Glauert Howard P, Tharappel Job C, Banerjee Subhashis, Chan Nelson L S, Kania-Korwel Izabela, Lehmler Hans-Joachim, Lee Eun Y, Robertson Larry W, Spear Brett T
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40506, USA.
Toxicol Appl Pharmacol. 2008 Oct 15;232(2):302-8. doi: 10.1016/j.taap.2008.06.013. Epub 2008 Jul 2.
Polychlorinated biphenyls (PCBs) are persistent and ubiquitous environmental chemicals that bioaccumulate and have hepatic tumor promoting activity in rodents. The present study examined the effect of deleting the p50 subunit of NF-kappaB on the hepatic tumor promoting activity of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) in mice. Both wild-type and p50-/- male mice were injected i.p. with diethylnitrosamine (DEN, 90 mg/kg) and then subsequently injected biweekly with 20 i.p. injections of PCB-153 (300 micromol/kg/injection). p50 deletion decreased the tumor incidence in both PCB- and vehicle-treated mice, whereas PCB-153 slightly (P=0.09) increased the tumor incidence in wild-type and p50-/- mice. PCB-153 increased the total tumor volume in both wild-type and p50-/- mice, but the total tumor volume was not affected by p50 deletion in either PCB- or vehicle-treated mice. The volume of tumors that were positive for glutamine synthetase (GS), which is indicative of mutations in the beta-catenin gene, was increased in both wild-type and p50-/- mice administered PCB-153 compared to vehicle controls, and inhibited in p50-/- mice compared to wild-type mice (in both PCB- and vehicle-treated mice). The volume of tumors that were negative for GS was increased in p50-/- mice compared to wild-type mice but was not affected by PCB-153. PCB-153 increased cell proliferation in normal hepatocytes in wild-type but not p50-/- mice; this increase was inhibited in p50-/- mice. In hepatic tumors, the rate of cell proliferation was much higher than in normal hepatocytes, but was not affected by PCB treatment or p50 deletion. The rate of apoptosis, as measured by the TUNEL assay, was not affected by PCB-153 or p50 deletion in normal hepatocytes. In hepatic tumors, the rate of apoptosis was lower than in normal hepatocytes; PCB-153 slightly (P=0.10) increased apoptosis in p50-/- but not wild-type mice; p50 deletion had no effect. Taken together, these data indicate that the absence of the NF-kappaB p50 subunit inhibits the promoting activity of PCB-153 and alters the proliferative and apoptotic changes in mouse liver in the response to PCBs.
多氯联苯（PCBs）是一类持久性且广泛存在的环境化学物质，它们会在生物体内蓄积，并在啮齿动物中具有肝脏肿瘤促进活性。本研究检测了敲除核因子κB（NF-κB）的p50亚基对2,2',4,4',5,5'-六氯联苯（PCB-153）在小鼠肝脏肿瘤促进活性方面的影响。野生型和p50基因敲除（p50-/-）的雄性小鼠均经腹腔注射二乙基亚硝胺（DEN，90 mg/kg），随后每两周经腹腔注射20次PCB-153（300 μmol/kg/次）。敲除p50基因降低了PCB处理组和溶剂处理组小鼠的肿瘤发生率，而PCB-153使野生型和p50-/-小鼠的肿瘤发生率略有增加（P=0.09）。PCB-153增加了野生型和p50-/-小鼠的肿瘤总体积，但在PCB处理组和溶剂处理组中，敲除p50基因均未影响肿瘤总体积。与溶剂对照组相比，给予PCB-153的野生型和p50-/-小鼠中谷氨酰胺合成酶（GS）阳性的肿瘤体积增加，谷氨酰胺合成酶阳性表明β-连环蛋白基因发生突变，且与野生型小鼠相比，p50-/-小鼠中该肿瘤体积受到抑制（在PCB处理组和溶剂处理组中均如此）。与野生型小鼠相比，p50-/-小鼠中GS阴性的肿瘤体积增加，但不受PCB-153影响。PCB-153增加了野生型小鼠而非p50-/-小鼠正常肝细胞的细胞增殖；p50-/-小鼠中这种增加受到抑制。在肝肿瘤中，细胞增殖速率远高于正常肝细胞，但不受PCB处理或敲除p50基因的影响。通过TUNEL法检测的凋亡率在正常肝细胞中不受PCB-153或敲除p50基因的影响。在肝肿瘤中，凋亡率低于正常肝细胞；PCB-153使p50-/-小鼠的凋亡率略有增加（P=0.10），但对野生型小鼠无此作用；敲除p50基因无影响。综上所述，这些数据表明NF-κB p50亚基的缺失抑制了PCB-153的促进活性，并改变了小鼠肝脏对PCBs反应中的增殖和凋亡变化。
