Chemical-specific alterations in ras, p53, and β-catenin genes in hemangiosarcomas from B6C3F1 mice exposed to o-nitrotoluene or riddelliine for 2 years
| Autor: | Natasha P. Clayton, June K. Dunnick, Po-Chuen Chan, Cindy R. Moomaw, Theodora R. Devereux, Robert C. Sills, T. V. Ton, Hue-Hua L. Hong |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Ratón Hemangiosarcoma Biology Toxicology Polymerase Chain Reaction Pathogenesis Mice Exon chemistry.chemical_compound Animals Missense mutation Pyrrolizidine Alkaloids beta Catenin Carcinogen Pharmacology Muscle Neoplasms Riddelliine DNA Neoplasm Sequence Analysis DNA Genes p53 Immunohistochemistry Cytoskeletal Proteins Genes ras chemistry Catenin Mutation Trans-Activators Cancer research Female Toluene |
| Zdroj: | Toxicology and Applied Pharmacology. 191:227-234 |
| ISSN: | 0041-008X |
| Popis: | The most prominent neoplastic lesions in mice in the 2-year studies of o -nitrotoluene and riddelliine were hemangiosarcomas. Fifteen o -nitrotoluene-induced hemangiosarcomas of the skeletal muscle, subcutaneous tissue, and mesentery; 12 riddelliine-induced hemangiosarcomas of the liver; and 15 spontaneous subcutaneous hemangiosarcomas were examined for genetic alterations in ras , p53 , and β-catenin genes. Mutations in at least one of these genes were identified in 13 of 15 (87%) of the o -nitrotoluene-induced hemangiosarcomas with missense mutations in p53 exons 5-8 detected in 11 of 15 (73%) of these neoplasms. Seven of 15 (47%) hemangiosarcomas from mice exposed to o -nitrotoluene had deletions at exon 2 splice sites or smaller deletions in the β-catenin gene. K- ras mutation was detected in only 1 of the 15 (7%) o -nitrotoluene-induced hemangiosarcomas. In contrast to the o -nitrotoluene study, 7/12 (58%) riddelliine-induced hemangiosarcomas had K- ras codon 12 GTT mutations and, when screened by immunohistochemistry, 9/12 (75%) had strong staining for the p53 protein in malignant endothelial cells, the cells of origin of hemangiosarcomas. Riddelliine-induced hemangiosarcomas were negative for the β-catenin protein. Spontaneous hemangiosarcomas from control mice lacked both p53 and β-catenin protein expression and ras mutations. Our data indicated that p53 and β-catenin mutations in the o -nitrotoluene-induced hemangiosarcomas and K- ras mutations and p53 protein expression in riddelliine-induced hemangiosarcomas most likely occurred as a result of the genotoxic effects of these chemicals. It also suggests that these mutations play a role in the pathogenesis of the respective hemangiosarcomas in B6C3F1 1 mice. |
| Databáze: | OpenAIRE |
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