title: Nanosized zinc oxide particles do not promote DHPN-induced lung carcinogenesis but cause reversible epithelial hyperplasia of terminal bronchioles.
abstract: 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 μg/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 Zn(2+). 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 Zn(2+) from the lung.
authors.affiliation: Laboratory of Nanotoxicology Project, Nagoya City University, 3-1 Tanabedohri Mizuho-ku, Nagoya, 467-8603, Japan.
authors.forename: Jiegou
authors.initials: J
authors.lastname: Xu
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Futakuchi
authors.forename: David B
authors.initials: DB
authors.lastname: Alexander
authors.forename: Katsumi
authors.initials: K
authors.lastname: Fukamachi
authors.forename: Takamasa
authors.initials: T
authors.lastname: Numano
authors.forename: Masumi
authors.initials: M
authors.lastname: Suzui
authors.forename: Hideo
authors.initials: H
authors.lastname: Shimizu
authors.forename: Toyonori
authors.initials: T
authors.lastname: Omori
authors.forename: Jun
authors.initials: J
authors.lastname: Kanno
authors.forename: Akihiko
authors.initials: A
authors.lastname: Hirose
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuda
mesh_terms: D000818:Animals; D055745:Bronchioles / Q000187:drug effects / Q000473:pathology*; D015197:Carcinogenicity Tests / Q000379:methods; D002712:Chlorides / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced* / Q000473:pathology; D017563:Lung Diseases, Interstitial / Q000139:chemically induced / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000473:pathology; D053758:Nanoparticles / Q000633:toxicity*; D009602:Nitrosamines / Q000633:toxicity*; D000090063:Proto-Oncogene Mas; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017967:Zinc Compounds / Q000494:pharmacology; D015034:Zinc Oxide / Q000633:toxicity*
chemical_list: D002712:Chlorides; C000715470:MAS1 protein, human; D009602:Nitrosamines; D000090063:Proto-Oncogene Mas; D017967:Zinc Compounds; C012457:diisopropanolnitrosamine; C016837:zinc chloride; D015034:Zinc Oxide