Carcinogenic susceptibility of rasH2 mice to troglitazone.
To evaluate the carcinogenicity of troglitazone in rasH2 mice, 7-week-old male and female rasH2 mice were fed a diet containing 0, 3,000 or 6,000 ppm troglitazone for 26 weeks. An increased tendency in the incidence of vascular tumors was observed in females of the 6,000 ppm group. The preliminary analysis using a high-density oligonucleotide microarray on a splenic hemangiosarcoma of a high dose female that could be obtained as a fresh sample showed that several genes related to the ras/MAPK pathway activation, angiogenesis, cell cycle and cell multiplication were up-regulated. In addition, most of the genes up-regulated were confirmed by the reverse transcriptase-polymerase chain reaction (RT-PCR). These results may suggest that the carcinogenic susceptibility of rasH2 mice to troglitazone is relatively low and up-regulations of the ras/MAPK pathway and angiogenesis-related genes are probably involved in the production of splenic hemangiosarcomas in rasH2 mice given troglitazone.
Jin
Meilan
M
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan. meilan@cc.tuat.ac.jp
Takahashi
Miwa
M
Moto
Mitsuyoshi
M
Muguruma
Masako
M
Ito
Kazumi
K
Watanabe
Kyoko
K
Kenmochi
Yusuke
Y
Kono
Taichi
T
Hasumi
Keiji
K
Mitsumori
Kunitoshi
K
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods; D002839:Chromans / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D011905:Genes, ras / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006394:Hemangiosarcoma / Q000235:genetics / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D000077288:Troglitazone; D014617:Vacuoles / Q000187:drug effects
D002839:Chromans; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077288:Troglitazone