PERTURBATION OF HEPATOCYTE NUCLEAR POPULATIONS INDUCED BY IRON AND POLYCHLORINATED-BIPHENYLS IN C57BL/10SCSN MICE DURING CARCINOGENESIS
PERTURBATION OF HEPATOCYTE NUCLEAR POPULATIONS INDUCED BY IRON AND POLYCHLORINATED-BIPHENYLS IN C57BL/10SCSN MICE DURING CARCINOGENESIS
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DOI：
10.1093/carcin/16.4.719
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发表时间：
1995-04-01
期刊：
影响因子：
4.7
通讯作者：
SMITH, AG
中科院分区：
文献类型：
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作者：
MADRA, S;STYLES, J;SMITH, AG
多氯联苯（PCBs）诱发C57 BL/10 ScSn小鼠肝癌的作用可被铁显著增强。为了研究铁和PCBs对C57 BL/10 ScSn小鼠细胞核群的影响，我们用单剂量的铁-葡聚糖对C57 BL/10 ScSn小鼠进行了实验（600毫克铁/公斤），并喂食含有0.01%的多氯联苯混合物Aroclor 1254的饮食长达6个月，通过流式细胞术估计分离的细胞核和肝细胞的DNA含量，与对照组相比，6个月后从Aroclor处理的小鼠中分离的细胞悬液和细胞核含有增加的二倍体（2N）群体。相反，小鼠的铁处理在2周时显著提高了二倍体（8 N）细胞核的分数，并且这种效果持续了6个月。当Aroclor 1254和铁一起给药时，单核二倍体部分协同增加，这在2周时显著，在6个月时高度显著，这成为主要的核效应。在6个月时，Aroclor 1254和铁（单独和联合）也增加了肝细胞中的DNA合成速率，如溴脱氧尿苷（BrdU）掺入所测量的。进一步研究了单独铁过载的慢性多倍化效应，结果表明与剂量成比例，早在600 mg Fe/kg后2天和150 mg Fe/kg后1周即可检测到。口服铁螯合剂CP 94可抑制细胞核的多倍化。铁还诱导双核细胞发生率的长期降低。在组织学上，由于铁引起的核增大局限于肝小叶的中间带区域，而铁沉积在门静脉周围区域最大，600 mg/kg的铁也引起成年大鼠和沙鼠肝细胞核多倍体状态的增加。同样，当用铁处理时，（300 mg/kg），表现出向四倍体（4 N）群体的显著转变和增殖的显著增加，如通过BrdU掺入和增殖细胞核抗原（PCNA）检测所测量的，这些结果表明，Aroclor 1254和铁诱导小鼠肝细胞群的变化，分别涉及2N和8 N细胞核，联合治疗导致单核二倍体群体的出现和增殖，如在化学性肝癌发生中经常观察到的。铁的慢性多倍化效应的原因尚不清楚，但可能意味着DNA合成增加和核分裂受损，这与人类铁过载状况有关。
The induction of hepatocarcinogenesis by polychlorinated biphenyls (PCBs) in C57BL/10ScSn mice is markedly potentiated by iron, To investigate the effects of iron and PCBs on nuclear populations, C57BL/10ScSn mice 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 by flow cytometry, Cell suspensions and nuclei isolated from Aroclor treated mice after 6 months contained increased diploid (2N) populations compared to controls, In contrast, iron treatment of mice markedly enhanced fractions of octoploid (8N) nuclei by 2 weeks and this effect persisted over the 6 month period, When Aroclor 1254 and iron were administered together there was a synergistic increase in the mononucleated diploid fraction which was significant at 2 weeks and highly significant at 6 months, This became the predominant nuclear effect, At six months, Aroclor 1254 and iron, both alone and in combination, also increased the rate of DNA synthesis in hepatocytes as measured by bromodeoxyuridine (BrdU) incorporation. The chronic polyploidizing effect of iron overload alone was investigated further and shown to be proportional to the dose and was detectable as early as 2 days after 600 mg Fe/kg and 1 week after 150 mg Fe/kg. Polyploidization of nuclei was inhibited by the oral iron chelator CP94. Iron also induced a prolonged reduction in the incidence of binucleated cells. Histologically, nuclear enlargement due to iron was confined to the midzonal region of the liver lobule, whereas iron deposition was greatest in the periportal region, 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 and proliferative cell nuclear antigen (PCNA) detection, These results indicate that Aroclor 1254 and iron induce changes in the mouse hepatocyte population that involve 2N and 8N nuclei respectively, The combination treatment leads to the emergence and proliferation of a mononucleated, diploid population as observed frequently in chemical hepatocarcinogenesis, The reason for the chronic polyploidizing effect of iron is unknown, but may imply both increased DNA synthesis and impairment of nuclear division with implications in human conditions of iron overload.