A Genetic Model for the Inheritance of Pituitary Tumor Susceptibility in F344 Rats*

An 8-week period of continuous diethylstilbestrol (DES) treatment results in the development of pituitary tumors in 100% of male or female F344 rats. Similar treatment of Holtzman male or female rats results in a very low incidence of pituitary tumor development (2-6%). A series of crosses was performed between F344 and Holtzman rats to produce the F1 hybrid, the F2 generation, and the backcrosses of the F1 hybrid to either the F344 parent or the Holtzman parent. The incidence of DES-induced pituitary tumors was measured in these animals. The results indicate that pituitary tumor susceptibility does not result from the expression of genes that are simple dominant or recessive genes, since the tumor's incidence in the F1 hybrid is intermediate to that in the parental strains. However, the data are compatible with the involvement of a small number of genetic loci. We present a genetic model involving three independently segregating loci which agrees reasonably well with the experimental results. In the model, the Holtzman strain has normal alleles at these loci which prevent uncontrolled proliferation. The highly inbred F344 strain is homozygous mutant at these three loci and in unable to control DES-induced proliferation.