Genetics of chemical carcinogenesis. 1. Bidirectional selective breeding of susceptible and resistant lines of mice to two-stage skin carcinogenesis

Abstract

Six generations of a bidirectional selective breeding model for producing lines of mice susceptible (Car-S) and resistant (Car-R) to two-stage skin carcinogenesis are described. Initiation was with 9,10-dimethyl-1,2-benzanthracene (DMBA single application), and promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA twice weekly). The selective breeding was initiated with a highly genetically polymorph foundation population, produced by the intercrossing of eight inbred mouse strains. The Car-S line was produced by assortative mating of the mice presenting the largest number of tumors induced by low DMBA and TPA doses, the Car-R line by mating tumorless mice or mice showing the smallest number of tumors induced by large DMBA and TPA doses. The character investigated was expressed as per cent tumor incidence and as tumor multiplicity per mouse. The mean heritability of the susceptibility character for the two first generations was 0.84 for tumor incidence and 1.3 for tumor multiplicity; these values decreased to 0.53 and 0.44 respectively for the two consecutive generations. The heritability of the resistance character maintained a constant value of 0.29 +/- 0.04 for tumor incidence, and 0.53 +/- 0.08 for tumor multiplicity. The progressive response to selection indicates that the characters investigated are subject to polygenic regulation, even though some genes may have a major effect on the susceptibility character. The interline separation in F5, challenged with the same initiation and promotion schedule, is very large. In the Car-S line, tumor incidence was 82.5% and tumor multiplicity 4.9/mouse on promotion day 49, whereas the corresponding values for the Car-R line were 4.5% and 0.1/mouse on promotion day 81.