The potential of genetically altered mice as animal models for carcinogen identification.
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Animals↗
Biomedical subjects
R R Maronpot
Publications and source records attributed to R R Maronpot.
Impact of Helicobacter hepaticus infection in B6C3F1 mice from twelve National Toxicology Program two-year carcinogenesis studies.
Male and female B6C3F1 mice from 12 National Toxicology Program (NTP) 2-yr carcinogenesis studies were found to be infected with Helicobacter hepaticus. Many of the male mice from 9 of these studies had an associated hepatitis (affected studies). Helicobacter hepaticus has been reported to be associated with an increased incidence of hepatitis and hepatocellular neoplasms in the A/JCr male mouse. We attempted to determine if the data from the Helicobacter-affected NTP B6C3F1 mouse studies were compromised and unsuitable for cancer hazard identification. The incidences of neoplasms of the liver (both hepatocellular and hemangiosarcoma) but not of other organs in control male B6C3F1 mice were increased in affected studies as compared with control males from unaffected studies. The increased incidence of hepatocellular neoplasms was observed in those males exhibiting H. hepaticus-associated hepatitis. Other observations further differentiated control male mice from affected and unaffected studies. H-ras codon 61 CAA to AAA mutations were less common in liver neoplasms from males from affected studies as compared with historical and study controls. In addition, increases in cell proliferation rates and apoptosis were observed in the livers of male mice with H. hepaticus-associated hepatitis. These data support the hypothesis that the increased incidence of liver neoplasms is associated with H. hepaticus and that hepatitis may be important in the pathogenesis. Therefore, interpretation of carcinogenic effects in the liver of B6C3F1 mice may be confounded if there is H. hepaticus-associated hepatitis.
Animals↗
Disseminated thrombosis and bone infarction in female rats following inhalation exposure to 2-butoxyethanol.
Groups of 10 male and 10 female F344/N rats were exposed to 0, 31, 62.5, 125, 250, and 500 ppm of 2-butoxyethanol (BE) by inhalation, 6 hr/day, 5 days/wk, for 13 wk. Four moribund female rats from the 500 ppm group were sacrificed during the first 4 days of exposure, and 1 moribund female from the same group was sacrificed during week 5. Dark irregular mottling and/or loss of the distal tail were noted in sacrificed moribund rats. Similar gross lesions were noted in the terminally sacrificed females exposed to 500 ppm BE. Histologic changes noted in the day 4 sacrificed moribund rats included disseminated thrombosis involving the coccygeal vertebrae, cardiac atrium, lungs, liver, pulp of the incisor teeth, and the submucosa of the anterior section of the nasal cavity. Alterations noted in coccygeal vertebrae from the 500 ppm sacrificed moribund rats included ischemic necrosis and/or degeneration of bone marrow cells, bone-lining cells, osteocytes (within cortical and trabecular bone), and chondrocytes (both articular and growth plate), changes that are consistent with an infarction process. The moribund female rat that was sacrificed during week 5 and those female rats treated with 500 ppm and sacrificed following 13 wk of treatment lacked thrombi, but they had coccygeal vertebral changes consistent with prior infarction and transient or complete bone growth arrest. No bone lesions or thrombi were noted in the male rats treated with the same doses of BE. In conclusion, exposure to 500 ppm BE vapors caused acute disseminated thrombosis and bone infarction in female rats. Possible pathogenic mechanisms are discussed.
Administration, Inhalation↗
The association between severe nephropathy and pheochromocytoma in the male F344 rat -- the National Toxicology Program experience.
The possible correlation between the severity of chronic progressive glomerulonephropathy (CPN) and the incidence of adrenal pheochromocytoma was examined in selected studies of male Fischer 344 (F344) rats at the National Toxicology Program (NTP). The NTP historical control database was first examined in order to determine whether there was association between the severity of CPN and the occurrence of adrenal pheochromocytoma in unexposed animals. Following this analysis, the 125 most recent NTP studies conducted in F344 rats were examined in order to determine how frequently chemicals that cause increased severity of CPN showed an increased incidence of pheochromocytoma. Finally, we examined the association between the incidence of pheochromocytoma and the severity of CPN in those NTP studies with chemically related increased rates of pheochromocytoma. In control male F344 rats surviving beyond 21 mo, the incidence of adrenal pheochromocytoma was consistently higher in animals with more severe CPN. This association was significant (p < 0.05) both for 900 NTP inhalation study controls and 900 NTP feeding study controls. An association was not consistently observed when dosed groups were considered. Although 22% (28/125) of NTP studies reported a chemically related increased severity of CPN, only 3 of these reported a corresponding significant increase in the incidence of pheochromocytoma. Of 6 NTP studies that reported increased incidence of pheochromocytoma, animals with pheochromocytoma from 5 of those studies had some degree of increased severity of CPN. However, the estimated strength of the correlation with the severity of CPN varied from study to study and was often quite different from that indicated by an analysis of the more extensive NTP control databases. The possible correlation between the severity of CPN and the incidence of pheochromocytoma may influence interpretation of carcinogenic effects observed at this site.
Administration, Inhalation↗
The nomenclature of cell death: recommendations of an ad hoc Committee of the Society of Toxicologic Pathologists.
The last several years have seen considerable confusion regarding the terms "apoptosis" and "necrosis" in pathology. This situation prompted the Society of Toxicologic Pathologists to charter the Committee on the Nomenclature of Cell Death, which was charged with making recommendations about the use of the terms "apoptosis" and "necrosis" in toxicity studies. The Committee recommends use of the term "necrosis" to describe findings comprising dead cells in histological sections, regardless of the pathway by which the cells died. The modifiers "apoptotic" and "oncotic" or "mixed apoptotic and oncotic" are recommended to specify the predominant morphological cell death pathway or pathways, when appropriate. Other standard modifiers, indicating the lesion distribution and severity, may also be used in conjunction with these. "Individual cell necrosis" (also known as "single cell necrosis") may be either of the apoptotic, oncotic, or mixed types. In many cases, more traditional terms such as "coagulation necrosis" may be used to convey a meaning similar to oncotic necrosis. It is important that pathologists use terms that accurately and concisely convey the level of information appropriate to the study's needs. Furthermore, toxicologic pathologists should actively help to disseminate these recommendations to other biologists and to regulatory authorities.
Animals↗
Histomorphology and ultrastructure of spontaneous pulmonary neoplasms in strain A mice.
The microscopic and ultrastructural characteristics of spontaneous pulmonary neoplasms in strain A (strA) mice are described. Fifty-one spontaneous lung tumors were identified in 34 out of 57, 11-23-month-old male strA/Hen mice. Grossly, all tumors appeared as yellow-white, discrete nodules ranging in size from 1.0-10 mm. Tumor types were randomly distributed throughout the lung; however, the right lung lobes were most frequently involved. Histologically, tumors were classified as adenoma (34/51) or carcinoma (17/51) as defined by standard histopathologic criteria. Adenomas were usually less than 4 mm in diameter and had solid (16/34), papillary (10/34), or mixed (8/34) histologic growth patterns. Carcinomas were usually greater than 4 mm in diameter and had papillary (13/17) or mixed (4/17) histologic growth patterns. Ultrastructurally, benign tumors consisted of solid or papillary areas of neoplastic type II-like cells. Cells comprising malignant tumors had varying ultrastructural characteristics ranging from well-differentiated alveolar cell types to undifferentiated cells having intracytoplasmic osmiophilic dense bodies, vacuoles, or few specialized organelles commonly observed in mature nonneoplastic pulmonary epithelial cells.
Adenoma↗
Proliferative lesions of the mouse lung: progression studies in strain A mice.
The progression of pulmonary neoplasia was examined in strain A/J male mice treated with a single dose of vinyl carbamate (60 mg/kg, i.p.) 6 weeks after birth. Interim sacrifices were performed at 7, 8, 10, 12, or 14 months. Proliferative lesions of the lung were divided into four categories: hyperplasias, adenomas, carcinomas arising within adenomas, and carcinomas. Grossly visible surface tumor counts, histologic diagnoses, and morphometric measurements of histologic lesions were used to evaluate progression. Vinyl carbamate-treated mice showed increased mean surface tumor counts at all time points. Diagnostic evaluation suggested that as a function of time, the relative frequency of hyperplasias decreased and the relative frequency of adenomas increased. The relative frequency of adenomas subsequently decreased, whereas the relative frequency of carcinomas increased. At all time points, carcinomas arising within adenomas were present. As time progressed, the number of carcinomas arising within adenomas decreased, whereas the number of "pure" carcinomas increased. Morphometric analysis of lesions indicated hyperplasias to be small, that adenomas were larger than hyperplasias, and carcinomas were larger than adenomas and hyperplasias, suggesting that few adenomas or carcinomas arise de novo. Collectively, these data suggest that the majority of pulmonary tumors in A/J mice treated with vinyl carbamate arise as hyperplasias, progress to adenomas, and ultimately result in carcinomas.
Animals↗
Role of Clara cells and type II cells in the development of pulmonary tumors in rats and mice following exposure to a tobacco-specific nitrosamine.
The role of the Clara and type II cell in the development of pulmonary tumors in the A/J mouse and Fischer rat was investigated by determining the relationship of DNA methylation and repair in pulmonary cells to oncogene activation and by characterizing the morphology of pulmonary tumors induced by treatment with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Marked differences in the formation of the promutagenic adduct O6-methylguanine (O6MG) were observed in pulmonary cells following treatment of rats with NNK. Concentrations of this adduct in Clara cells greatly exceeded (3- to 30-fold) those detected in type II cells and whole lung with doses of NNK ranging from 0.1 to 50 mg/kg. In addition, very low rates of repair of this adduct were detected in Clara cells, whereas efficient adduct removal occurred in type II cells. The importance of this adduct and the role of cell specificity was suggested by the fact that a strong correlation was observed between the concentration of O6MG in Clara cells and tumor incidence in the Fischer rat with doses of NNK ranging from 0.03-50 mg/kg. In contrast, no differences in adduct concentration between type II and Clara cells from A/J mice were observed under conditions resulting in pulmonary tumor formation. Activation of the K-ras gene was detected in lung tumors from A/J mice. This gene was activated by a mutation in codon 12 involving a GC to AT transition (GGT to GAT) and is consistent with base mispairing produced by the formation of O6MG. Activation of this gene was not associated with lung tumor formation in the Fischer rat. DNA from rat lung tumors did induce tumors in the nude mouse carcinogenicity assay. In addition, rat repetitive sequences were detected in DNA isolated from these nude mouse tumors. In spite of the cell selectivity for DNA methylation in Clara cells from rat and the relationship between O6MG formation and tumorigenicity, early proliferative lesions observed in both mice and rats involved the alveolar areas. Ultrastructural examination of these lesions and adenomas revealed morphologic features characteristic of the type II cell. Thus the lack of agreement between biochemical and morphological findings makes it difficult to hypothesize a cell of origin for the pulmonary neoplasms induced by NNK. However, these studies indicate that the concentration of O6MG in Clara cells is an excellent indicator of the carcinogenic potency of NNK in the rat.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Pulmonary carcinogenesis in transgenic mice.
Use of genetically engineered mice offers a unique approach to identifying and investigating factors that may influence tumor development. We have used conventional histopathologic and ultrastructural techniques to characterize lung tumors in three lines of transgenic mice bearing an albumin enhancer/promoter linked to a mutated human H-ras gene. Mice in all three lines developed multiple alveolar-bronchiolar (A/B) adenocarcinomas that are eventually lethal. The large diversity in tumor morphological features and differential tumor growth rates suggests that secondary events contribute to tumor phenotype and biological behavior. Two of the transgenic lines developed numerous A/B neoplasms within 6 to 8 weeks and thus may be useful animal models for testing potential anticancer chemotherapeutic agents. The other line lived for approximately 10 months, had fewer A/B tumors, but also developed bronchiogenic tumors. All three transgenic lines may be useful models for studying factors that affect lung tumor development.
Albumins↗
Activation of protooncogenes in mouse lung tumors.
The detection of activated protooncogenes in mouse lung tumors has led to a major advance in our understanding of carcinogenesis of the lung at the molecular level. A high frequency of activated K-ras protooncogenes has been detected in tetranitromethane (TNM)- and 1,3-butadiene-induced lung tumors in B6C3F1 mice. In the past several years, we have pursued protooncogene activation in spontaneous and chemically induced tumors of strain A mice. The strain A mouse has a high incidence of spontaneous lung tumors and is susceptible to tumor induction by chemical carcinogens. We have detected and characterized the activated protooncogenes in the DNA of both spontaneously occurring and chemically induced lung tumors of strain A mice. Activated K-ras genes were detected using the NIH/3T3 transfection assay, and the activating mutations were identified by utilizing the polymerase chain reaction (PCR) and direct sequence analysis. A strong selectivity of mutations in the K-ras genes were observed in chemically induced lung tumors, as compared to spontaneous tumors, indicating that the carcinogens directly induced point mutations in the K-ras protooncogene. These findings suggest that the strain A mouse lung tumor model appears to be a very sensitive system to identify the mechanism by which chemical carcinogens activate the K-ras gene in lung tissue in vivo.
Animals↗
Correlation of data from the strain A mouse bioassay with long-term bioassays.
Fifty-nine chemicals that had completed National Cancer Institute rat and mouse 2-year carcinogenicity tests were tested in the strain A mouse pulmonary tumor assay. Without knowledge of chemical identity, 53 chemicals were tested in strain A mice in one laboratory and 30 were tested in a second independent laboratory. Strain A tests on 24 of these chemicals were conducted in both laboratories. The strain A results were generally not predictive of the 2-year rat and mouse carcinogenicity test results. Furthermore, there was poor agreement of strain A results between the two laboratories. Although a variety of explanations may be invoked to explain the lack of concordance between the strain A tests and the 2-year rat and mouse tests, no one factor is sufficient to rationalize the poor concordance between strain A and 2-year carcinogenicity bioassay results.
Animals↗