Induction of lacZ mutation by 7,12-dimethylbenz[a]anthracene in various tissues of transgenic mice

The induction of gene mutations was examined in Muta(TM)Mouse after an intr aperitoneal injection of 7,8-dimethyl-benz[a]anthracene (DMBA) at 20 mg/kg in a collaborative study participated by four laboratories. Although the DM BA dose used was lower than the level that has been reported to induce micr onucleated erythrocytes maximally in several mouse strains, a killing effec t appeared after day 9 of the post-treatment interval. Mutations in lacZ tr ansgene were detected by the positive selection assay following in vitro pa ckaging of phage lambda from the genomic DNA of the transgenic animals that survived. The mutant induction was evaluated in the bone marrow, liver, sk in, colon, kidney, thymus, and testis 7 to 28 days after the treatment. In the bone marrow, the mutant frequency reached a maximum, approximately a 30 -fold increase, 14 days after the treatment and the increased frequency per sisted at least up to day 28 of the post-treatment. Induction of mutants wa s detected in the liver, colon, thymus, and skin to lesser extents. Margina l responses were obtained in the kidney and testis, The slight increases in the mutant frequencies in the kidney and testis observed in some laborator ies were within laboratory-to-laboratory or animal-to-animal variations. In contrast to the gene mutation induction in the bone marrow, the frequency of micronucleated reticulocytes increased transiently 3 days after the trea tment and returned to a control level before day 8 of the post-treatment. I t was suggested that DMBA induced gene mutation is fixed in stem cells depe nding on cell proliferation while DNA damages responsible for chromosome br eakage are not transmitted to progeny cells. (C) 1999 Elsevier Science B.V. All rights reserved.