Divergent synergic effects in carcinogenesis initiation by simultaneous exposure to two genotoxic carcinogens

Carcinogenesis is a complex and multistep process starting from initiation to tumor progression. Synergistic mechanisms can occur at every step of the process. The aim of this work was to provide information about the effect of chemical carcinogens which, if administered in combination, result in positive as well as negative synergistic effects. In order to evaluate whether for some carcinogens synergism occurs at the initiation step, we compared the effects of Ethylmethanesulfonate (EMS) on Benzo[a]pyrene (BP)-DNA adducts formation in the liver and lung of male Swiss mice treated for seven days by i.p. dose of EMS (1.2 mg/Kg b.w.) alone or by simultaneous administration of three doses of BP (25, 50, 100 mg/Kg b.w.) injected i.p. or the first day of treatment. A group of Swiss mice was treated by BP alone. At it was demonstrated in our laboratory that previous immunization toward BP influences the adduct levels of this carcinogen (14), the same treatments (BaP alone and BaP with EMS) were carried out in mice previously immunized toward BP. Liver and lung 1 BP-DNA adducts were detected in all the groups treated by both BP and EMS as compared to the group treated with BP alone. The EMS-BP association in non-immunized mice showed an antagonistic effect in the liver and a synergistic effect in the lung. In immunized mice a synergistic effect was obtained in both liver and lung. Moreover, the efficiency of both the synergistic and antagonistic effect, depended on BP dose of treatment. It is reasonable to draw the conclusion that simultaneous exposure to BP and EMS leads to different organ-specific and dose-dependent effects. This first preliminary result showed that the pattern of the interaction between genotoxic carcinogens is more complex that was foreseen, even at the stage of DNA adducts formation.