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Identification of hepatocarcinogen-resistance genes in DBA/2 mice
G H Lee1, L M Bennett, R A Carabeo
1McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison 53706.
Abstract:
Male DBA/2J mice are approximately 20-fold more susceptible than male C57BL/6J mice to hepatocarcinogenesis induced by perinatal treatment with N,N-diethylnitrosamine (DEN). In order to elucidate the genetic control of hepatocarcinogenesis in DBA/2J mice, male BXD recombinant inbred, D2B6F1 x B6 backcross, and D2B6F2 intercross mice were treated at 12 days of age with DEN and liver tumors were enumerated at 32 weeks. Interestingly, the distribution of mean tumor multiplicities among BXD recombinant inbred strains indicated that hepatocarcinogen-sensitive DBA/2 mice carry multiple genes with opposing effects on the susceptibility to liver tumor induction. By analyzing D2B6F1 x B6 backcross and D2B6F2 intercross mice for their liver tumor multiplicity phenotypes and for their genotypes at simple sequence repeat marker loci, we mapped two resistance genes carried by DBA/2J mice, designated Hcr1 and -2, to chromosomes 4 and 10, respectively. Hcr1 and Hcr2 resolved the genetic variance in the backcross population well, indicating that these resistance loci are the major determinants of the variance in the backcross population. Although our collection of 100 simple sequence repeat markers allowed linkage analysis for approximately 95% of the genome, we failed to map any sensitivity alleles for DBA/2J mice. Thus, it is likely that the susceptibility of DBA/2J mice is the consequence of the combined effects of multiple sensitivity loci.
Insights
DBA/2J mice exhibit higher susceptibility to liver cancer after N,N-diethylnitrosamine (DEN) exposure. Genetic mapping identified two resistance genes (Hcr1 and Hcr2) on chromosomes 4 and 10, suggesting multiple sensitivity genes contribute to DBA/2J susceptibility.
Area of Science:
- Genetics
- Toxicology
- Cancer Research
Background:
- Male DBA/2J mice are significantly more susceptible to chemically induced liver cancer (hepatocarcinogenesis) compared to male C57BL/6J mice.
- Perinatal exposure to N,N-diethylnitrosamine (DEN) is a common model for studying liver tumor development.
Purpose of the Study:
- To investigate the genetic factors controlling hepatocarcinogenesis susceptibility in DBA/2J mice.
- To identify specific genes and chromosomal locations associated with resistance or susceptibility to DEN-induced liver tumors.
Main Methods:
- Utilized BXD recombinant inbred strains, D2B6F1 x B6 backcross, and D2B6F2 intercross mouse models.
- Administered DEN at 12 days of age and enumerated liver tumors at 32 weeks.
- Performed linkage analysis using simple sequence repeat (SSR) markers to map quantitative trait loci (QTLs).
Main Results:
- Identified two major resistance genes, Hcr1 and Hcr2, located on chromosomes 4 and 10, respectively, in DBA/2J mice.
- These resistance loci explained a significant portion of the genetic variance in liver tumor multiplicity in the backcross population.
- No specific sensitivity alleles from DBA/2J mice were mapped, indicating a complex genetic basis for susceptibility.
Conclusions:
- DBA/2J mice possess multiple genetic factors that confer resistance to DEN-induced hepatocarcinogenesis.
- The high susceptibility of DBA/2J mice is likely due to the combined action of several unmapped sensitivity genes.
- Understanding these genetic controls can provide insights into differential cancer susceptibility.