BENZENE INDUCES GENE-DUPLICATING BUT NOT GENE-INACTIVATING MUTATIONS AT THE GLYCOPHORIN-A LOCUS IN EXPOSED HUMANS

Occupational exposure to benzene is known to cause leukemia, but the m echanism remains unclear. Unlike most other carcinogens, benzene and i ts metabolites are weakly or nonmutagenic in most simple gene mutation assays. Benzene and its metabolites do, however, produce chromosomal damage in a variety of systems, Here, we have used the glycophorin A ( GPA) gene loss mutation assay to evaluate the nature of DNA damage pro duced by benzene in 24 workers heavily exposed to benzene and 23 match ed control individuals in Shanghai, China, The GPA assay identifies st em cell or precursor erythroid cell mutations expressed in peripheral erythrocytes of MN-heterozygous subjects, distinguishing the NN and NO mutant variants. A significant increase in the NN GPA variant cell fr equency (V-f) was found in benzene-exposed workers as compared with un exposed control individuals (mean +/- SEM, 13.9 +/- 1.7 per million te lls vs. 7.4 +/- 1.1 per million cells in control individuals; P = 0.00 02). In contrast, no significant difference existed between the two gr oups for the NO V-f (9.1 +/- 0.9 vs. 8.8 +/- 1.8 per million cells; P = 0.21). Further, lifetime cumulative occupational exposure to benzene was associated with the NN V-f (P = 0.005) but not with the NO V-f (P = 0.31), suggesting that NN mutations occur in longer-lived bone marr ow stem cells. NN variants result from loss of the GPA M allele and du plication of the N allele, presumably through recombination mechanisms , whereas NO variants arise from gene inactivation, presumably due to point mutations and deletions, Thus, these results suggest that benzen e produces gene-duplicating mutations but does not produce gene-inacti vating mutations at the GPA locus in bone marrow cells of humans expos ed to high benzene levels. This finding is consistent with data on the genetic toxicology of benzene and its metabolites and adds further we ight to the hypothesis that chromosome damage and mitotic recombinatio n are important in benzene-induced leukemia.