INDUCTION OF GERMLINE-LENGTH MUTATIONS AT THE MINISATELLITES PC-1 ANDPC-2 IN MALE-MICE EXPOSED TO POLYCHLORINATED-BIPHENYLS AND DIESEL EXHAUST EMISSIONS

PC-1 and PC-2 are hypervariable mouse minisatellites. The rates of spo ntaneous germline-length mutation have been shown to vary between diff erent mouse strains. PC-1 is composed of GGCAG repeat units and PC-2 o f GGCAGGA. Minisatellites frequently mutate by gaining or losing repea t units. Such length mutations in mini- and microsatellites have been associated with human disease and may therefore be an important endpoi nt in genetic toxicity testing. Carcinogenic activity of many chemical s is associated with their ability to induce heritable mutations. Sinc e minisatellites are highly prone to mutate to new lengths, which can be assayed by Southern analysis, we used this method to detect heritab le genetic effects in mice. Male mice exposed to diesel exhausts and/o r polychlorinted biphenyls (PCB) were investigated for effects on the germline mutation frequenallele lengths in parents and offspring. For PC-1 significantly higher mutation frequencies were found in males tre ated with diesel exhausts + PCB (6 of 35 alleles) and with PCB alone ( 6 of 51 alleles) as compared to the males in the control group (0 of 4 3 alleles). The mutation frequency in the diesel exhaust group was not significantly increased (2 of 43 alleles). For PC-2 the only mutation found occurred in the PCB group (1 of 51 alleles). This in vivo study demonstrates-for the first time-chemically induced minisatellite muta tions in the germline. (C) 1997 Wiley-Liss, Inc.