PERTURBATION OF HEPATOCYTE NUCLEAR POPULATIONS INDUCED BY IRON AND POLYCHLORINATED-BIPHENYLS IN C57BL 10SCSN MICE DURING CARCINOGENESIS/

The induction of hepatocarcinogenesis by polychlorinated biphenyls (PC Bs) in C57BL/10ScSn mice is markedly potentiated by iron, To investiga te the effects of iron and PCBs on nuclear populations, C57BL/10ScSn m ice received a single dose of iron-dextran (600 mg Fe/kg) and were fed a diet containing 0.01% of the PCBs mixture Aroclor 1254 for up to 6 months, DNA content of isolated nuclei and hepatocytes was estimated b y flow cytometry, Cell suspensions and nuclei isolated from Aroclor tr eated mice after 6 months contained increased diploid (2N) populations compared to controls, In contrast, iron treatment of mice markedly en hanced fractions of octoploid (8N) nuclei by 2 weeks and this effect p ersisted over the 6 month period, When Aroclor 1254 and iron were admi nistered together there was a synergistic increase in the mononucleate d diploid fraction which was significant at 2 weeks and highly signifi cant at 6 months, This became the predominant nuclear effect, At six m onths, Aroclor 1254 and iron, both alone and in combination, also incr eased the rate of DNA synthesis in hepatocytes as measured by bromodeo xyuridine (BrdU) incorporation. The chronic polyploidizing effect of i ron overload alone was investigated further and shown to be proportion al to the dose and was detectable as early as 2 days after 600 mg Fe/k g and 1 week after 150 mg Fe/kg. Polyploidization of nuclei was inhibi ted by the oral iron chelator CP94. Iron also induced a prolonged redu ction in the incidence of binucleated cells. Histologically, nuclear e nlargement due to iron was confined to the midzonal region of the live r lobule, whereas iron deposition was greatest in the periportal regio n, Iron (600 mg/kg) also caused increased nuclear polyploid states in hepatocytes of adult rats and gerbils, Similarly, weanling mice with a dominantly diploid cell population, when treated with iron (300 mg/kg ), exhibited a significant shift to a tetraploid (4N) population and a marked increase in proliferation as measured by BrdU incorporation an d proliferative cell nuclear antigen (PCNA) detection, These results i ndicate that Aroclor 1254 and iron induce changes in the mouse hepatoc yte population that involve 2N and 8N nuclei respectively, The combina tion treatment leads to the emergence and proliferation of a mononucle ated, diploid population as observed frequently in chemical hepatocarc inogenesis, The reason for the chronic polyploidizing effect of iron i s unknown, but may imply both increased DNA synthesis and impairment o f nuclear division with implications in human conditions of iron overl oad.