Nuclear enlargement induced by hepatocarcinogens alters ploidy

Treatment of rats with low doses of hepatocarcinogens is associated with a number of phenomena, including nuclear enlargement and altered nucleocytoplasmic compartmentation, which potentially reflect initiatory changes. Since a number of investigations have indicated that changes in ploidy may relate to the development of altered foci and/or hepatocellular carcinomas in liver, and since nuclear enlargement may be associated with changes in DNA content, we examined the ploidy of rat hepatocytes following essentially nontoxic low-dose carcinogen treatment. Treatments with thioacetamide, 2-acetylaminofluorene, or dimethylnitrosamine were all associated with a notable shift of nuclei from diploid to tetraploid, in the apparent absence of nuclear replication. These changes were similar in magnitude to that associated with the substantial liver regeneration induced by carbon tetrachloride. If it is argued that cell replication is a necessary prerequisite for the completion of initiation, these data suggest that there may be thresholds for initiation.