Ge R, Yang S, Kramer P M, Tao L, Pereira M A
Department of Pathology, Medical College of Ohio, 3055 Arlington Avenue, Toledo, OH 43614-5806, USA.
J Biochem Mol Toxicol. 2001;15(2):100-6. doi: 10.1002/jbt.5.
The chlorine disinfection by-products, dichloroacetic acid (DCA) and trichloroacetic acid (TCA), are carcinogenic in mouse liver. We have previously reported that DCA and TCA induced DNA hypomethylation in mouse liver. In the present study, we determined the temporal association for DNA hypomethylation and cell proliferation. Female B6C3F1 mice were administered daily doses of 500 mg/kg DCA or TCA by gavage and sacrificed at 24, 36, 48, 72, and 96 hours after the first dose. The proliferating cell nuclear antigen-labeling index in the liver was increased at 72 and 96 hours by both DCA and TCA, that is, at 72 hours the index was 1.00 +/- 0.21, 0.51 +/- 0.11, and 0.095 +/- 0.016 for DCA, TCA, and the vehicle control, respectively. The mitotic index was also significantly increased at 96 hours. The promoter region for the c-myc gene was hypomethylated only at 72 and 96 hours and not at the earlier sacrifices. Similarly, the methylation of the c-myc gene in the kidney and urinary bladder was decreased only at 72 and 96 hours. In summary, enhancement of cell proliferation and decreased methylation of the c-myc gene were first observed simultaneously at 72 hours after the start of exposure. Thus, the results support the hypothesis that DCA and TCA induce DNA hypomethylation by inducing DNA replication and preventing the methylation of the newly synthesized strands of DNA.
氯消毒副产物二氯乙酸（DCA）和三氯乙酸（TCA）在小鼠肝脏中具有致癌性。我们之前报道过，DCA和TCA可诱导小鼠肝脏中的DNA低甲基化。在本研究中，我们确定了DNA低甲基化与细胞增殖的时间关联。通过灌胃给予雌性B6C3F1小鼠每日剂量为500 mg/kg的DCA或TCA，并在首次给药后24、36、48、72和96小时处死。DCA和TCA均在72和96小时时使肝脏中的增殖细胞核抗原标记指数升高，即72小时时，DCA、TCA和溶剂对照组的指数分别为1.00±0.21、0.51±0.11和0.095±0.016。有丝分裂指数在96小时时也显著升高。c-myc基因的启动子区域仅在72和96小时时发生低甲基化，而在更早处死时未出现。同样，肾脏和膀胱中c-myc基因的甲基化仅在72和96小时时降低。总之，在开始接触后72小时首次同时观察到细胞增殖增强和c-myc基因甲基化降低。因此，这些结果支持了以下假说：DCA和TCA通过诱导DNA复制并阻止新合成的DNA链甲基化来诱导DNA低甲基化。
