MNU induction of neoplasia in a platyfish model

Interspecific hybrid crosses between members of the fish genus Xiphophorus have been used for over 70 years to study the genetic aspects of melanoma f ormation. In the well-established "Gordon-Kosswig" cross, the platyfish X. maculatus is outcrossed to the swordtail X. helleri, and the resulting back cross segregants spontaneously develop melanoma. We recently produced a dis tinct cross between X. maculatus and another platyfish species, X couchianu s. X. maculatus strain Jp 163 A is homozygous for several X-linked pigment pattern genes, including the Spotted dorsal (Sd), Dorsal red (Dr), and Anal fin spot (A. Af is a sex-limited trait, coding exclusively for melanophore s distributed on the modified anal fin or "gonopodium" in the adult male fi sh. Within F-1 and BC1 hybrids (to X couchianus), the Sd pigment pattern is phenotypically suppressed, whereas Dr and Af are enhanced. We exposed BC1 hybrids to the direct-acting carcinogen N-methyl-N-nitrosourea (MNU). Treat ment led to the development of schwannomas, fibrosarcomas, and retinoblasto mas. In addition, numerous MNU-treated males that inherited Af developed a pronounced melanotic phenotype, with melanin-containing cells oftentimes to tally covering the gonopodium and extending further to grow within the vent ral regions of the fish. Genetic linkage analysis of the BC, hybrids reveal ed a significant (p < 0.01) association between CDKN2X genotype and the phe notypic degree of melanization. Such an association is consistent with a lo cus within linkage group V playing a role in the development of melanosis a nd delineates three genetic preconditions and a carcinogenic scheme resulti ng in melanosis of the ventral regions of hybrid fish. The overall study fu rther alludes to the potential of using Xiphophorus fish to study carcinoge nic mechanisms for tumors other than melanoma (schwannoma, fibrosarcoma, an d retinoblastoma) and should enable extensive pathologic and molecular gene tic studies of derived neoplastic abnormalities.