Nanosized zinc oxide particles do not promote DHPN-induced lung carcinogenesis but cause reversible epithelial hyperplasia of terminal bronchioles

作者：Xu Jiegou; Futakuchi Mitsuru; Alexander David B; Fukamachi Katsumi; Numano Takamasa; Suzui Masumi; Shimizu Hideo; Omori Toyonori; Kanno Jun; Hirose Akihiko; Tsuda Hiroyuki^*

来源：Archives of Toxicology, 2014, 88(1): 65-75.

DOI：10.1007/s00204-013-1086-5

• Nanosized zinc oxide particles
• Lung toxicity
• Lung carcinogenesis
• Epithelial hyperplasia of terminal bronchioles
• Interstitial pneumonitis
• Lung fibrosis

Zinc oxide (ZnO) is known to induce lung toxicity, including terminal bronchiolar epithelial hyperplasia, which gives rise to concerns that nanosized ZnO (nZnO) might lead to lung carcinogenesis. We studied the tumor promoting activity of nZnO by an initiation-promotion protocol using human c-Ha-ras proto-oncogene transgenic rats (Hras128 rats). The rats were given 0.2 % N-nitrosobis(2-hydroxypropyl)amine (DHPN) in the drinking water for 2 weeks and then treated with 0.5 ml of 250 or 500 mu g/ml nZnO suspension by intra-pulmonary spraying once every 2 weeks for a total of 7 times. Treatment with nZnO particles did not promote DHPN-induced lung carcinogenesis. However, nZnO dose-dependently caused epithelial hyperplasia of terminal bronchioles (EHTB) and fibrosis-associated interstitial pneumonitis (FAIP) that were independent of DHPN treatment. Tracing the fate of EHTB lesions in wild-type rats indicated that the hyperplastic lesions almost completely disappeared within 12 weeks after the last nZnO treatment. Since nZnO particles were not found in the lung and ZnCl2 solution induced similar lung lesions and gene expression profiles, the observed lesions were most likely caused by dissolved Zn2+. In summary, nZnO did not promote carcinogenesis in the lung and induced EHTB and FAIP lesions that regressed rapidly, probably due to clearance of surplus Zn2+ from the lung.

• 出版日期2014-1