The nongenotoxic hepatocarcinogens diethylhexylphthalate and methylclofenapate induce DNA synthesis preferentially in octoploid rat hepatocytes

Diethylhexylphthalate (DEHP), a rodent carcinogen, and 1,4-dichlorobenzene (DCB), a noncarcinogen in rat liver, are potent hepatomitogens. We have rep orted previously that 7-day dosing with DEHP induced a higher bromodeoxyuri dine labeling index (LI) in binuclear octoploid (2x4N) rat hepatocytes than did DCB, suggesting that induction of DNA synthesis in 2x4N hepatocytes mi ght represent a more substantial carcinogenic risk. We compared 2 additiona l rodent hepatocarcinogens, methylclofenapate (MCP) and phenobarbitone, wit h ethylene thiourea (ETU), a noncarcinogenic hepatomitogen in rat. All 3 ch emicals increased hepatic LI; the 8N population had the highest LI, but onl y the carcinogens increased LI in the 2x4N and 4N populations. To identify the target population for induction of DNA synthesis, we used a I-hour puls e label at the peak of induction. The results were consistent with the 7-da y data, and again the highest LI was in the 8N population. The nongenotoxic rodent carcinogens MCP and DEHP induced a significant increase in the LI i n the 2x4N population, whereas ETU and DCB did not. These data support the hypothesis that increased DNA synthesis within the minority 2x4N population may be more significant for subsequent hepatocarcinogenesis.