Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans
- National Cancer Institute, Bethesda, MD (United States); and others
Occupational exposure to benzene is known to cause leukemia, but the mechanism remains unclear. Unlike most other carcinogens, benzene and its metabolites are weakly or nonmutagenic. Benzene and its metabolites do, however, produce some chromosomal damage. Glycophorin A (GPA) gene loss mutation assay is used to evaluate the nature of DNA damage produced by benzene in 24 workers heavily exposed to benzene and 23 matched control individuals in Shanghai, China. The GPA assay identifies stem cell or precursor erythroid cell mutations expressed in peripheral erythrocytes of MN-heterozygous subjects, distinguishing the NN and N{O} mutant variants. A significant increase in the NN GPA variant cell frequency (V{sub f}) was found in benzene-exposed workers as compared with unexposed control individuals (mean {+-}SEM, 13.9 {+-} 1.7 per million cells vs. 7.4 {+-} 1.1 per million cells in control individuals; P = 0.0002). In contrast, no significant difference existed between the two groups for the N{O} V{sub 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{sub f} (P = 0.005) but not with the N{O} V{sub f} (P = 0.31), suggesting that NN mutations occur in longer-lived bone marrow stem cells. NN variants result from loss of the GPA M allele and duplication of the N allele, presumably through recombination mechanisms, whereas N{O} variants arise from gene inactivation, presumably due to point mutations and deletions. Thus, these results suggest that benzene produces gene-duplicating mutations but does not produce gene-inactivating mutations at the GPA locus in bone marrow cells of humans exposed to high benzene levels. This finding is consistent with data on the genetic toxicology of benzene and its metabolites and adds further weight to the hypothesis that chromosome damage and mitotic recombination are important in benzene-induced leukemia. 39 refs., 2 figs., 3 tabs.
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC04-76EV01013
- OSTI ID:
- 96327
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, Issue 9; Other Information: PBD: 25 Apr 1995
- Country of Publication:
- United States
- Language:
- English
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