( g takes place in colon cells. Ethyl...)Tissue Specificity for Mutation Parallels Tissue Specificity for Cancer

Ethyleneoxide and Benzene

Sisk et al.⁷ studied mutation induction in lacI transgenic mice after the mice inhaled 200 ppm of ethylene oxide. The mutant frequency increased significantly in the lung (9.1 x 10^-5 versus 6.2 x 10^-5 in the controls) but not the spleen, bone marrow, and male germ cells. The lung is indeed a major target organ for tumor formation in the mouse. In another mouse inhalation study with benzene,⁸ which induces lung tumors, leukemia, and lymphomas, mutations significantly increased in the lung and spleen (a 1.7- and 1.5-fold increase, respectively) but not in the liver tissue. Benzene metabolism takes place partially in the liver, while final oxidation steps can take place in the bone marrow.

Conclusions

The Big Blue transgenic rodent assay system accurately predicts mutations in specific tissues. In a number of cases, mutations are recovered in tissues that are not targets for carcinogenesis. While this eases the screening for mutagenic compounds, it becomes more difficult to determine mutagenic mechanisms and how they relate to carcinogenesis.⁹ For example, we recently determined that mutation induction in the kidney after TDBP treatment is highest in the cortex layer and less in the outer and inner medulla (de Boer, et al., in preparation). Tumors, however, do not arise in the cortex but in the outer medulla layer. This and other findings indicate that cell proliferation is equally important for tissue-specific tumor formation.

REFERENCES

1. De Boer, J.G., et al.(1996) Environ. Mol. Mutagen. 28: 418-423.

2. Mirsalis, J.C., et al.(1993) Mutagenesis 8: 265-271.

3. Suzuki, T., et al. (1996) Environ. Mol. Mutagen. 28: 348-353.'"/>