THE MUTAGENIC RESPONSE AT THE OUABAIN RESISTANCE LOCUS IN T-CELLS OF MICE EXPOSED TO N-ETHYL-N-NITROSOUREA PARALLELS THE RESPONSE AT THE HPRT LOCUS AND CORRELATES WITH MUTATION TARGET SIZE

The lymphocyte Hprt gene has been used extensively as a reporter locus to monitor the mutational effects of the exposure of animals to genot oxicants, Implicit in this view of the function of a reporter gene is the assumption that its mutagenic response is representative of that o f other genes in the organism, As a test of this hypothesis we compare d the frequency of 6-thioguanine-resistant (TG(r)) mutants at the Hprt locus with the mutant frequency (MF) induced at another locus, the ou abain resistance (Oua) locus, The frequency of spontaneous OUA(R) muta nts was estimated to be 1.1x10(-7) (MF between <0.3 and 1.1x10(-7)), w hich was similar to 30-fold less than the spontaneous TG(r) MF. Follow ing treatment with N-ethyl-N-nitrosourea (ENU), the induced OUA(R) MF at each of two dose levels (50 and 150 mg/kg ENU) and two time points (3 and 6 weeks postexposure) was consistently 8- to 9-fold lower than the corresponding TG(r) MF. Thus the mutagenic response of the Oua loc us closely paralleled that of the Hprt locus, indicating a similarity in their response to ENU, In addition, the Oua locus was 3-4 times mor e sensitive than the Hprt locus to the mutagenic effect of ENU, as mea sured by the fold increase in MF over the background level. The number of ENU-mutable sites capable of resulting in a TG(r) or OUA(R) phenot ype, otherwise known as the mutation target size, was estimated to dif fer by an order of magnitude between the two loci, This difference in target size correlates with, and therefore may largely account for, th e difference in induced MF between both loci.