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Di(2-ethylhexyl)phthalate Induces Hepatocellular Adenoma in Transgenic Mice Carrying a Human Prototype c-Ha-ras Gene in a 26-Week Carcinogenicity Study

Developmental Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan, kaoru-toyozawa{at}dainippon-pharm.co.jp

Kazuo Okimoto

Developmental Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan

Izuru Kobayashi

Developmental Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan

Kazuyasu Kijima

Developmental Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan

Emi Kikawa

Developmental Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan

Mami Kohchi

Developmental Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan

Takatoshi Koujitani

Developmental Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan

Kohji Tanaka

Developmental Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan

Nobuo Matsuoka

Developmental Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Enoki 33-94, Suita, Osaka 564-0053, Japan

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, hydronephrosi s 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.

Key Words: Human prototype c-Ha-ras transgenic mice • rasH2 mice • Di(2-ethylhexyl)phthalate (DEHP) • peroxisome proliferator • rodent carcinogen • 26-week carcinogenicity study • transgenic mouse model • alternatives to carcinogenicity testing.

Toxicologic Pathology, Vol. 29, No. 4, 458-466 (2001)
DOI: 10.1080/01926230152499944


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