T. Chen et al., Gene- and tissue-specificity of mutation in Big Blue (R) rats treated withthe hepatocarcinogen N-hydroxy-2-acetylaminofluorene, ENV MOL MUT, 37(3), 2001, pp. 203-214
In a previous study, we Found that treating transgenic Big Blue(R) rats wit
h the hepatocarcinogen N-hydroxy-2-acetylaminofluorene (N-OH-AAF) produced
the same major DNA adduct in the target liver and the nontarget spleen lymp
hocytes and bone marrow cells, induced loci mutants in the liver, and induc
ed much lower frequencies of lad and hprt mutants in spleen lymphocytes. In
the present study, sequence analysis was conducted on loci DNA and hprt cD
NA from the mutants, to determine the mutational specificity of N-OH-AAF in
the rat. All the mutation spectra From N-OH-AAF-treated rats differed sign
ificantly from corresponding mutation profiles From untreated animals (P =
0.02 to P < 0.0001). Although there were similarities among the mutational
patterns derived From N-OH-AAF-treated rats (e.g., G:C --> T:A transversion
was the most common mutation in all mutation sets), there were significant
differences in the patterns of basepair substitution and frameshift mutati
on between the liver and spleen lymphocyte loci mutants (P = 0.02) and betw
een the spleen lymphocyte loci and hprt mutants (P = 0.04). Also, multiplex
PCR analysis of genomic DNA From the hprt mutants indicated that 12% of mu
tants from treated rats had major deletions in the hprt gene; no correspond
ing incidence of large deletions was evident among loci mutations. All the
mutation profiles reflect the general mutational specificity of the major D
NA adduct Formed by N-OH-AAF. The differences between N-OH-AAF mutation in
the endogenous gene and transgene can be partially explained by the structu
res of the two genes. The tissue-specificity of the mutation spectra may co
ntribute to targeting tumor formation to the liver. Environ. Mol. Mutagen.
37:203-214, 2001. Published 2001 Wiley-Liss, Inc.dagger