Hprt mutant frequency and p53 gene status in mice chronically exposed by inhalation to benzene.
Hprt mutant frequency and p53 gene status were assessed in wild-type and p53 heterozygous (p53+/-) mice exposed chronically by inhalation to benzene. Benzene exposures to 100 ppm for 6h on Monday-Friday, 100 ppm for 10h on Monday-Wednesday-Friday, or 200 ppm for 5h on Monday-Wednesday-Friday yielded the same total exposures (concentration x time) of 3000 ppm x h/week. Hprt mutations in splenic T-lymphocytes were significantly increased in all benzene groups, ranging from 3.8- to 8.0-fold greater than control values. Wild-type and p53+/- mice were equally susceptible to benzene mutagenesis. Hprt wild-type and mutant isolates from control and exposed animals were examined for TCR gene rearrangements (as markers of in vivo clonality) and for loss of p53 wild-type or mutant alleles. Moderate clonal amplifications were observed among the Hprt mutant but not Hprt wild-type isolates but was not sufficient to account for the increases in Hprt mutant frequencies. Most isolates, whether Hprt wild-type or mutant, retained both p53 alleles in the benzene-exposed p53+/- animals (54% and 63%, respectively, for the Hprt wild-type and mutants). However, 37% of the Hprt wild-type isolates and 46% of the Hprt mutant isolates lost the p53 mutant allele. Only a small percentage of either type of isolate lost the p53 wild-type allele, and this was always in isolates that that previously lost the p53 mutant allele. Loss of the p53 mutant allele was independent of benzene exposure, Hprt status, or 6-thioguanine selection. These findings contrast with the p53 status of thymic lymphomas that had preferentially lost the wild-type p53 allele in some of these same mice. Possible reasons for loss of the mutant p53 allele in the Hprt mutant and wild-type isolates are discussed.
Albertini
Richard J
RJ
Department of Pathology, University of Vermont, Burlington, VT 05404, USA. Ralbert315@aol.com
Judice
Stephen A
SA
Recio
Leslie
L
Walker
Vernon E
VE
D000818:Animals; D001554:Benzene / Q000009:adverse effects*; D016158:Genes, p53 / Q000235:genetics*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D019570:Inhalation Exposure / Q000009:adverse effects*; D019656:Loss of Heterozygosity; D016399:Lymphoma, T-Cell / Q000175:diagnosis; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000494:pharmacology*; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
D009153:Mutagens; D011948:Receptors, Antigen, T-Cell; D007041:Hypoxanthine Phosphoribosyltransferase; D001554:Benzene