1997 Fiscal Year Final Research Report Summary
Analysis on genomic Instability with aging in rats developed spontaneous hepaticis hepatoma Senior Research Scientist
| Project/Area Number |
08838027
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
老化(加齢)
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| Research Institution | National Institute For Environmental Studies (NIES) |
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Principal Investigator |
SONE Hideko NIES, 地域環境研究グループ・化学物質健康リスク評価チーム, 主任研究員 (60280715)
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| Project Period (FY) |
1996 – 1997
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| Keywords | aging / liver cancer / hepatitis / gencmic instability / LEC rats / lacI transgenic / oxidative stress |
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| Research Abstract |
The LEC (Long-Evans Cinnamon) mutant strain of rat accumulates copper in the liver due to a mutation in the Atp7b gene, which encodeds a copper-ATPase. It spontaneously develops hepatitis, and subsequently hepatocellular carcinomas and cholangiofibrosis. Excess intracellular copper has been thought to induce DNA damage throughout reactive oxygen species (ROS) produced by Cu (II) /Cu (I) redox cycling and also by direct interaction with DNA.We developed 1acl transgenic LEC rats, by mating LEC and Big Blue F344 rats carrying a lambda shuttle vector harbo6ng the lacI and utilized them to examine rates of somatic mutation in vivo. At 24 weeks of age, the livers of four Big Blue F344 rats and of eight lacI transgenic LEC rats were analyzed for the mutant frequency of lacI using the color screening technique. The mutant frequencies (mean+-SD) in the lacI transgenic LEC rats was 12.8+-8.3 x 10-5,25-fold higher than that in Big Blue case. The level of copper accumulation in the livers of lacI transgenic LEC rats was 265+-72 micro g/g, 53-fold the amount in Big Blue F344 rats. Plasma levels of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase, assayd as markers of hepatitis development, were also much higher in lacI transgenic LEC rats. We hypothesize that the remarkable increase in mutant frequency in the LEC rat liver may play a crucial role in its hepatocarcinogenesis.
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