Analysis on genomic Instability with aging in rats developed spontaneous hepaticis hepatoma Senior Research Scientist

LEC（Long-Evans Cinnamon）突变型大鼠品系由于Atp 7 b基因突变而在肝脏中积累铜，Atp 7 b基因编码铜ATP酶。它自发地发展为肝炎，随后发展为肝细胞癌和胆管纤维化。本研究通过将携带lacI的λ穿梭载体的LEC和Big Blue F344大鼠交配，建立了1acI转基因LEC大鼠，并利用它们在体内检测了体细胞突变率。在24周龄时，使用颜色筛选技术分析了4只Big Blue F344大鼠和8只lacI转基因LEC大鼠的肝脏的lacI突变频率。lacI转基因LEC大鼠的突变频率（平均值± SD）为12.8 ± 8.3 × 10 ~（-5），比大蓝鼠高25倍。lacI转基因LEC大鼠肝脏中的铜积累水平为265 ± 72微克/克，是Big Blue F344大鼠的53倍。在lacI转基因LEC大鼠中，作为肝炎发展标志物的谷草转氨酶和谷丙转氨酶的血浆水平也要高得多。我们推测LEC大鼠肝脏突变频率的显著增加可能在其肝癌发生中起着至关重要的作用。

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.