Increased Nuclear Ploidy, Not Cell Proliferation, Is Sustained in the Peroxisome Proliferator-Treated Rat Liver

Peroxisome proliferators are believed to induce liver tumors in rodents due to sustained increase in cell proliferation and oxidative stress resulting from the induction of peroxisomal enzymes. The objective of this study was to conduct a sequential analysis of the early changes in cell-cycle kinetics and the dynamics of rat liver DNA synthesis after treatment with a peroxisome proliferator. Immunofluorescent detection of proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) incorporation into DNA during S phase were used to assess rat hepatocyte proliferation in vivo during dietary administration of Wy-14,643, a known peroxisome proliferator and hepatocarcinogen in rodents. Rats were placed on a diet containing 0.1% Wy-14,643 and implanted subcutaneously with 5-bromo-2'-deoxyuridine containing osmotic pumps 4 days prior to being sacrificed on days 4, 11, and 25 of treatment. Isolated liver nuclei labeled with fluorscein isothiocyanate (FITC)-anti-BrdU/PI and FITC-anti-PCNA/PI were analyz...