Tasaki Masako, Kuroiwa Yuichi, Inoue Tomoki, Hibi Daisuke, Matsushita Kohei, Kijima Aki, Maruyama Soichi, Nishikawa Akiyoshi, Umemura Takashi
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Exp Toxicol Pathol. 2014 Jan;66(1):19-26. doi: 10.1016/j.etp.2013.07.003. Epub 2013 Aug 27.
To explore the role of oxidative stress in chemical carcinogenesis driven by non-genotoxic mechanisms, nrf2-deficient (nrf2(-/-)) and nrf2-wild-type (nrf2(+/+)) mice were exposed to pentachlorophenol (PCP) at concentrations of 600 or 1200 ppm for 60 weeks, or piperonyl butoxide (PBO) at concentrations of 3000 or 6000 ppm in the diet for 52 weeks, respectively. Additional studies were performed to examine 8-hydroxydeoxyguanosine (8-OHdG) levels in liver DNA and hepatotoxicological parameters in serum following 8 weeks of exposure of each group to PBO at the same doses as in the long-term study. Exposure to 600 ppm PCP caused cholangiofibrosis (CF) only in nrf2(-/-) mice, while 1200 ppm PCP induced CF in both genotypes. Moreover, cholangiocarcinomas were found with significant incidence only in nrf2(-/-) mice treated with 1200 ppm PCP. Short-term exposure to 6000 ppm PBO caused significant elevation of 8-OHdG levels in both genotypes, while exposure to 3000 ppm caused a significant increase in 8-OHdG only in nrf2(-/-) mice. There were no inter-genotype changes in the incidences of regenerative hepatocellular hyperplasia (RHH) following long-term exposure to PBO. However, the incidence and multiplicity of hepatocellular adenomas, especially those observed in RHH, were much higher in nrf2-/- mice treated with 6000 ppm PBO than in nrf2+/+ mice treated with 6000 ppm PBO. Therefore, oxidative stress generated through PCP or PBO metabolism may promote the proliferation and progression of preneoplastic lesions to neoplasms.
为探究氧化应激在非遗传毒性机制驱动的化学致癌作用中的角色，分别将nrf2基因敲除（nrf2(-/-)）和nrf2野生型（nrf2(+/+)）小鼠暴露于浓度为600或1200 ppm的五氯苯酚（PCP）中60周，或分别在饮食中给予浓度为3000或6000 ppm的胡椒基丁醚（PBO）52周。进行了额外的研究，以检测每组小鼠在按照长期研究中的相同剂量暴露于PBO 8周后，肝脏DNA中的8-羟基脱氧鸟苷（8-OHdG）水平以及血清中的肝毒理学参数。暴露于600 ppm PCP仅在nrf2(-/-)小鼠中引起胆管纤维化（CF），而1200 ppm PCP在两种基因型小鼠中均诱导CF。此外，仅在接受1200 ppm PCP处理的nrf2(-/-)小鼠中发现胆管癌的发生率显著增加。短期暴露于6000 ppm PBO导致两种基因型小鼠的8-OHdG水平均显著升高，而暴露于3000 ppm PBO仅在nrf2(-/-)小鼠中导致8-OHdG显著增加。长期暴露于PBO后，再生性肝细胞增生（RHH）的发生率在不同基因型之间没有变化。然而，接受6000 ppm PBO处理的nrf2-/-小鼠中肝细胞腺瘤的发生率和多发性，尤其是在RHH中观察到的，远高于接受6000 ppm PBO处理的nrf2+/+小鼠。因此，通过PCP或PBO代谢产生的氧化应激可能促进癌前病变向肿瘤的增殖和进展。
