Di(2-ethylhexyl)phthalate induces hepatocellular adenoma in transgenic mice carrying a human prototype c-Ha-ras gene in a 26-week carcinogenicity study
To evaluate the transgenic mouse carrying a human prototype c-Ha-ras gene (rasH2 mouse) as a model for 26-week carcinogenicity tests, Di(2-ethylhexyl)phthalate (DEHP), a peroxisome proliferator, was administered to 15 rasH2 mice/sex/group at concentrations of 1,500, 3,000 or 6,000 ppm, and to 15 wil...
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Published in | Toxicologic pathology Vol. 29; no. 4; p. 458 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
01.07.2001
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Abstract | To evaluate the transgenic mouse carrying a human prototype c-Ha-ras gene (rasH2 mouse) as a model for 26-week carcinogenicity tests, Di(2-ethylhexyl)phthalate (DEHP), a peroxisome proliferator, was administered to 15 rasH2 mice/sex/group at concentrations of 1,500, 3,000 or 6,000 ppm, and to 15 wild-type (non-Tg) mice/sex/group at a concentration of 6,000 ppm in their diets for 26 weeks. Survival rates and food consumption in the groups treated with DEHP and in the control group were similar. Body weight gain in rasH2 and non-Tg mice at 6,000 ppm in the terminal week decreased about 10% as compared to the control group. Common findings related to treatment with DEHP in rasH2 and non-Tg mice included hypertrophy with coarse granules and deposit of pigment in the liver, hydronephrosis and tubular regeneration in the kidney, focal atrophy in the testis, and increased eosinophilic body in the nasal cavity. Hepatocellular adenoma was induced by treatment with DEHP, and was confined to male rasH2; mice the incidence being 7%(1/15), 13%(2/15), and 27%(4/15) in the 1,500-, 3,000-, and 6,000-ppm group, respectively. Point mutation was not detected in codon 12 and 61 of human c-Ha-ras transgene upon DNA analyses on frozen samples taken from these hepatocellular adenomas. From the results obtained in this 26-week carcinogenicity study, it is concluded that DEHP is a hepato-carcinogen for transgenic mouse carrying a human prototype c-Ha-ras gene. |
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AbstractList | To evaluate the transgenic mouse carrying a human prototype c-Ha-ras gene (rasH2 mouse) as a model for 26-week carcinogenicity tests, Di(2-ethylhexyl)phthalate (DEHP), a peroxisome proliferator, was administered to 15 rasH2 mice/sex/group at concentrations of 1,500, 3,000 or 6,000 ppm, and to 15 wild-type (non-Tg) mice/sex/group at a concentration of 6,000 ppm in their diets for 26 weeks. Survival rates and food consumption in the groups treated with DEHP and in the control group were similar. Body weight gain in rasH2 and non-Tg mice at 6,000 ppm in the terminal week decreased about 10% as compared to the control group. Common findings related to treatment with DEHP in rasH2 and non-Tg mice included hypertrophy with coarse granules and deposit of pigment in the liver, hydronephrosis and tubular regeneration in the kidney, focal atrophy in the testis, and increased eosinophilic body in the nasal cavity. Hepatocellular adenoma was induced by treatment with DEHP, and was confined to male rasH2; mice the incidence being 7%(1/15), 13%(2/15), and 27%(4/15) in the 1,500-, 3,000-, and 6,000-ppm group, respectively. Point mutation was not detected in codon 12 and 61 of human c-Ha-ras transgene upon DNA analyses on frozen samples taken from these hepatocellular adenomas. From the results obtained in this 26-week carcinogenicity study, it is concluded that DEHP is a hepato-carcinogen for transgenic mouse carrying a human prototype c-Ha-ras gene. |
Author | Kijima, K Kikawa, E Toyosawa, K Koujitani, T Kohchi, M Okimoto, K Tanaka, K Matsuoka, N Kobayashi, I |
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Snippet | To evaluate the transgenic mouse carrying a human prototype c-Ha-ras gene (rasH2 mouse) as a model for 26-week carcinogenicity tests, Di(2-ethylhexyl)phthalate... |
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SubjectTerms | Adenoma, Liver Cell - chemically induced Adenoma, Liver Cell - genetics Adenoma, Liver Cell - pathology Administration, Oral Animals Carcinogenicity Tests - methods Diethylhexyl Phthalate - administration & dosage Diethylhexyl Phthalate - toxicity Dose-Response Relationship, Drug Female Genes, ras Kidney - drug effects Kidney - pathology Kidney Tubules - drug effects Kidney Tubules - pathology Liver - drug effects Liver - pathology Liver Neoplasms, Experimental - chemically induced Liver Neoplasms, Experimental - genetics Liver Neoplasms, Experimental - pathology Male Mice Mice, Transgenic Nasal Cavity - drug effects Nasal Cavity - pathology Peroxisome Proliferators - administration & dosage Peroxisome Proliferators - toxicity Polymorphism, Single-Stranded Conformational Sex Factors Survival Rate Testis - drug effects Testis - pathology Time Factors |
Title | Di(2-ethylhexyl)phthalate induces hepatocellular adenoma in transgenic mice carrying a human prototype c-Ha-ras gene in a 26-week carcinogenicity study |
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