Evaluation of the Carcinogenic Potential of Clofibrate in the rasH2 Mouse
| Autor: | Jane S. Allen, Michael J. Santostefano, Sarah R. Nesfield, Debie J. Hoivik, Douglas Rickert, Thomas C. Williams, Krzysztof Selinger, Richard T. Miller |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Genetically modified mouse medicine.medical_specialty Time Factors Carcinogenicity Tests Mice Transgenic Spleen 010501 environmental sciences Toxicology Risk Assessment 030226 pharmacology & pharmacy 01 natural sciences Mice 03 medical and health sciences Harderian gland Liver Neoplasms Experimental 0302 clinical medicine Oral administration Internal medicine medicine Animals Humans Clofibrate Intubation Gastrointestinal Carcinogen 0105 earth and related environmental sciences Dose-Response Relationship Drug Harderian Gland Chemistry Eye Neoplasms Dose–response relationship Genes ras medicine.anatomical_structure Endocrinology Female Peroxisome Proliferators Micronucleus medicine.drug |
| Zdroj: | International Journal of Toxicology. 24:301-311 |
| ISSN: | 1092-874X 1091-5818 |
| Popis: | The purpose of the study was to support of the International Life Sciences Institute (ILSI) alternative carcinogenicity models initiative to evaluate the carcinogenic potential of the nongenotoxic carcinogen, clofibrate, a peroxisome proliferator-activated receptor (PPAR) α agonist, following oral administration to rasH2 mice. Peroxisome proliferators are one of the most widely studied of the nongenotoxic carcinogens and have diverse industrial and therapeutic uses (Gonzalez et al. J. Nat. Cancer Inst. 90: 1702–1709, 1998); however, the nongenotoxic mechanism of carcinogenicity is currently unknown. Male mice were administered doses of clofibrate at 50, 100, or 200 mg/kg/day and female mice were administered doses of 50, 150, or 250 mg/kg/day by oral gavage at 10 ml/kg for 27 weeks. In addition, rasH2 male and female mice were treated with N-nitroso- N-methylurea (NMU). Nontransgenic male and female mice were treated with 200 and 250 mg/kg/day, respectively, of clofibrate. The NMU-treated mice were given a single intraperitoneal dose of 75 mg/kg, which was followed by a 90-day observation period; all others were sacrificed after 6 months of daily dosing. Hepatocellular neoplasms were observed in clofibrate-treated rasH2 male mice after 6 months of treatment but not in nontransgenic males or females. Clofibrate treatment (250 mg/kg/day) of female rasH2 mice was associated with a slight increase in the incidence of various neoplasms (harderian gland, lungs, skin, spleen, tail, thymus, and uterus) compared with untreated transgenic mice and with similarly treated nontransgenic mice. Non-neoplastic changes were found in the liver of transgenic and nontransgenic mice of both sexes and in the kidneys of male mice. NMU produced findings are consistent with previous studies. The data suggest that the rasH2 mice are a good model for testing epigenetic carcinogens in a shorter timeframe than conventional mouse carcinogenicity bioassays. |
| Databáze: | OpenAIRE |
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