Quantitative Trait Loci Associated with Promoting Effects of Sodium l‐Ascorbate on Two‐stage Bladder Carcinogenesis in Rats

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Abstract
In the two‐stage rat bladder carcinogenesis model using N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN) as an initiator and sodium l‐ascorbate (SA) as a promoter, we found a notable strain difference between F344/DuCrj (F344) and WS/Shi (WS) rats in susceptibility to the promoting effect of SA. Twenty each of F344, WS and reciprocal F1 hybrid rats were given 0.05% BBN in their drinking water for 4 weeks and then a basal diet with (BBN‐SA group) or without (BBN group) a 5% SA supplement for 32 weeks. In F344 and also in reciprocal F1 hybrids, the number of tumors per rat was significantly higher in the BBN‐SA group than in the BBN group (P<0.0001). In contrast, WS rats were not significantly affected by either treatment (P=0.8). These findings indicate that F344 rats are highly susceptible to the promoter effect of SA, but WS rats are not. Linkage analysis of 108 WS X (WSXF344) F1 backcrosses revealed that this difference was related to a quantitative trait locus mapped on rat Chr. 17 (maximum LOD score, 3.86) named Bladder Tumor Susceptible‐I and possibly another locus on Chr. 5 (maximum LOD score, 2.39). This study has provided the first evidence that host genes influence the risk of bladder cancer development.