Inheritance of resistance to promotion of preneoplastic liver lesions in Copenhagen rats

Previously, we have shown that Copenhagen (Cop) rats are highly resistant t o the induction of putative preneoplastic, glutathione S-transferase 7-7- ( GST 7-7) positive liver lesions following treatment with a modified resista nt hepatocyte (RH) protocol. The objective of this study was to determine i f resistance is inherited in a dominant or recessive manner and to derive a n estimate of the number of genetic loci involved. We crossed male and fema le Cop rats with F344 rats to produce F1 offspring. Backcross rats were gen erated using female 171 rats and either Cop or F344 males, resulting in B1c and B1f generations, respectively. The male rats from all these crosses we re initiated with diethylnitrosamine (200 mg/kg) at 7 to 8 weeks of age and were promoted 3 weeks later with the RH protocol (2-acetyl-aminofluorene a nd a two-thirds partial hepatectomy). The rats were sacrificed 3 weeks afte r the partial hepatectomy and their livers were sectioned and stained for G ST 7-7-positive lesions. The susceptibility of F1 rats was in between Cop a nd F344 rats, having 21.7% +/- 2.0% (mean +/- SEM) of their liver volume oc cupied by lesions versus 4.2% +/- 0.8% for Cop and 53.0% +/- 5.8% for F344 rats. As expected, B1c rats had a volume of liver occupied by lesions that was in between the F1 and Cop rats at 13.5% +/- 1.6%. Surprisingly, B1f rat s were similar to Bic rats in their resistance (9.1% +/- 2.1%). These resul ts point to a complex, polygenic inheritance pattern that can be explained by a minimum of four loci, one of which shows recessive epistasis.