© 1996 Oxford University Press
review-article |
Variability in Gene Expression and Tumor Formation within Genetically Homogeneously Animal Populations in Bioassays1
National Center for Toxicological Research, Food and Drug Administration, U.S. Department of Health and Human Services Jefferson, Arkansas 72079 and Departments of Biochemistry/Molecular Biology and Pharmacology/Toxicology University of Arkansas for Medical Sciences Little Rock, Arkansas 72205
Received April 14, 1995; accepted August 21, 1995
Considerable variation in susceptibility to tissue-specific tumor formation in response to chronic treatment with low or intermediate dose levels of putative carcinogens is observed within populations of genetically homogeneous test animals under controlled environmental conditions. Experimental evidence from National Toxicology Program studies is reviewed, as are studies of differing degrees of carcinogenic response and tumor promotion among iso- and congenic mice carrying the Avy (viable yellow) mutation. The data suggest that individual variations in carcinogenic response among genetically homogeneous animals may derive primarily from differences in regulation of gene transcription. Differences in posttranscriptional and posttranslational processing of gene products are probably also contributing factors. The viable yellow Avy/a mouse model system is uniquely suited for investigating the developmental and molecular bases of this phenotypic variability in genetically homogeneous populations since various degrees of carcinogenic response and promotion of tumor formation can be predicted, a priori, at least as early as 7 days of age by correlation with coat color patterns. Ectopic expression of the agouti protein results in enhanced susceptibility to tumor formation in tissues which are already sensitized to neoplastic transformation by their strain genome. The differences in tumorigenic response and coat color pattern among Avy/– mice appear to be associated with different DNA methylation states of the promoter of an intracisternal A particle inserted into exon 1A of the agouti gene.