mice, p53 and related pathways play a secondary role in responses to FB1 toxicity and carcinogenesis.
Asunto(s)
Fumonisinas/toxicidad , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Adenoma de los Conductos Biliares/inducido químicamente , Adenoma de Células Hepáticas/inducido químicamente , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Dieta , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Heterocigoto , Homocigoto , Hígado/citología , Hígado/efectos de los fármacos , Neoplasias Hepáticas/inducido químicamente , Ratones , Ratones Transgénicos , Distribución AleatoriaRESUMEN
UNLABELLED: DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized, they accumulate in body tissue, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, which is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 2,2',4,4',5,5'-Hexachlorobiphenyl (PCB 153) was produced as a component of some commercial PCB mixtures before 1977 for the electric industry as a dielectric insulating fluid for transformers and capacitors. Manufacture and use of the chemical was stopped due to increased PCB residues in the environment, but it continues to be released into the environment through the use and disposal of products containing PCBs, as by-products during the manufacture of certain organic chemicals, and during the combustion and biodegradation of some waste materials. Bioaccumulation of PCB 153 results in persistent levels in animal and human tissues. PCB 153 was selected for study by the National Toxicology Program as a part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. PCB 153 was included since it is present at the highest PCB concentrations in human samples on a molar basis. PCB 153 was also included in a mixture study with PCB 126, since previous studies have demonstrated interactions between PCB 153 and DLCs on pharmacokinetic and biological effects. While one of the aims of this study was a comparative analysis of effects seen with PCB 126 and the mixture of PCB 126 and PCB 153, in this Technical Report only the results of the present study of PCB 153 are presented and discussed. 2-YEAR STUDY: Female Harlan Sprague-Dawley rats were administered PCB 153 (greater than 99% pure) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. Groups of 80 (3,000 microg PCB 153/kg body weight), 81 (100, 300, and 1,000 microg/kg), or 82 (10 microg/kg) female rats received PCB 153 in corn oil:acetone (99:1) by gavage at doses of 10, 100, 300, 1,000, or 3,000 microg/kg 5 days per week for up to 105 weeks; a group of 81 female rats received the corn oil:acetone (99:1) vehicle alone. A stop-exposure group of 50 female rats was administered 3,000 microg/kg for 30 weeks and then the vehicle for the remainder of the study. Dose selection for the PCB 153 study was based on the range of PCB 153 doses used in the mixture study of PCB 126 and PCB 153 (10 to 3,000 microg/kg). Survival of dosed groups was similar to that of the vehicle control group. Mean body weights of 3,000 microg/kg core study rats were less than those of the vehicle controls after week 69 of the study. Thyroid Hormone Concentrations: Serum total thyroxine (T4), free T4, and total triiodothyronine (T3) concentrations in the 3,000 microg/kg group were significantly lower than those in the vehicle controls at the 14-week interim evaluation. At the 31-week interim evaluation, no significant differences were observed in serum total T4, free T4, T3, or thyroid stimulating hormone concentrations. At the 53-week interim evaluation, serum total T4 and free T4 concentrations in the 3,000 microg/kg group were significantly lower than in the vehicle controls. Hepatic Cell Proliferation Data: No significant differences in hepatocellular labeling index were observed between the vehicle control and dosed groups at any of the interim evaluations. Cytochrome P450 Enzyme Activities Hepatic pentoxyresorufin-O-deethylase activities were highly and significantly elevated relative to the vehicle control groups. Maximum increases over controls at 14, 31, and 53 weeks were 136-, 140-, and 40-fold, respectively. Hepatic 7-ethoxyresorufin-O-deethylase (EROD) and acetanilide-4-hydroxylase (A4H) activities were significantly elevated over controls at 14 and 31 weeks; increases were less than twofold. At 14 weeks, EROD activities in the lung were dose-dependently reduced compared to vehicle controls. Determinations of PCB 153 Concentrations in Tissues: In the fat from vehicle controls, detectable levels of PCB 153 were observed at 14, 31, and 53 weeks and at the end of the 2-year study. Fat concentrations of PCB 153 increased with increasing doses of PCB 153 and tended to increase with the longer exposure durations. In the fat of the 3,000 microg/kg stop-exposure group, PCB 153 concentrations were between the levels observed in the 300 and 1,000 microg/kg groups. In the liver of vehicle controls, no measurable concentrations of PCB 153 were observed at any time point. In dosed groups, hepatic concentrations of PCB 153 increased with increasing dose and longer exposure duration. Measurable concentrations of PCB 153 were observed in the lungs of vehicle control rats at 31 and 53 weeks and at 2 years. At all time points, PCB 153 lung and blood concentrations increased with increasing dose, and blood concentrations increased with duration of exposure. In liver, lung, and blood of rats from the 3,000 microg/kg stop-exposure group, PCB 153 concentrations were slightly above or below the levels observed in the 1,000 microg/kg group. Organ Weights: Absolute liver weights of 1,000 microg/kg rats and absolute and relative liver weights of 3,000 microg/kg rats were significantly greater than those of vehicle controls at week 14. At week 31, relative liver weights of 1,000 microg/kg rats and absolute and relative liver weights of 3,000 microg/kg rats were significantly greater than those of vehicle controls. At week 53, absolute and relative liver weights were significantly greater in rats administered 100 microg/kg or greater compared to vehicle controls. Absolute kidney weights of all exposed groups and the relative kidney weight of 3,000 microg/kg rats were significantly increased at week 53. Pathology and Statistical Analyses: The incidences of hepatocyte hypertrophy were significantly increased in the 1,000 and 3,000 microg/kg groups at 14 weeks and in all groups administered 300 microg/kg or greater at 31 and 53 weeks. At 2 years, the incidences of hepatocyte hypertrophy were significantly increased in all dosed groups. The incidences of diffuse fatty change in the 300 microg/kg or greater groups and bile duct hyperplasia of the liver in 300 microg/kg and 3,000 microg/kg (core and stop-exposure) groups were significantly increased. The incidences of oval cell hyperplasia and pigmentation of the liver were significantly increased in the 3,000 microg/kg core study group. At 2 years, two cholangiomas were seen in the 1,000 microg/kg group and two cholangiomas were seen in the 3,000 microg/kg stop-exposure group. A single hepatocellular adenoma was observed in the 3,000 microg/kg core study group. At 53 weeks, sporadic incidences of minimal to mild follicular cell hypertrophy of the thyroid gland occurred in all groups (except 10 microg/kg). At 2 years, the incidences of minimal to mild follicular cell hypertrophy were significantly increased in the 300 microg/kg and 3,000 microg/kg (core and stop-exposure) groups. At 2 years, significantly increased incidences of chronic active inflammation in the ovary and oviduct occurred in the 1,000 and 3,000 microg/kg core study groups. Incidences of suppurative inflammation of the uterus in the 1,000 microg/kg group and chronic active inflammation in the 3,000 microg/kg core study group were significantly greater than those in the vehicle control group. CONCLUSIONS: Under the conditions of this 2-year gavage study there was equivocal evidence of carcinogenic activity of PCB 153 in female Harlan Sprague-Dawley rats based on the occurrences of cholangioma of the liver. PCB 153 administration caused increased incidences of nonneoplastic lesions of the liver, thyroid gland, ovary, oviduct, and uterus in female rats.
Asunto(s)
Conductos Biliares Intrahepáticos/patología , Carcinógenos/toxicidad , Bifenilos Policlorados/toxicidad , Adenoma de los Conductos Biliares/inducido químicamente , Adenoma de los Conductos Biliares/patología , Administración Oral , Animales , Neoplasias de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/patología , Aumento de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Hígado/efectos de los fármacos , Hígado/patología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Hormonas Tiroideas/sangre , Pruebas de ToxicidadRESUMEN
Human liver cancers have been associated mainly with chronic inflammations such as viral hepatitis B or C. This suggests that prolonged cell damage by chronic inflammation is critical in cancer development. Overproduction of nitric oxide (NO.) and its derivative (NOx, peroxynitrite) has been implicated as a cause of tissue damage by inflammation, thus contributing to tumor promotion. We have demonstrated the expression of the inducible isoform of nitric oxide synthase (iNOS) and 3-nitrotyrosine, a marker of peroxynitrite formation, by immunohistochemistry in preneoplastic and neoplastic rat liver tissues induced by continuous infusion of N-nitrosodiethylamine with mini-pumps. The preneoplastic lesions were characterized by proliferation of phenotypically altered hepatic foci (PAHF), dysplastic hepatocytes and oval cells. Histologically, the tumors were hepatocellular carcinomas (HCCs) of trabecular, (pseudo)glandular and solid types with or without cholangiocellular involvement. iNOS was located mainly in oval cells, capillary endothelial and muscular cells, epithelia of cholangiomas and glandular HCCs. 3-Nitrotyrosine was observed in the cytoplasms of PAHF and dysplastic hepatocytes in preneoplasias and in the cytoplasms of some living or apoptotic HCC cells, connective tissues, proteinaceous fluids, sinusoidal endothelia of tumorous hepatocytes and cholangiomas in tumors. From these observations, we suggest that: (i) chronic tissue damage by chemical carcinogens may act to induce iNOS and peroxynitrite formation; (ii) oval cells play a key role in development and/or growth of tumor tissues by producing NO. via iNOS, which may also cause tissue damage by peroxynitrite; (iii) iNOS can be considered as a phenotypic marker in cells of oval cell lineage and neovascularized capillaries in tumor tissues.
Asunto(s)
Neoplasias Hepáticas/enzimología , Óxido Nítrico Sintasa/metabolismo , Tirosina/análogos & derivados , Adenoma de los Conductos Biliares/inducido químicamente , Adenoma de los Conductos Biliares/enzimología , Adenoma de los Conductos Biliares/patología , Animales , Apoptosis , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/patología , Dietilnitrosamina , Inmunohistoquímica , Hígado/enzimología , Hígado/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/patología , Masculino , Óxido Nítrico Sintasa de Tipo II , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/enzimología , Lesiones Precancerosas/patología , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Tirosina/metabolismoRESUMEN
The modifying effects of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a mutagenic by-product in chlorinated water, on the development of glandular stomach cancers were investigated in Wistar rats. A total of 120 males, 6 weeks of age, were divided into six groups. After initiation with 100 ppm N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) solution and 5% NaCl diet for 8 weeks, 30 rats each in groups 1-3 were given MX in the drinking water at concentrations of 30, 10, or 0 ppm for the following 57 weeks. Ten animals each in groups 4-6 were administered the MX without prior carcinogen exposure. There were no statistical significant differences in final body weights between the groups. The incidences and multiplicities of adenocarcinomas in the glandular stomachs were significantly higher (P < 0.05) in the initiated 30 ppm MX group than those in the MNNG/NaCl group. The incidences of atypical hyperplasias in the glandular stomachs were also significantly increased (P < 0.05 or 0.01) by the MX treatments. With their multiplicity, the effects were clearly dose dependent. Interestingly, the 30 ppm MX alone itself induced atypical hyperplasias in the pylorus, although the incidences and severity were low. Moreover, MX showed a tendency to enhance the development of intrahepatic cholangiocellular tumors and thyroid follicular cell tumors in the MNNG-treated animals. The results of the present study thus indicate that MX exerts promoting effects when given during the postinitiation phase of two-stage glandular stomach carcinogenesis in rats.
Asunto(s)
Adenocarcinoma/inducido químicamente , Carcinógenos/toxicidad , Furanos/toxicidad , Metilnitronitrosoguanidina/toxicidad , Mutágenos/toxicidad , Neoplasias Gástricas/inducido químicamente , Contaminantes Químicos del Agua/toxicidad , Adenocarcinoma Folicular/inducido químicamente , Adenoma de los Conductos Biliares/inducido químicamente , Animales , Neoplasias de los Conductos Biliares/inducido químicamente , Conductos Biliares Intrahepáticos/efectos de los fármacos , Conductos Biliares Intrahepáticos/patología , Peso Corporal/efectos de los fármacos , Colangiocarcinoma/inducido químicamente , Cocarcinogénesis , Fibrosis , Hiperplasia , Masculino , Tamaño de los Órganos/efectos de los fármacos , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/patología , Píloro/efectos de los fármacos , Píloro/patología , Ratas , Ratas Wistar , Estómago/efectos de los fármacos , Estómago/patología , Gastropatías/inducido químicamente , Gastropatías/patología , Neoplasias de la Tiroides/inducido químicamenteRESUMEN
Immunohistochemical studies have suggested that the tyrosine kinase growth factor receptor p185neu is overexpressed in a high percentage of human cholangiocarcinomas. To establish the specificity and temporal relationship between the expression of this receptor in cholangiocarcinogenesis, we investigated c-neu expression in precancerous cholangiofibrotic tissue and subsequently derived primary and transplantable cholangiocarcinomas originated in the livers of furan-treated rats. Proliferated bile ductules formed in rat models of bile ductular hyperplasia and the cell types of normal adult rat liver were also analyzed for c-neu expression. c-neu expression was not detected in normal adult rat liver by either Western blotting, immunohistochemistry, or in situ hybridization. In comparison, all of the cholangiocarcinomas analyzed, which were characterized by intestinal-type mucin-producing neoplastic glands, exhibited a prominent band with a molecular weight 185 kd, corresponding to p185neu. Only the neoplastic glandular epithelia of the cholangiocarcinomas showed a strong immunoreactivity for p185neu, which was predominantly localized to their cell surface but also observed cytoplasmically. In situ hybridization further revealed the cytoplasm of the tumor glandular epithelial cells to be strongly positive for c-neu mRNA transcripts. Of particular interest was our finding that c-neu is expressed early in furan cholangiocarcinogenesis, being more pronounced in the metaplastic intestinal glands of cholangiofibrotic tissue than in hyperplastic biliary epithelial cells in either the same tissue or in hyperplastic bile ductule tissue. Our results demonstrate that c-neu overexpression is a prominent feature of intestinal-type cholangiocarcinomas as well as of metaplastic intestinal glands that precede their development and is detected at lower levels in hyperplastic biliary epithelia. The overexpression of c-neu in the metaplastic and malignant neoplastic glands also correlated with their increased proliferating cell nuclear antigen (PCNA) labeling indices relative to those of hyperplastic biliary ducts and ductules and also appeared to correlate with their intestinal glandular pattern of differentiation.
Asunto(s)
Adenoma de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/metabolismo , Neoplasias Experimentales/metabolismo , Receptor ErbB-2/biosíntesis , Adenoma de los Conductos Biliares/inducido químicamente , Adenoma de los Conductos Biliares/patología , Animales , Neoplasias de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Western Blotting , Colestasis/inducido químicamente , Colestasis/metabolismo , Colestasis/patología , Modelos Animales de Enfermedad , Furanos , Regulación Neoplásica de la Expresión Génica , Hiperplasia/metabolismo , Hiperplasia/patología , Técnicas para Inmunoenzimas , Hibridación in Situ , Hígado/metabolismo , Hígado/patología , Ratas , Ratas Endogámicas F344 , Receptor ErbB-2/genéticaRESUMEN
Vinyl chloride is a DNA-damaging carcinogen which induces liver angiosarcomas in humans and animals. Activation of the Ki-ras 2 gene by a GC-->AT transition at the second base of codon 13 in human liver angiosarcomas associated with occupational exposure to vinyl chloride has been reported recently. In order to compare the molecular pathways of carcinogenesis in humans and animals, Sprague-Dawley rats were exposed to vinyl chloride and hepatic tumors, including two hepatocellular carcinomas and five liver angiosarcomas, were investigated for mutations at codons 12, 13 and 61 of the Ha-ras, Ki-ras and N-ras genes. High molecular weight DNA was amplified by the polymerase chain reaction and point mutations were analyzed by allele specific oligonucleotide hybridization, direct sequencing of polymerase chain reaction products and sequencing after cloning. None of the tumors exhibited a mutation in codons 12, 13 and 61 of the Ki-ras gene, nor in codons 12 of the Ha-ras gene or 61 of the N-ras gene. However, an activating AT-->TA transversion at base 2 of codon 61 of the Ha-ras gene was detected in the two hepatocellular carcinomas. Mutations involving codon 13 (GGC-->GAC) and codon 36 (ATA-->CTA) of the N-ras A gene were detected in two liver angiosarcomas, suggesting that the nature of the ras gene affected by a given carcinogen depends on host factors specific to cell types. Several additional base pair substitutions were found in exon 1 of the N-ras B and C sequences. NIH 3T3 transfection assays and Southern blot analysis of DNA from transformed NIH 3T3 cells confirmed the presence of a dominant activated N-ras gene. These results emphasize the differences in the molecular pathways leading to tumors in humans and rats and within a given species between different cell types.
Asunto(s)
Adenoma de los Conductos Biliares/genética , Codón/genética , Genes ras/genética , Hemangiosarcoma/genética , Neoplasias Hepáticas Experimentales/genética , Mutación Puntual , Células 3T3 , Adenoma de los Conductos Biliares/inducido químicamente , Animales , Secuencia de Bases , Femenino , Hemangiosarcoma/inducido químicamente , Neoplasias Hepáticas Experimentales/inducido químicamente , Masculino , Ratones , Datos de Secuencia Molecular , Embarazo , Ratas , Ratas Sprague-Dawley , Transfección , Cloruro de ViniloRESUMEN
The case of a 71-year-old man with thorotrastosis and a cholangiocarcinoma detected by MRI is presented, and the radiographic appearance of the cholangiocarcinoma is discussed. We concluded that MR is more useful for detecting Thorotrast-induced liver tumors than US and CT, but CT is more useful for the detection of Thorotrast deposits.
Asunto(s)
Adenoma de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/inducido químicamente , Conductos Biliares Intrahepáticos/patología , Dióxido de Torio/efectos adversos , Adenoma de los Conductos Biliares/diagnóstico , Anciano , Neoplasias de los Conductos Biliares/diagnóstico , Medios de Contraste , Gadolinio DTPA , Humanos , Imagen por Resonancia Magnética , Masculino , Compuestos Organometálicos , Ácido Pentético , Tomografía Computarizada por Rayos XRESUMEN
This study was performed to clarify the promoting effects of primary or secondary bile acid load on the occurrence of cholangiocarcinoma, using Syrian golden hamsters. These hamsters received subcutaneously diisopropanolnitrosamine (DIPN) once weekly for 10 weeks, and simultaneously were given a standard pellet diet (control group) containing taurocholic acid (TCA group) or deoxycholic acid (DCA group). The rates of cholangiocarcinoma at 20 weeks were 23% in the control group, 60% in the TCA group and 59% in the DCA group. There were significant differences between the control and the TCA or DCA groups (p < 0.05). The rates of proliferation of bile ductules or hyperplasia of the bile duct epithelium and the bromodeoxyuridine labeling indices of bile duct epithelial cells were high in both groups treated with bile acids, compared with those in the control group. Regarding the composition of bile acids in the intraductal bile, the TCA and DCA groups revealed a decrease in primary bile acids and an increase in DCA. These results suggest that both TCA and DCA given orally promote the occurrence of DIPN-induced cholangiocarcinoma.
Asunto(s)
Adenoma de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/inducido químicamente , Carcinógenos , Cocarcinogénesis , Ácido Desoxicólico/farmacología , Nitrosaminas , Ácido Taurocólico/farmacología , Animales , Peso Corporal/efectos de los fármacos , Cricetinae , Ácido Desoxicólico/administración & dosificación , Ingestión de Alimentos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Mesocricetus , Índice Mitótico , Ácido Taurocólico/administración & dosificaciónRESUMEN
The clinical, pathological and laparoscopic data of five patients with liver disease due to Thorotrast are presented. Laparoscopy showed various degrees of fibrosis and nodularity. One patient developed cholangiocarcinoma and two showed dysplasia at biopsy. The laparoscopic appearance is practically diagnostic.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Dióxido de Torio/efectos adversos , Adenoma de los Conductos Biliares/inducido químicamente , Adenoma de los Conductos Biliares/patología , Anciano , Neoplasias de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/patología , Biopsia , Neoplasias Óseas/inducido químicamente , Neoplasias Óseas/patología , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/patología , Femenino , Fibrosis/inducido químicamente , Fibrosis/patología , Humanos , Laparoscopía , Hígado/efectos de los fármacos , Hígado/patología , Hepatopatías/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Osteosarcoma/inducido químicamente , Osteosarcoma/patologíaAsunto(s)
Anabolizantes/efectos adversos , Carcinoma Hepatocelular/inducido químicamente , Anticonceptivos Orales/efectos adversos , Neoplasias Hepáticas/inducido químicamente , Congéneres de la Testosterona/efectos adversos , Adenoma de los Conductos Biliares/inducido químicamente , Hemangiosarcoma/inducido químicamente , Humanos , Dióxido de Torio/efectos adversosAsunto(s)
Adenoma de los Conductos Biliares/etiología , Azatioprina/efectos adversos , Neoplasias de los Conductos Biliares/etiología , Trasplante de Riñón , Adenoma de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/inducido químicamente , Cadáver , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
The Golden Syrian hamster, which has a bile acid profile similar to that of humans, is often used as an experimental model for cholangiocarcinoma. Unfortunately, most chemical carcinogens result in other tumour types also being induced which can be disadvantageous. In the present study, we describe the development of cholangiocarcinoma associated with precursor lesions of bile duct proliferation and dysplasia which occurred following a single i.v. dose of methylazoxymethyl acetate (10, 20 or 40 mg/kg body weight). Moreover, no other tumours were induced. This model may, therefore, prove useful in investigating the steps involved in the carcinogenesis of cholangiocarcinoma.
Asunto(s)
Adenoma de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/patología , Adenoma de los Conductos Biliares/inducido químicamente , Animales , Neoplasias de los Conductos Biliares/inducido químicamente , Cricetinae , Masculino , Mesocricetus , Acetato de MetilazoximetanolRESUMEN
To simulate the chronic alpha radiation of Thorotrast, the liver of female Wistar rats was exposed to fractionated neutron irradiation at 14-d intervals (0.2 Gy per fraction) over 2 y to a total dose of 10.0 Gy. Prior to the start of irradiation, one-half of the animals received 120 microL of non-radioactive Zirconotrast (ZrO2), which is comparable to Thorotrast with regard to all other physical and chemical properties. One year after beginning irradiation, the first liver tumor was detected. At the end of the life-span study, the incidence of irradiated animals with liver tumors was about 40%. In the animals treated additionally with ZrO2, the incidence, time of onset, and overall number of liver tumors was nearly equal, indicating that the fractionated neutron irradiation was the exclusive cause of tumor development. The lifelong-deposited ZrO2 colloid had no stimulating effect. Compared to earlier animal studies dealing with Thorotrast, the same histological types of benign and malignant liver tumors were found.
Asunto(s)
Neoplasias Hepáticas/etiología , Neoplasias Inducidas por Radiación , Neutrones , Circonio/toxicidad , Adenoma de los Conductos Biliares/inducido químicamente , Adenoma de los Conductos Biliares/etiología , Animales , Femenino , Hemangioma/inducido químicamente , Hemangioma/etiología , Hemangiosarcoma/inducido químicamente , Hemangiosarcoma/etiología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/etiología , Ratas , Ratas Endogámicas , Sarcoma Experimental/inducido químicamente , Sarcoma Experimental/etiologíaRESUMEN
The expression and localization of epidermal growth factor (EGF) receptor were investigated immunohistochemically using anti-EGF receptor antibody in the normal rat liver and 3'-methyl-4-dimethylaminoazobenzen (3'-Me-DAB) induced tumors in rats. In 8 weeks after 3'-Me-DAB treatment, multiple nodules of cholangiocarcinoma were found in the rat liver, and atypical nodules of hepatocytes were also found 14 weeks later. Immunoreactive products against EGF receptor were only slightly positive in the normal liver, the nodule of cholangiocarcinoma, and atypical nodule of hepatocytes. It was noted that EGF receptor immunoreactivity was more intense in non-cancerous tissue adjacent to tumorous nodules than in the cancerous tissue. The present finding suggests that the expression of EGF receptor may be associated with regenerating as well as carcinogenetic processes in the rat liver.
Asunto(s)
Receptores ErbB/metabolismo , Neoplasias Hepáticas Experimentales/metabolismo , Hígado/metabolismo , Adenoma de los Conductos Biliares/inducido químicamente , Adenoma de los Conductos Biliares/metabolismo , Animales , Inmunohistoquímica , Neoplasias Hepáticas Experimentales/inducido químicamente , Masculino , Metildimetilaminoazobenceno , Ratas , Ratas EndogámicasRESUMEN
Aflatoxin B1 has been suggested as a causative agent for a G to T mutation at codon 249 in the p53 gene in human hepatocellular carcinomas from southern Africa and Qidong in China. To test this hypothesis, nine tumors induced by aflatoxin B1 in nonhuman primates were analyzed for mutations in the p53 gene. These included four hepatocellular carcinomas, two cholangiocarcinomas, a spindle cell carcinoma of the bile duct, a hemangioendothelial sarcoma of the liver, and an osteogenic sarcoma of the tibia. None of the tumors showed changes at the third position of codon 249 by cleavage analysis of the HaeIII enzyme site at codon 249. A point mutation was identified in one hepatocellular carcinoma at the second position of codon 175 (G to T transversion) by sequencing analysis of the four conserved domains (II to V) in the p53 gene. These data suggest that mutations in the p53 gene are not necessary in aflatoxin B1 induced hepatocarcinogenesis in nonhuman primates. The occurrence of mutation in codon 249 of the p53 gene in selective samples of human hepatocellular cancers may indicate involvement of environmental carcinogens other than aflatoxin B1 or that hepatitis B virus-related hepatitis is a prerequisite for aflatoxin B1 induction of G to T transversion in codon 249.
Asunto(s)
Aflatoxina B1/toxicidad , Genes p53 , Mutagénesis , Neoplasias Experimentales/genética , Adenoma de los Conductos Biliares/inducido químicamente , Animales , Secuencia de Bases , Neoplasias de los Conductos Biliares/inducido químicamente , Neoplasias Óseas/inducido químicamente , Carcinoma/inducido químicamente , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Exones , Genes p53/efectos de los fármacos , Hemangioendotelioma/inducido químicamente , Intrones , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas Experimentales/inducido químicamente , Macaca fascicularis , Macaca mulatta , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Osteosarcoma/inducido químicamente , Reacción en Cadena de la PolimerasaRESUMEN
In order to investigate the early cellular changes in liver associated with furan cholangiocarcinogenesis, young adult male Fischer 344 rats were administered furan by gavage once a day, 5 days a wk for 2 to 3 wk at doses ranging from 15 to 60 mg/kg of body weight per day. The most conspicuous feature observed in the liver of animals receiving the higher doses of furan was a rapidly developed cholangiofibrosis characterized by the presence of bile ductular hyperplasia, intestinal metaplasia, and fibrosis. Moreover, this lesion was found to be almost exclusively localized to the caudate liver lobe, which by morphometric analysis was further determined to be largely replaced by cholangiofibrotic tissue. Both the hyperplastic bile ductular epithelial cells and the intestinal-like epithelial cells in these areas selectively exhibited a strongly positive immunohistochemical staining for cytokeratin 19 and were supported by well-developed basement membranes enriched in both laminin and type IV collagen. However, in contrast to the hyperplastic bile ductules, electron microscopy of the metaplastic intestinal glands revealed them to be composed mostly of columnar epithelial cells with well-developed striated borders, less numerous mucin-secreting goblet cells, and occasional neuroendocrine-like cells, thus closely resembling in their cellular composition that of intestinal mucosa. These metaplastic glands also showed a more heterogeneous pattern of staining for both gamma-glutamyl transpeptidase and the placental form of glutathione S-transferase than did the hyperplastic bile ductules. At the 60-mg/kg/day furan dose, cholangiolar-like structures composed of biliary epithelial cells and ductular hepatocytic cells at different stages of morphological differentiation were also observed. Phenotypically, the biliary epithelial and "ductular hepatocytes" of these cholangioles shared a common basement membrane containing laminin and type IV collagen, as well as a luminal plasma membrane gamma-glutamyl transpeptidase. On the other hand, only the biliary epithelial cells of the newly appearing mixed cell cholangioles stained positive for cytokeratin 19. Interestingly, unlike hepatocarcinogen-induced oval cells, alpha-fetoprotein expression was not detected in any of the cell types comprising the furan-induced cholangiofibrotic tissue. These results support a novel in vivo model for investigating cell lineages in the development in liver of intestinal metaplasia, "ductular hepatocytes," and cholangiofibrosis in relation to intrahepatic cholangiocarcinogenesis.
Asunto(s)
Adenoma de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos , Furanos/toxicidad , Neoplasias Hepáticas/patología , Hígado/patología , Adenoma de los Conductos Biliares/inducido químicamente , Animales , Neoplasias de los Conductos Biliares/inducido químicamente , Relación Dosis-Respuesta a Droga , Femenino , Furanos/administración & dosificación , Intestinos/patología , Hígado/efectos de los fármacos , Hígado/ultraestructura , Neoplasias Hepáticas/inducido químicamente , Masculino , Metaplasia/inducido químicamente , Metaplasia/patología , Microscopía Electrónica , Fenotipo , Ratas , Ratas Endogámicas F344RESUMEN
A semi-purified corn-based diet containing 50 mg/kg of pure (not less than 90%) fumonisin B1 (FB1), isolated from culture material of Fusarium moniliforme strain MRC 826, was fed to a group of 25 rats over a period of 26 months. A control group of 25 rats received the same diet without FB1. Five rats from each group were killed at 6, 12, 20 and 26 months. The liver was the main target organ in the FB1-treated rats and the hepatic pathological changes were identical to those previously reported in rats fed culture material of F.moniliforme MRC 826. All FB1-treated rats that died or were killed from 18 months onwards suffered from a micro- and macronodular cirrhosis and had large expansile nodules of cholangiofibrosis at the hilus of the liver. Ten out of 15 FB1-treated rats (66%) that were killed and/or died between 18 and 26 months developed primary hepatocellular carcinoma. Metastases to the heart, lungs or kidneys were present in four of the rats with hepatocellular carcinoma. No neoplastic changes were observed in any of the control rats. Chronic interstitial nephritis was present in the kidneys of FB1-treated rats killed after 26 months. No lesions were observed in the esophagus, heart or forestomach of FB1-treated rats and this is contrary to previous findings when culture material of the fungus was fed to rats. It is concluded that FB1 is responsible for the hepatocarcinogenic and the hepatotoxic but not all the other toxic effects of culture material of F.moniliforme MRC 826 in rats.
Asunto(s)
Carcinógenos Ambientales/toxicidad , Fumonisinas , Neoplasias Hepáticas Experimentales/inducido químicamente , Micotoxinas/toxicidad , Adenoma de los Conductos Biliares/inducido químicamente , Animales , Neoplasias Esofágicas/etiología , Microbiología de Alimentos , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática Experimental/inducido químicamente , Masculino , Lesiones Precancerosas/inducido químicamente , Ratas , Ratas EndogámicasRESUMEN
This study was carried out to clarify the influence of incomplete bile duct obstruction (IBDO) on the occurrence and proliferation of cholangiocarcinoma and to evaluate the effect of release of IBDO at an early stage, using 175 Syrian golden hamsters. These hamsters received 500 mg/kg body weight of diisopropanolnitrosamine (DIPN) once weekly for 10 weeks, and then were divided into 3 groups, consisting of the simple laparotomy group (SL group), the IBDO group and 2 week IBDO group, in which IBDO was released after 2 weeks. The occurrence rates of cholangiocarcinoma at 20 weeks were 42% in the SL group, 76% in the IBDO group and 30% in the 2 week IBDO group. The mean numbers of tumors per hamster in the IBDO group were significantly greater than those in other groups (p less than 0.05). Both occurrence rates and numbers of tumors in the 2 week IBDO group were similar to those in the SL group. The proliferation of bile ductules and isolation of bacteria from bile in the IBDO group had higher rates at 15, 20 weeks than those found in the other groups. These results suggest that IBDO has an influence, as promoter, on the occurrence of cholangiocarcinoma induced by DIPN, and the disappearance of its promoting effect is caused by release of the obstruction.
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Adenoma de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/inducido químicamente , Conductos Biliares Intrahepáticos , Colestasis/fisiopatología , Adenoma de los Conductos Biliares/patología , Animales , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Carcinógenos , Cricetinae , Masculino , Mesocricetus , NitrosaminasRESUMEN
The effects of selenium supplementation on induction of cholangiocarcinomas and related precancerous lesions in female Syrian Golden hamsters by N'-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Four-week-old animals were divided into two groups according to the selenium level contained in the drinking water (0.1 ppm or 4.0 ppm) and fed a purified diet containing less than 0.05 ppm of the trace element. Starting at Week 4 of the experiment, hamsters were administered 10 weekly injections of BOP (10 mg/kg body wt) and then killed 18 weeks after the last carcinogen administration. Animals receiving physiological saline alone served as controls. Cholangiocellular carcinomas tended to be reduced, and putative preneoplastic lesions of cholangiofibrosis were significantly decreased in the high-as opposed to the low-selenium groups in terms of both incidence rate and number per effective animal. The respective high and low selenium values for incidence and number were 24/38% and 0.34/0.66, respectively, for cholangiocarcinomas and 50/89% and 1.21/8.44, respectively, for cholangiofibroses. Proliferation of intrahepatic bile ducts was also significantly inhibited in the high-selenium group along with cyst formation. Biochemical investigation revealed both selenium level and glutathione peroxidase activity to be significantly greater in the high-than in the low-selenium group livers. The results thus suggest that selenium may inhibit BOP-induction of bile duct lesions, possibly via glutathione peroxidase-mediated alteration of carcinogenesis.