High-frequency induction of chromosomal rearrangements in mouse germ cells by the chemotherapeutic agent chlorambucil.

Recent mutagenesis studies have demonstrated that the chemotherapeutic agent, chlorambucil (CHL), is highly mutagenic in male germ cells of the mouse. Post-meiotic germ cells, and especially early spermatids, are the most sensitive to the cytotoxic and mutagenic effects of this agent. Genetic, cytogenetic and molecular analyses of many induced mutations have shown that, in these germ-cell stages, CHL induces predominantly chromosomal rearrangements (deletions and translocations), and mutation-rate studies show that, in terms of tolerated doses, CHL is perhaps five to ten times more efficient in inducing rearrangements than is radiation exposure. Appropriate breeding protocols, along with knowledge of the advantages and limitations associated with the use of CHL, can be used to expand the current resource of chromosomal rearrangements in the mouse and to provide new phenotype-associated mutations amenable to positional-cloning techniques. The analysis of CHL-induced mutations has also contributed to understanding the factors that affect the yield and nature of chemically induced germline mutations in mammals.