Inversion due to intrachromosomal recombination produced by carcinogens in a transgenic mouse model

Somatic intrachromosomal recombination (SICR) can result in inversions and deletions in the DNA. pKZ1 mice possess an Escherichia coli (E. coli) lacZ transgene which is only expressed after a DNA inversion involving the transgene occurs. The E. coli beta-galactosidase protein can then be detected in frozen tissue sections using a chromogenic substrate. Therefore, pKZ1 mice can be used to detect SICR inversion events in vivo in different tissues. We have tested the pKZ1 mouse for its potential as a general mutagenesis model for detecting SICR in spleen in response to carcinogens which have widely different mechanisms of genotoxicity. Animals were given a single exposure of carcinogen and spleen cells were examined 3 days later for inversion events by histochemical staining of tissue sections. Mitomycin C, X-irradiation, etoposide and methylene chloride caused significant induction of inversion events in spleen tissue, ranging from 1.6- to 4.2-fold induction with the doses used here. This is the first time that inversion events induced by these carcinogens have been specifically studied in vivo in a mouse model and the findings expand the repertoire of mutation events known to be caused by these agents. We suggest that the pKZ1 mouse can be used as a general mutagenesis model for detection of SICR events and is likely to be a useful model for studying the mechanism of SICR in response to DNA damaging agents.