The relation between reaction kinetics and mutagenic action of mono-functional alkylating agents in higher eukaryotic systems. II. Total and partial sex-chromosome loss in Drosophila.

In Drosophila the connection between primary alkylation pattern and genetic activity of 8 mono-functional alkylating agents (AA)--ENU, DEN, iPMS, MNU, DMN, EMS, MMS and DMS--was investigated in spermatozoa and spermatids of treated R 1 (2), y B/BS Y y+ males. The induction of ring-X loss, Y-chromosome loss, and Y-rearrangements served as parameters of their effectiveness to produce chromosomal aberrations. (1) The ability to cause chromosomal losses decreased in the sequence MMS = DMS greater than MNU = DMN greater than EMS greater than iPMS greater than ENU = DEN. This ranking is consistent with the sequence in effectiveness in producing translocations. (2) The low frequencies of Y-chromosome rearrangements made any meaningful comparison between the AA impossible. The diagnostic value of such tests is poor, because even at toxic concentrations large numbers of offspring must be scored to obtain statistically significant effects. (3) With MNU, DMN, EMS, MMS and DMS, a time-dependent increase in the frequencies of ring-X losses ("storage effect") was found. (4) A stage-by-stage comparison revealed a differential response of spermatozoa and spermatids to these AA. Mature spermatozoa tended to be more resistant to the induction of breaks by MNU, DMN, EMS and MMS. (5) A general observation with all the AA was a reduced rate in survival of X-bearing sperm after treatment with mutagen. There was, however, no apparent quantitative relationship between the shift in the sex ratios observed and the yield of chromosomal aberrations. It is concluded that differences between these AA in their selectivity to numerous nucleophiles of DNA, as expressed by their s values, account for most of the diversity in their genetic effectiveness. The significance for genetic activity of other parameters than the s value appeared from the lower activity of EMS relative to MNU, indicating that methylation was more effective than ethylation in breaking chromosomes.