Dose-dependent changes in the spectrum of mutations induced by ionizing radiation

We examined the influence of dose on the spectrum of mutations induced at t he hypoxanthine guanine phosphoribosyltransferase (Hprt) locus in Chinese h amster ovary (CHO) cells. Independent CHO-K1 cell mutants at the Hprt locus were isolated from cells exposed to 0, 0.5, 1.5, 3.0 and 6.0 Gy Cs-137 gam ma rays, and the genetic changes responsible for the mutations were determi ned by multiplex polymerase chain reaction (PCR)-based exon deletion analys is. We observed dose-dependent changes in mutation spectra. At low doses, t he principal radiation-induced mutations were point mutations. With increas ing dose, multibase deletion mutations became the predominant mutation type such that by 6.0 Gy, there were almost three times more deletion mutations than point mutations. The dose response for induction of point mutations w as linear while that for multibase deletions fit a linear-quadratic respons e. There was a biphasic distribution of deletion sizes, and different dose responses for small compared to large deletions. The frequency of large (>3 6 kb) total gene deletions increased exponentially, implying that they deve lop from the interaction between two independent events. In contrast, the d ose response for deletion mutations of less than 10 kb was nearly linear, s uggesting that these types of mutations develop mostly from single events a nd not the interactions between two independently produced lesions. The obs ervation of dose-dependent changes in radiation-induced mutation spectra su ggests that the types of alterations and therefore the risks from low-dose radiation exposure cannot be easily extrapolated from high-dose effects. (C ) 2000 by Radiation Research Society.