A diurnal variation in the tumorigenic response of mouse epidermis to a single application of the strong short-acting chemical carcinogen methylnitrosourea. A dose-response study of 1, 2 and 10 mg.
A total of 670 hairless mice (hr/hr Oslo strain, 50% females) were exposed to a single topical application of two doses of MNU dissolved in 100 microliters reagent grade acetone in order to study whether there really is a diurnal variation in the sensitivity of epidermal cells to the short-acting alkylating carcinogen methylnitrosourea (MNU). Three hundred and fifty-one mice were exposed in groups to a single application of 1 mg MNU at either 04:00, 08:00, 12:00, 16:00, 20:00 or 24:00 Central European time. A number of 287 mice were exposed in three groups to single application of 2 mg MNU at 8:00, 12:00 or 20:00. To look at the dose-response relationship we also treated an additional group of 32 mice with 10 mg MNU at 12:00. The mice were kept in plastic cages located in the same room in an animal department with controlled temperature, air flow, humidity and a constant light/darkness rhythm (07:30 - 19:30). The development of all types of skin tumors was observed and the results presented as tumor rates (percentage of tumor-bearing animals in relation to the number of animals alive a appearance of the first tumor related to time), and tumor yields (the cumulative occurrence of all skin tumors standardized for comparison of groups of 32 mice related to time). Most animals were examined once a week for 54 weeks, but those to which 10 mg MNU was applied were observed for only 34 weeks. Modern, well accepted statistical methods were used to analyse the significance of differences between the results. A diurnal variation in tumor production after a single application of 1 mg MNU was demonstrated with a relatively high tumor crop after application in the period from 24:00 to a peak at 08:00, and a lower crop at 12:00 to 20:00 with a trough at 16:00. When 2 mg MNU was applied, there was definitely a low tumor production after application at 12:00 compared to the two other times. There was a good and almost straight-line dose-response relationship after 1, 2 and 10 mg MNU. The results give a strong support to the hypothesis that there is a diurnal variation in the sensitivity of epidermal cells to the short-acting alkylating carcinogen MNU.(ABSTRACT TRUNCATED AT 400 WORDS)
Iversen
O H
OH
Institute of Pathology, University of Oslo, Norway.
Iversen
U M
UM
D000236:Adenoma / Q000139:chemically induced; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced; D002453:Cell Cycle / Q000187:drug effects; D002940:Circadian Rhythm; D004305:Dose-Response Relationship, Drug; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced; D008223:Lymphoma / Q000139:chemically induced; D008297:Male; D008770:Methylnitrosourea / Q000008:administration & dosage; D051379:Mice; D008812:Mice, Hairless; D012867:Skin / Q000187:drug effects*; D012878:Skin Neoplasms / Q000139:chemically induced*; D013997:Time Factors
D008770:Methylnitrosourea