Persistence of ethyl carbamate-induced DNA damage in vivo as indicated by sister chromatid exchange analysis

Abstract

Various treatment protocols were designed to investigate sister chromatid exchanges (SCEs) induced over successive posttreatment cell cycles in bone marrow and alveolar macrophage cells following treatment of C57BL/6J X DBA/2J F1 mice by i.p. injection of ethyl carbamate (3.3 mmol/kg). The same initial extent of alkylation in bone marrow and alveolar macrophages was suggested by identical SCE frequencies produced in both cell types by a one-cycle exposure protocol. The relatively lower responses in bone marrow cells by all other protocols may be a result of its faster mean population-cycling time. Second- and third-division cell SCE data produced by the various protocols indicate persistence of SCE-inducing lesions with no evidence of repair. In spite of the demonstrated lack of repair, first-cycle ethyl carbamate treatment was less effective than was second-cycle treatment in inducing SCEs. These results could not be attributed to selection of less-damaged cells over 2 cycles or to enhanced bromodeoxyuridine sensitivity in the second-cycle treatment protocol. It is speculated that the apparent cancellation of SCEs occurring over two successive cycles in the two-cycle exposure protocol may indicate the transient presence of ethyl carbamate-induced DNA interstrand cross-links. A possible mechanism of action of ethyl carbamate involving the formation of a transient cross-link and a persistent DNA monoadduct is postulated.