Genetics of susceptibility in the platyfish/swordtail tumor system to develop fibrosarcoma and rhabdomyosarcoma following treatment with N-methyl-N-nitrosourea (MNU).

Abstract

About 7000 animals of 65 different genotypes of the xiphophorine fish were treated with the direct acting chemical carcinogen N-methyl-N-nitrosourea (MNU; 10(-3)M; four times for 1 hour in two week intervals), in order to find out whether the susceptibility for development of fibrosarcomas and rhabdomyosarcomas is directly related to the genotype. A genotype specific susceptibility was found, ranging from zero to about nine percent. The highest susceptibles were found in certain backcross hybrids involving P.variatus/X.helleri-hybrids and X.helleri, as the recurrent parent. These genotypes were further analysed. Both P.variatus and X.helleri, as werr as their F1 proved to be insusceptible; while from the three backcrosses, which were tested, namely the BC1, BC4 and BC15, both the BC1, and the BC4, were susceptible, but the BC15 was insusceptible. The results are interpreted on the basis of the assumption that the differential susceptibility is a function of the type of control of a tumor gene (Tu-Fi-Rh) endogenous to P.variatus and involved in development of fibrosarcomas and rhabdomyosarcomas. Accordingly, in P.variatus and in the F1 the Tu-Fi-Rh is controlled by repressing genes (R-genes) linked as well as non-linked to Tu-Fi-Rh; because simultaneous mutation of both R-genes following treatment with MNU is an extremely unlikely event, these genotypes have an extremely low susceptibility. By contrast, in the BC1 and the BC4 the non-linked R-genes become eliminated and only the linked R-gene remains for repression of Tu-Fi-Rh; this condition confers a high degree of susceptibility, because one single mutation may lead to impairment of the R-gene and to Tu-Fi-Rh-mediated formulation of fibrosarcomas and rhabdomysarcomas. In the BC15, furthermore, also the Tu-Fi-Rh has become eliminated, resulting in a loss of the susceptibility. The results suggest that in the xiphophophorine fish the susceptibility for responding to MNU-treatment with the development of fibrosarcomas and rhabdomysarcomas is related directly to the genotype.