INDUCTION OF SOMATIC INTRACHROMOSOMAL RECOMBINATION INVERSION EVENTS BY CYCLOPHOSPHAMIDE IN A TRANSGENIC MOUSE MODEL

Somatic intrachromosomal recombination (SICR) can result in chromosoma l inversion and deletion, mechanisms which are important in carcinogen esis. We have utilised a transgenic mouse model to study SICR inversio n events in spleen cells. The transgenic construct is designed so that expression of an Escherichia coli lacZ transgene only occurs in a cel l when an SICR inversion event occurs in the region of the transgene. The inversion events can then be detected by histochemical staining of frozen spleen sections for transgene expression and by polymerase cha in reaction across the inversion breakpoints. The spontaneous inversio n frequency in spleen rose 2-fold from 1.54 +/- 0.24 x 10(-4) (mean +/ - SE) in 4-month-old transgenic mice to 3.12 +/- 0.67 x 10(-4) in 22-m onth-old mice. Four-or 8-month-old mice were treated with a single int raperitoneal injection of cyclophosphamide, with doses ranging from 0. 01 to 100 mg/kg. The animals were killed 3 days after treatment. A sig nificant induction of SICR inversions was detected at all doses with a 3.2-fold maximum induction of inversions detected at 10 mg/kg. These results suggest that the transgenic mouse model used here may he a sen sitive model for studying the role of SICR in mutation and in studying risk assessment of environmental DNA-damaging agents. (C) 1998 Elsevi er Science B.V.