ENHANCED SOMATIC MUTATION-RATES INDUCED IN STEM-CELLS OF MICE BY LOW CHRONIC EXPOSURE TO ETHYLNITROSOUREA

We have found that the somatic mutation rate at the Dlb-1 locus increa ses exponentially during low daily exposure to ethylnitrosourea over 4 months. This effect, enhanced mutagenesis, was not observed at a lacI transgene in the same tissue, although the two loci respond very simi larly to acute doses, Since both mutations are neutral, the mutant fre quency was expected to increase linearly with time in response to a co nstant mutagenic exposure, as it did for lacI. Enhanced mutagenesis do es not result from an overall sensitization of the animals, since mice that had first been treated with a low daily dose for 90 days and the n challenged with a large acute dose were not sensitized to the acute dose. Nor was the increased mutant frequency due to selection, since a nimals that were treated for 90 days and then left untreated for up to 60 days showed little change from the 90-day frequency, The effect is substantial: about 8 times as many Dlb-1 mutants were induced between 90 and 120 days as in the first 30 days. This resulted in a reverse d ose rate effect such that 90 mg/kg induced more mutants when delivered at 1 mg/kg per day than at 3 mg/kg per day, We postulate that enhance d mutagenesis arises from increased stem cell proliferation and the pr eferential repair of transcribed genes, Enhanced mutagenesis may be im portant for risk evaluation, as the results show that chronic exposure s can be more mutagenic than acute ones and raise the possibility of s ynergism between chemicals at low doses.