Lack of nrf2 results in progression of proliferative lesions to neoplasms induced by long-term exposure to non-genotoxic hepatocarcinogens involving oxidative stress

• Published in: Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie 2014-01, Vol.66 (1), p.19-26
• Main Authors: Tasaki, Masako, Kuroiwa, Yuichi, Inoue, Tomoki, Hibi, Daisuke, Matsushita, Kohei, Kijima, Aki, Maruyama, Soichi, Nishikawa, Akiyoshi, Umemura, Takashi
• Format: Article
• Language: English
• Subjects: Animals; Carcinogens - toxicity; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cholangiofibrosis; Disease Models, Animal; Disease Progression; Liver Neoplasms - chemically induced; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Male; Mice; Mice, Knockout; NF-E2-Related Factor 2 - deficiency; NF-E2-Related Factor 2 - genetics; nrf2-Deficient mice; Oxidative Stress - genetics; Pentachlorophenol; Piperonyl butoxide; Precancerous Conditions - chemically induced; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Regenerative hepatocellular hyperplasia
• ISSN: 0940-2993; 1618-1433
• DOI: 10.1016/j.etp.2013.07.003

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 1200ppm for 60 weeks, or piperonyl butoxide (PBO) at concentrations of 3000 or 6000ppm 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 600ppm PCP caused cholangiofibrosis (CF) only in nrf2−/− mice, while 1200ppm PCP induced CF in both genotypes. Moreover, cholangiocarcinomas were found with significant incidence only in nrf2−/− mice treated with 1200ppm PCP. Short-term exposure to 6000ppm PBO caused significant elevation of 8-OHdG levels in both genotypes, while exposure to 3000ppm 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 6000ppm PBO than in nrf2+/+ mice treated with 6000ppm PBO. Therefore, oxidative stress generated through PCP or PBO metabolism may promote the proliferation and progression of preneoplastic lesions to neoplasms.