Abstract
Enlarged nuclei have been frequently observed as an early carcinogen-induced change in both cultured cells and in target tissues in vivo. The purpose of this project was to examine the occurence of nuclear enlargement in the upper respiratory tract of rats to provide further evidence of whether nuclear enlargement is a reliable marker of carcinogenesis, and if it could be used a short-term test for respiratory carcinogens. The first approach to this problem was to use an in vivo model. Carcinogen-induced nuclear enlargement is best demonstrated when the tissue involved has been undergoing rapid replication. Rats were thus concommitantly exposed to sulphur dioxide by inhalation (which causes a hyperplastic response in the nasal cavity) and an N-nitrosamine i. p. (nitrosopyrrolidine, nitrosomorpholine, nitrosopiperidine or nitroso-di-n-propylamine) known to cause nasal tumours in rats following systemic administration. Sections were prepared from the nasal cavity and nuclear areas were measured. There were some increases in nuclear size 24 and 72 hours after the start of treatment. This effect had been reversed 120 hours after treatment. Attempts were also made to study the effects of carcinogens in cultured respiratory epithelial cells. The culture of nasal turbinate cells (either as tissue cultures or as primary cell cultures) was unsuccessful, however tracheal rings and tracheal epithelial cells were cultured. In both these model systems the epithelial cells grew rapidly, and so no further treatment was necessary to induce a hyperplastic response. Exposure of tracheal rings to benzo(a)pyrene failed to produce any nuclear enlargement during the time period examined. This was expected as benzo(a)pyrene is not tumourigenic in rat trachea in vivo. Nitroquinoline-N-oxide and dimethylnitrosamine are both potent carcinogens in the respiratory tract and induced nuclear enlargement. A number of carcinogens and noncarcinogens were also tested for their ability to induce increases in nuclear size in primary tracheal epithelial cell cultures. The results obtained were generally in agreement with the tumourigenicity of the test chemicals. The exception to this was benzo(a)pyrene which produced a significant increase in nuclear size. This project appears to provide evidence that exposure to carcinogens can lead to increased nuclear size in the respiratory tract of rats, above that produced by a concommitant hyperplastic control, and that this may be useful as a tissue-specific shortterm test for carcinogens. The relationship between nuclear enlargement, increases in nuclear DNA content and the process of carcinogenesis is discussed.