Evidence for cyclophosphamide-induced gene conversion and mutation in mouse germ cells

Toxicology and Applied Pharmacology
K J SchimentiJ C Schimenti

Abstract

Cyclophosphamide (CP) is a widely used antineoplastic drug. It tests positive in several genotoxicity assays, including those with endpoints such as chromosomal aberrations in mammalian cells, mitotic recombination in Drosophila melanogaster, and dominant lethal mutations in rodents. We have explored the effects of CP on genome stability of mouse (Mus domesticus) spermatogenic cells, using a recombination-based transgenic assay called MUSCATEER. In this system, intrachromosomal gene conversion events between two mutually defective lacZ genes generates beta-galactosidase activity in spermatids. The frequency of gene conversion events is determined by scoring spermatids stained with the lacZ substrate, X-gal. A dose-dependent induction of lacZ-positive spermatids was observed following single intraperitoneal CP exposures of 10, 100, and 200 mg/kg. At 200 mg/kg, there was a 25-fold increase over baseline. Treatment of a control transgenic line containing only a frame-shifted lacZ transgene provided an indication that CP also induced reversion mutations. The timing of the response indicated that the induction of recombination and/or mutation occurred primarily in meiotic stage cells. These results demonstrate potent germline mutage...Continue Reading

Citations

May 13, 1999·Immunological Reviews·K Högstrand, J Böhme
Jul 23, 1999·Annals of the New York Academy of Sciences·D L PittmanJ C Schimenti
Dec 2, 2015·Oncology Letters·Wei ZhengJianbo Wang
Jan 8, 2014·Laboratory animal research·Sung-Hwan KimJong-Choon Kim
Feb 28, 2018·Drug and Chemical Toxicology·Isha Nagpal, Suresh K Abraham
Feb 15, 2001·Genesis : the Journal of Genetics and Development·A RuvinskyF Costantini
Jan 23, 1999·American Journal of Human Genetics·J C Schimenti

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