Mutation of human lymphoblasts exposed to low concentrations of chemical mutagens for long periods of time

Abstract

Methylnitrosourea (MNU), ethyl methanesulfonate (EMS), and 4-nitroquinoline-N-oxide (4NQO) induce mutation to 6-thioguanine resistance and trifluorothymidine resistance in diploid human lymphoblasts (TK6). In single exposure experiments in which greater than 10% of treated cells survive, mutation as a function of concentration is linear for MNU, accelerates for EMS and appears to reach a plateau for 4NQO. In order to probe the bases of these concentration dependencies, human lymphoblasts were exposed for 20 days to each of the three mutagens. Each individual exposure chosen was in itself insufficient to induce statistically significant mutation and each resulted in a cellular survival of greater than 95%. Under this regimen, induced mutation as a function of the number of exposures was linear for all three mutagens. Prior exposure to low concentrations of mutagens was found to have no significant effect on the amount of mutation induced in subsequent exposures. Thus, no biological evidence was found for the induction of repair of misrepair systems.