RESUMEN

Antimony trioxide (AT) is used as a flame retardant in fabrics and plastics. Occupational exposure in miners and smelters is mainly through inhalation and dermal contact. Chronic inhalation exposure to AT particulates in B6C3F1/N mice and Wistar Han rats resulted in increased incidences and tumor multiplicities of alveolar/bronchiolar carcinomas (ABCs). In this study, we demonstrated Kras (43%) and Egfr (46%) hotspot mutations in mouse lung tumors (n = 80) and only Egfr (50%) mutations in rat lung tumors (n = 26). Interestingly, there were no differences in the incidences of these mutations in ABCs from rats and mice at exposure concentrations that did and did not exceed the pulmonary overload threshold. There was increased expression of p44/42 mitogen-activated protein kinase (MAPK) (Erk1/2) protein in ABCs harboring mutations in Kras and/or Egfr, confirming the activation of MAPK signaling. Transcriptomic analysis indicated significant alterations in MAPK signaling such as ephrin receptor signaling and signaling by Rho-family GTPases in AT-exposed ABCs. In addition, there was significant overlap between transcriptomic data from mouse ABCs due to AT exposure and human pulmonary adenocarcinoma data. Collectively, these data suggest chronic AT exposure exacerbates MAPK signaling in ABCs and, thus, may be translationally relevant to human lung cancers.

Asunto(s)

Adenocarcinoma Bronquioloalveolar , Neoplasias Pulmonares , Ratones , Ratas , Humanos , Animales , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/patología , Proteínas Quinasas Activadas por Mitógenos , Exposición por Inhalación/efectos adversos , Ratas Wistar , Ratones Endogámicos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Receptores ErbB/genética

RESUMEN

This article describes data related to the research article entitled "Carcinogenic activity of pentabrominated diphenyl ether mixture (DE-71) in rats and mice" (Dunnick et al., 2018). PBDE-induced hepatocellular tumors harbored Hras and Ctnnb1 mutations and the methods for these studies are provided. Tissue levels of PBDE congeners in rats and mice after oral exposure to PBDE mixture increased with increasing dose of PBDE. There was no correlation between AhR status and the incidence of hepatocellular tumors in female Wistar Han rats. This manuscript provides additional information on the methods for conducting mutational analysis, PBDE tissue level determinations, and AhR genotyping.

RESUMEN

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide; however, the mutational properties of HCC-associated carcinogens remain largely uncharacterized. We hypothesized that mechanisms underlying chemical-induced HCC can be characterized by evaluating the mutational spectra of these tumors. To test this hypothesis, we performed exome sequencing of B6C3F1/N HCCs that arose either spontaneously in vehicle controls ( n = 3) or due to chronic exposure to gingko biloba extract (GBE; n = 4) or methyleugenol (MEG; n = 3). Most archived tumor samples are available as formalin-fixed paraffin-embedded (FFPE) blocks, rather than fresh-frozen (FF) samples; hence, exome sequencing from paired FF and FFPE samples was compared. FF and FFPE samples showed 63% to 70% mutation concordance. Multiple known (e.g., Ctnnb1T41A, BrafV637E) and novel (e.g., Erbb4C559S, Card10A700V, and Klf11P358L) mutations in cancer-related genes were identified. The overall mutational burden was greater for MEG than for GBE or spontaneous HCC samples. To characterize the mutagenic mechanisms, we analyzed the mutational spectra in the HCCs according to their trinucleotide motifs. The MEG tumors clustered closest to Catalogue of Somatic Mutations in Cancer signatures 4 and 24, which are, respectively, associated with benzo(a)pyrene- and aflatoxin-induced HCCs in humans. These results establish a novel approach for classifying liver carcinogens and understanding the mechanisms of hepatocellular carcinogenesis.

Asunto(s)

Carcinógenos/toxicidad , Exoma/genética , Perfilación de la Expresión Génica , Neoplasias Hepáticas Experimentales/genética , Hígado/efectos de los fármacos , Mutación , Análisis de Secuencia de ADN/métodos , Animales , Criopreservación , ADN de Neoplasias/genética , Eugenol/análogos & derivados , Eugenol/toxicidad , Femenino , Formaldehído/química , Ginkgo biloba , Hígado/patología , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones Endogámicos , Adhesión en Parafina , Extractos Vegetales/toxicidad , Reproducibilidad de los Resultados , Fijación del Tejido

RESUMEN

Vinylidene chloride (VDC) has been widely used in the production of plastics and flame retardants. Exposure of B6C3F1 mice to VDC in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increases in renal cell hyperplasia, renal cell adenoma, and renal cell carcinomas (RCCs). Among those differentially expressed genes from controls and RCC of VDC-exposed mice, there was an overrepresentation of genes from pathways associated with chronic xenobiotic and oxidative stress as well as c-Myc overexpression and dysregulation of TP53 cell cycle checkpoint and DNA damage repair pathways in RCC. Trend analysis comparing RCC, VDC-exposed kidney, and chamber control kidney showed a conservation of pathway dysregulation in terms of overrepresentation of xenobiotic and oxidative stress, and DNA damage and cell cycle checkpoint pathways in both VDC-exposed kidney and RCC, suggesting that these mechanisms play a role in the pathogenesis of RCC in VDC-exposed mice.

Asunto(s)

Carcinoma de Células Renales , Dicloroetilenos/toxicidad , Neoplasias Renales , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética , Animales , Carcinoma de Células Renales/inducido químicamente , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/fisiopatología , Relación Dosis-Respuesta a Droga , Femenino , Perfilación de la Expresión Génica , Riñón/efectos de los fármacos , Riñón/patología , Neoplasias Renales/inducido químicamente , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/fisiopatología , Masculino , Ratones , Mutación , Pruebas de Toxicidad Crónica , Proteína p53 Supresora de Tumor/metabolismo

RESUMEN

Endometrial carcinoma is the most common gynecologic malignancy is the United States and accounts for 6% of all cancers in women. The disease is classified as type I or type II based on clinicopathologic and molecular features. It is a multifactorial disease with a number of risk factors, including environmental exposures. How environmental exposures, such as flame retardants, may affect the incidence of endometrial cancer is a topic of current and ongoing interest. Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant found in a variety of household products. A recent 2-year National Toxicology Program carcinogenicity study found that exposure to TBBPA was associated with a marked increase in the development of uterine tumors, specifically uterine carcinomas, in Wistar Han rats. Molecularly, TBBPA-induced uterine carcinomas in Wistar Han rats were characterized by a marked increase in tumor protein 53 mutation compared to spontaneous uterine carcinomas, as well as overexpression of human epidermal growth factor receptor 2. Similar to spontaneous carcinomas, tumors in TBBPA-exposed rats were estrogen receptor-alpha positive and progesterone receptor negative by immunohistochemistry. The morphologic and molecular features of uterine carcinomas in TBBPA-exposed rats resemble those of high-grade type I tumors in women, and these data suggest that exposure to TBBPA may pose an increased cancer risk.

Asunto(s)

Neoplasias Endometriales/genética , Mutación/genética , Bifenilos Polibrominados/toxicidad , Proteína p53 Supresora de Tumor/genética , Neoplasias Uterinas/inducido químicamente , Neoplasias Uterinas/genética , Animales , Femenino , Humanos , Inmunohistoquímica , Ratas , Ratas Wistar , Neoplasias Uterinas/metabolismo , Útero/química , Útero/patología

RESUMEN

The cell of origin of hepatoblastoma (HB) in humans and mice is unknown; it is hypothesized to be a transformed hepatocyte, oval cell, or hepatic progenitor cell. In mice, current dogma is that HBs arise from preexisting hepatocellular neoplasms as a result of further neoplastic transformation. However, there is little evidence supporting this direct relationship. To better understand the relationship between hepatocellular carcinoma (HCC) and HB and determine molecular similarities between mouse and human HB, global gene expression analysis and targeted mutation analysis were performed using HB, HCC, and adjacent liver from the same animals in a recent National Toxicology Program bioassay. There were significant differences in Hras and Ctnnb1 mutation spectra, and by microarray, HBs showed dysregulation of embryonic development, stem cell pluripotency, and genomic imprinting compared to HCC. Meta-analysis showed similarities between HB, early mouse embryonic liver, and hepatocyte-derived stem/progenitor cells compared to HCC. Our data show that there are striking differences between HB and HCC and suggest that HB is a significantly different entity that may arise from a hepatic precursor cell. Furthermore, mouse HB is similar to the human disease at the pathway level and therefore is likely a relevant model for evaluating human cancer hazard.

Asunto(s)

Carcinoma Hepatocelular/genética , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Animales , Carcinoma Hepatocelular/metabolismo , Hepatoblastoma/metabolismo , Humanos , Inmunohistoquímica , Hígado/química , Neoplasias Hepáticas/metabolismo , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Patología Molecular , Toxicología

RESUMEN

Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kirsten rat sarcoma oncogene homolog (Kras), epidermal growth factor receptor (Egfr), and tumor protein 53 (Tp53) mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD)-induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominant in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assay indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents.

Asunto(s)

Adenocarcinoma Bronquioloalveolar/inducido químicamente , Adenocarcinoma Bronquioloalveolar/genética , Cobalto/toxicidad , Receptores ErbB/genética , Genes p53/genética , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma Bronquioloalveolar/patología , Animales , Análisis Mutacional de ADN , ADN de Neoplasias/biosíntesis , ADN de Neoplasias/genética , Polvo , Receptores ErbB/efectos de los fármacos , Exones/genética , Femenino , Genes p53/efectos de los fármacos , Exposición por Inhalación , Neoplasias Pulmonares/patología , Masculino , Ratones , Pruebas de Mutagenicidad , Mutación/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Ratas

RESUMEN

A majority (∼80%) of human malignant mesotheliomas are asbestos-related. However, non-asbestos risk factors (radiation, chemicals, and genetic factors) account for up to 30% of cases. A recent 2-year National Toxicology Program carcinogenicity bioassay showed that male F344/N rats exposed to the industrial toxicant vinylidene chloride (VDC) resulted in a marked increase in malignant mesothelioma. Global gene expression profiles of these tumors were compared to spontaneous mesotheliomas and the F344/N rat mesothelial cell line (Fred-PE) in order to characterize the molecular features and chemical-specific profiles of mesothelioma in VDC-exposed rats. As expected, mesotheliomas from control and VDC-exposed rats shared pathways associated with tumorigenesis, including cellular and tissue development, organismal injury, embryonic development, inflammatory response, cell cycle regulation, and cellular growth and proliferation, while mesotheliomas from VDC-exposed rats alone showed overrepresentation of pathways associated with pro-inflammatory pathways and immune dysfunction such as the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, interleukin (IL)-8 and IL-12 signaling, interleukin responses, Fc receptor signaling, and natural killer and dendritic cells signaling, as well as overrepresentation of DNA damage and repair. These data suggest that a chronic, pro-inflammatory environment associated with VDC exposure may exacerbate disturbances in oncogene, growth factor, and cell cycle regulation, resulting in an increased incidence of mesothelioma.

Asunto(s)

Dicloroetilenos/toxicidad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Enfermedades del Sistema Inmune/inducido químicamente , Inflamación/inducido químicamente , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Mesotelioma/inducido químicamente , Mesotelioma/genética , Animales , Línea Celular Tumoral , Daño del ADN , Femenino , Genes cdc/efectos de los fármacos , Enfermedades del Sistema Inmune/inmunología , Inflamación/fisiopatología , Masculino , Mesotelioma Maligno , Análisis por Micromatrices , Neoplasias Peritoneales/inducido químicamente , Neoplasias Peritoneales/patología , ARN Neoplásico/biosíntesis , Ratas , Ratas Endogámicas F344 , Transducción de Señal/efectos de los fármacos , Neoplasias Testiculares/inducido químicamente , Neoplasias Testiculares/patología

RESUMEN

3,3',4,4'-tetrachloroazobenzene (TCAB) is a contaminant formed during manufacture of various herbicide compounds. A recent National Toxicology Program study showed B6C3F1 mice exposed to TCAB developed a treatment-related increase in lung carcinomas in the high-dose group, and urethral carcinomas, an extremely rare lesion in rodents, in all dose groups. As the potential for environmental exposure to TCAB is widespread, and the mechanisms of urethral carcinogenesis are unknown, TCAB-induced urethral and pulmonary tumors were evaluated for alterations in critical human cancer genes, Kras and Tp53. Uroplakin III, CK20, and CK7 immunohistochemistry was performed to confirm the urothelial origin of urethral tumors. TCAB-induced urethral carcinomas harbored transforming point mutations in K-ras (38%) and Tp53 (63%), and 71% displayed nuclear TP53 expression, consistent with formation of mutant protein. Transition mutations accounted for 88% of Tp53 mutations in urethral carcinomas, suggesting that TCAB or its metabolites target guanine or cytosine bases and that these mutations are involved in urethral carcinogenesis. Pulmonary carcinomas in TCAB-exposed animals harbored similar rates of Tp53 (55%) and Kras (36%) mutations as urethral carcinomas, suggesting that TCAB may induce mutations at multiple sites by a common mechanism. In conclusion, TCAB is carcinogenic at multiple sites in male and female B6C3F1 mice through mechanisms involving Tp53 and Kras mutation.

Asunto(s)

Compuestos Azo/toxicidad , Clorobencenos/toxicidad , Neoplasias Pulmonares , Mutágenos/toxicidad , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/genética , Neoplasias Uretrales , Animales , Análisis Mutacional de ADN , Femenino , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Masculino , Ratones , Mutación , Neoplasias Uretrales/inducido químicamente , Neoplasias Uretrales/genética

RESUMEN

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and is rising in incidence worldwide. The molecular mechanisms leading to the development of HCC are complex and include both genetic and epigenetic events. To determine the relative contribution of these alterations in liver tumorigenesis, we evaluated epigenetic modifications at both global and gene specific levels, as well as the mutational profile of genes commonly altered in liver tumors. A mouse model of fibrosis-associated liver cancer that was designed to emulate cirrhotic liver, a prevailing disease state observed in most humans with HCC, was used. Tumor and nontumor liver samples from B6C3F1 mice treated with N-nitrosodiethylamine (DEN; a single ip injection of 1 mg/kg at 14 days of age) and carbon tetrachloride (CCl4; 0.2 ml/kg, 2 times/week ip starting at 8 weeks of age for 14 weeks), as well as corresponding vehicle control animals, were analyzed for genetic and epigenetic alterations. H-ras, Ctnnb1 and Hnf1α genes were not mutated in tumors in mice treated with DEN+CCl4 . In contrast, the increased tumor incidence in mice treated with DEN+CCl4 was associated with marked epigenetic changes in liver tumors and nontumor liver tissue, including demethylation of genomic DNA and repetitive elements, a decrease in histone 3 lysine 9 trimethylation (H3K9me3) and promoter hypermethylation and functional downregulation of Riz1, a histone lysine methyltransferase tumor suppressor gene. Additionally, the reduction in H3K9me3 was accompanied by increased expression of long interspersed nucleotide elements 1 and short interspersed nucleotide elements B2, which is an indication of genomic instability. In summary, our results suggest that epigenetic events, rather than mutations in known cancer-related genes, play a prominent role in increased incidence of liver tumors in this mouse model of fibrosis-associated liver cancer.

Asunto(s)

Carcinoma Hepatocelular/genética , Transformación Celular Neoplásica/genética , Metilación de ADN/genética , Epigénesis Genética , Cirrosis Hepática/genética , Neoplasias Hepáticas/genética , Animales , Tetracloruro de Carbono , Carcinoma Hepatocelular/patología , Transformación Celular Neoplásica/patología , Cromatina/genética , Cromatina/metabolismo , Dietilnitrosamina , Modelos Animales de Enfermedad , Regulación hacia Abajo , Inestabilidad Genómica/genética , Factor Nuclear 1-alfa del Hepatocito/genética , N-Metiltransferasa de Histona-Lisina/biosíntesis , Histonas/metabolismo , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Elementos de Nucleótido Esparcido Largo/genética , Masculino , Ratones , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Elementos de Nucleótido Esparcido Corto/genética , Factores de Transcripción/biosíntesis , beta Catenina/genética

RESUMEN

Ginkgo biloba leaf extract (GBE) has been used for centuries in traditional Chinese medicine and today is used as an herbal supplement touted for improving neural function and for its antioxidant and anticancer effects. Herbal supplements have the potential for consumption over extended periods of time, with a general lack of sufficient data on long-term carcinogenicity risk. Exposure of B6C3F1 mice to GBE in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increase in hepatocellular tumors, including hepatocellular carcinoma (HCC). We show that the mechanism of hepatocarcinogenesis in GBE exposed animals is complex, involving alterations in H-ras and Ctnnb1 mutation spectra, WNT pathway dysregulation, and significantly altered gene expression associated with oncogenesis, HCC development, and chronic xenobiotic and oxidative stress compared to spontaneous HCC. This study provides a molecular context for the genetic changes associated with hepatocarcinogenesis in GBE exposed mice and illustrates the marked differences between these tumors and those arising spontaneously in the B6C3F1 mouse. The molecular changes observed in HCC from GBE-treated animals may be of relevance to those seen in human HCC and other types of cancer, and provide important data on potential mechanisms of GBE hepatocarcinogenesis.

Asunto(s)

Medicamentos Herbarios Chinos/toxicidad , Ginkgo biloba/química , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/genética , Administración Oral , Animales , Pruebas de Carcinogenicidad , Análisis por Conglomerados , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inmunohistoquímica , Hígado/química , Hígado/efectos de los fármacos , Hígado/patología , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Pruebas de Mutagenicidad , Estrés Oxidativo/efectos de los fármacos , Reproducibilidad de los Resultados , Transducción de Señal/efectos de los fármacos , beta Catenina/metabolismo

RESUMEN

Lung cancer is the leading cause of cancer-related death in people and is mainly due to environmental factors such as smoking and radon. The National Toxicology Program (NTP) tests various chemicals and mixtures for their carcinogenic hazard potential. In the NTP chronic bioassay using B6C3F1 mice, the incidence of lung tumors in treated and control animals is second only to the liver tumors. In order to study the molecular mechanisms of chemically induced lung tumors, an understanding of the genetic changes that occur in spontaneous lung (SL) tumors from untreated control animals is needed. The authors have evaluated the differential transcriptomic changes within SL tumors compared to normal lungs from untreated age-matched animals. Within SL tumors, several canonical pathways associated with cancer (eukaryotic initiation factor 2 signaling, RhoA signaling, PTEN signaling, and mammalian target of rapamycin signaling), metabolism (Inositol phosphate metabolism, mitochondrial dysfunction, and purine and pyramidine metabolism), and immune responses (FcγR-mediated phagocytosis, clathrin-mediated endocytosis, interleukin 8 signaling, and CXCR4 signaling) were altered. Meta-analysis of murine SL tumors and human non-small cell lung cancer transcriptomic data sets revealed a high concordance. These data provide important information on the differential transcriptomic changes in murine SL tumors that will be critical to our understanding of chemically induced lung tumors and will aid in hazard analysis in the NTP 2-year carcinogenicity bioassays.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos , Proteínas de Neoplasias/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Especificidad de la Especie

RESUMEN

Aloe vera is one of the most commonly used botanicals for various prophylactic and therapeutic purposes. Recently, NTP/NCTR has demonstrated a dose-dependent increase in large intestinal tumors in F344 rats chronically exposed to Aloe barbadensis Miller (Aloe vera) non-decolorized whole leaf extract (AVNWLE) in drinking water. The morphological and molecular pathways of AVNWLE-induced large intestinal tumors in the F344 rats were compared to human colorectal cancer (hCRC) literature. Defined histological criteria were used to compare AVNWLE-induced large intestinal tumors with hCRC. The commonly mutated genes (Kras, Ctnnb1, and Tp53) and altered signaling pathways (MAPK, WNT, and TGF-ß) important in hCRC were evaluated within AVNWLE-induced large intestinal tumors. Histological evaluation of the large intestinal tumors indicated eight of twelve adenomas (Ads) and four of twelve carcinomas (Cas). Mutation analysis of eight Ads and four Cas identified point mutations in exons 1 and 2 of the Kras gene (two of eight Ads, two of four Cas), and in exon 2 of the Ctnnb1 gene (three of eight Ads, one of four Cas). No Tp53 (exons 5-8) mutations were found in Ads or Cas. Molecular pathways important in hCRC such as MAPK, WNT, and TGF-ß signaling were also altered in AVNWLE-induced Ads and Cas. In conclusion, the AVNWLE-induced large intestinal tumors in F344 rats share several similarities with hCRC at the morphological and molecular levels.

Asunto(s)

Aloe/química , Neoplasias Colorrectales/metabolismo , Neoplasias Intestinales/inducido químicamente , Neoplasias Intestinales/metabolismo , Extractos Vegetales/toxicidad , Adenoma/inducido químicamente , Adenoma/metabolismo , Adenoma/patología , Animales , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Histocitoquímica , Humanos , Neoplasias Intestinales/patología , Intestino Grueso/patología , Hojas de la Planta/química , Análisis de Componente Principal , Ratas , Ratas Endogámicas F344 , Transducción de Señal/efectos de los fármacos

RESUMEN

Tumor response in the B6C3F1 mouse, F344 rat, and other animal models following exposure to various compounds provides evidence that people exposed to these or similar compounds may be at risk for developing cancer. Although tumors in rodents and humans are often morphologically similar, underlying mechanisms of tumorigenesis are often unknown and may be different between the species. Therefore, the relevance of an animal tumor response to human health would be better determined if the molecular pathogenesis were understood. The underlying molecular mechanisms leading to carcinogenesis are complex and involve multiple genetic and epigenetic events and other factors. To address the molecular pathogenesis of environmental carcinogens, the authors examine rodent tumors (e.g., lung, colon, mammary gland, skin, brain, mesothelioma) for alterations in cancer genes and epigenetic events that are associated with human cancer. National Toxicology Program (NTP) studies have identified several genetic alterations in chemically induced rodent neoplasms that are important in human cancer. Identification of such alterations in rodent models of chemical carcinogenesis caused by exposure to environmental contaminants, occupational chemicals, and other compounds lends further support that they are of potential human health risk. These studies also emphasize the importance of molecular evaluation of chemically induced rodent tumors for providing greater public health significance for NTP evaluated compounds.

Asunto(s)

Carcinógenos Ambientales/toxicidad , Modelos Animales de Enfermedad , Neoplasias Experimentales/inducido químicamente , Animales , Bioensayo , Pruebas de Carcinogenicidad , Epigénesis Genética/efectos de los fármacos , Genes Relacionados con las Neoplasias/efectos de los fármacos , Humanos , Ratones , Programas Nacionales de Salud , Neoplasias/inducido químicamente , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Ratas , Ratas Endogámicas F344 , Medición de Riesgo

RESUMEN

A transplacental carcinogenicity study was conducted by exposing pregnant Swiss (CD-1) mice to 0, 50, 100, 200, or 300 mg 3'-azido-3'-deoxythymidine (AZT)/kg body weight (BW) daily for the duration of gestation (18-19 days) [National Toxicology Program,2006]. The incidence of alveolar/bronchiolar adenomas and carcinomas in the 200 and 300 mg/kg groups was significantly higher (P = 0.027 and 0.007, respectively) in male offspring, but not in females (P = 0.338 and 0.315, respectively). The purpose of the present study was to evaluate K-ras mutation status in lung tumors from the female offspring in AZT exposed groups and to determine whether at the molecular level there were signature K-ras mutations in lung tumors that were different from spontaneous tumors. K-ras mutation was detected by cycle sequencing of polymerase chain reaction (PCR)-amplified DNA, isolated from formalin-fixed, paraffin-embedded lung tumors. K-ras mutations were detected in 17 of 28 (61%) lung tumors from the female offspring in AZT exposed groups. No K-ras mutations were detected in the 8 tumors examined from the female control group. The predominant mutations were Codon 12 G-->T transversions in the 50, 100, and 300 mg/kg groups, and Codon 12 G-->C transversions in the 200 and 300 mg/kg groups. K-ras Codon 12 G-->T transversions (TGT mutations) may be induced by oxidative DNA damage and 8-oxoguanine (8-oxoG), while K-ras Codon 12 G-->C transversions (CGT mutations) may be due to further oxidative lesions of guanine and 8-oxoG.

Asunto(s)

Genes ras/genética , Neoplasias Pulmonares/etiología , Mutación/efectos de los fármacos , Zidovudina/toxicidad , Animales , Femenino , Neoplasias Pulmonares/genética , Masculino , Exposición Materna/efectos adversos , Ratones , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/genética , Factores Sexuales

RESUMEN

The incidences of alveolar/bronchiolar adenomas and carcinomas in cumene-treated B6C3F1 mice were significantly greater than those of the control animals. We evaluated these lung neoplasms for point mutations in the K-ras and p53 genes that are often mutated in humans. K-ras and p53 mutations were detected by cycle sequencing of PCR-amplified DNA isolated from paraffin-embedded neoplasms. K-ras mutations were detected in 87% of cumene-induced lung neoplasms, and the predominant mutations were exon 1 codon 12 G to T transversions and exon 2 codon 61 A to G transitions. P53 protein expression was detected by immunohistochemistry in 56% of cumene-induced neoplasms, and mutations were detected in 52% of neoplasms. The predominant mutations were exon 5, codon 155 G to A transitions, and codon 133 C to T transitions. No p53 mutations and one of seven (14%) K-ras mutations were detected in spontaneous neoplasms. Cumene-induced lung carcinomas showed loss of heterozygosity (LOH) on chromosome 4 near the p16 gene (13%) and on chromosome 6 near the K-ras gene (12%). No LOH was observed in spontaneous carcinomas or normal lung tissues examined. The pattern of mutations identified in the lung tumors suggests that DNA damage and genomic instability may be contributing factors to the mutation profile and development of lung cancer in mice exposed to cumene.

Asunto(s)

Derivados del Benceno/toxicidad , Genes p53/genética , Genes ras , Neoplasias Pulmonares/genética , Proteína p53 Supresora de Tumor/genética , Adenocarcinoma Bronquioloalveolar/inducido químicamente , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/patología , Animales , Carcinoma/inducido químicamente , Carcinoma/genética , Carcinoma/patología , Codón , Exones , Inmunohistoquímica , Pérdida de Heterocigocidad , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos , Mutación Puntual

RESUMEN

National Toxicology Program (NTP) inhalation studies demonstrated that cumene significantly increased the incidence of alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice. Cumene or isopropylbenzene is a component of crude oil used primarily in the production of phenol and acetone. The authors performed global gene expression analysis to distinguish patterns of gene regulation between cumene-induced tumors and normal lung tissue and to look for patterns based on the presence or absence of K-ras and p53 mutations in the tumors. Principal component analysis segregated the carcinomas into groups with and without K-ras mutations, but failed to separate the tumors based on p53 mutation status. Expression of genes associated with the Erk MAP kinase signaling pathway was significantly altered in carcinomas with K-ras mutations compared to tumors without K-ras mutations or normal lung. Gene expression analysis also suggested that cumene-induced carcinomas with K-ras mutations have greater malignant potential than those without mutations. In addition, significance analysis of function and expression (SAFE) demonstrated expression changes of genes regulated by histone modification in carcinomas with K-ras mutations. The gene expression analysis suggested the formation of alveolar/bronchiolar carcinomas in cumene-exposed mice typically involves mutation of K-ras, which results in increased Erk MAP kinase signaling and modification of histones.

Asunto(s)

Derivados del Benceno/toxicidad , Genes ras/genética , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Transducción de Señal/genética , Adenocarcinoma Bronquioloalveolar/inducido químicamente , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/patología , Animales , Femenino , Regulación Neoplásica de la Expresión Génica , Inmunohistoquímica , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos , Transducción de Señal/fisiología

RESUMEN

Lung cancer is the leading cause of cancer death worldwide, and the need to develop better diagnostic techniques and therapies is urgent. Mouse models have been utilized for studying carcinogenesis of human lung cancers, and many of the major genetic alterations detected in human lung cancers have also been identified in mouse lung tumors. The importance of mouse models for understanding human lung carcinogenic processes and in developing early diagnostic techniques, preventive measures and therapies cannot be overstated. In this report, the major known molecular alterations in lung tumorigenesis of mice are reviewed and compared to those in humans.

Asunto(s)

Adenocarcinoma/genética , Modelos Animales de Enfermedad , Neoplasias Pulmonares/genética , Adenocarcinoma/diagnóstico , Animales , Diagnóstico Precoz , Regulación Neoplásica de la Expresión Génica , Genes ras/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Ratones , Mutación , Especificidad de la Especie , Proteína p53 Supresora de Tumor/genética

RESUMEN

Ethylene oxide is a multisite carcinogen in rodents and classified as a human carcinogen by the National Toxicology Program. In 2-year mouse studies, ethylene oxide (EO) induced lung, Harderian gland (HG), and uterine neoplasms. We evaluated representative EO-induced and equivalent spontaneous neoplasms for K-ras mutations in codons 12, 13, and 61. K-ras mutations were identified in 100% (23/23) of the EO-induced lung neoplasms and 25% (27/108) of the spontaneous lung neoplasms. Codon 12 G to T transversions were common in EO-induced lung neoplasms (21/23) but infrequent in spontaneous lung neoplasms (1/108). K-ras mutations were found in 86% (18/21) of the EO-induced HG neoplasms and 7% (2/27) of the spontaneous HG neoplasms. Codon 13 G to C and codon 12 G to T transversions were predominant in the EO-induced HG neoplasms but absent in spontaneous HG neoplasms (0/27). K-ras mutations occurred in 83% (5/6) of the EO-induced uterine carcinomas and all were codon 13 C to T transitions. These data show a strong predilection for development of K-ras mutations in EO-induced lung, Harderian gland, and uterine neoplasms. This suggests that EO specifically targets the K-ras gene in multiple tissue types and that this event is a critical component of EO-induced tumorigenesis.

Asunto(s)

Adenocarcinoma/genética , Adenoma/genética , Carcinógenos/toxicidad , Óxido de Etileno/toxicidad , Genes ras , Neoplasias Pulmonares/genética , Neoplasias de las Glándulas Sebáceas/genética , Neoplasias Uterinas/genética , Adenocarcinoma/inducido químicamente , Adenocarcinoma/patología , Adenoma/inducido químicamente , Adenoma/patología , Animales , ADN de Neoplasias/análisis , Desinfectantes/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Glándula de Harder/efectos de los fármacos , Glándula de Harder/patología , Exposición por Inhalación , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos , Mutación , Neoplasias de las Glándulas Sebáceas/inducido químicamente , Neoplasias de las Glándulas Sebáceas/patología , Neoplasias Uterinas/inducido químicamente , Neoplasias Uterinas/patología

RESUMEN

1,3-Butadiene and chloroprene are multisite carcinogens in B6C3F1 mice with the strongest tumor response being the induction of lung neoplasms in females. Incidence of brain tumors in mice exposed to 1,3-butadiene was equivocal. This article reviews the efforts of our laboratory and others to uncover the mechanisms of butadiene and chloroprene induced lung and brain tumor responses in the B6C3F1 mouse. The formation of lung tumors by these chemicals involved mutations in the K-ras cancer gene and loss of heterozygosity in the region of K-ras on distal chromosome 6, while alterations in p53 and p16 were implicated in brain tumorigenesis.

Asunto(s)

Neoplasias Encefálicas/genética , Butadienos/toxicidad , Carcinógenos/toxicidad , Cloropreno/toxicidad , Genes Relacionados con las Neoplasias/genética , Neoplasias Pulmonares/genética , Mutagénesis/efectos de los fármacos , Alelos , Animales , Neoplasias Encefálicas/inducido químicamente , Butadienos/administración & dosificación , Carcinógenos/administración & dosificación , Cloropreno/administración & dosificación , Cromosomas de los Mamíferos/efectos de los fármacos , Aductos de ADN/efectos de los fármacos , Aductos de ADN/metabolismo , Femenino , Genes ras , Humanos , Exposición por Inhalación , Pérdida de Heterocigocidad/efectos de los fármacos , Neoplasias Pulmonares/inducido químicamente , Masculino , Ratones