Sargent L, Dragan Y P, Erickson C, Laufer C J, Pitot H C
McArdle Laboratory for Cancer Research, Department of Oncology, Medical School, University of Wisconsin, Madison 53706.
Carcinogenesis. 1991 May;12(5):793-800. doi: 10.1093/carcin/12.5.793.
Polychlorinated biphenyls (PCBs) are a group of industrial chemicals that are widely distributed in the environment. Because these compounds occur as mixtures, studies of their possible interactive effects are essential for an understanding of the mechanism of the toxicity of these mixtures. For the determination of a possible interaction of the effects in vivo of 2,5,2',5'-tetrachlorobiphenyl (TCB) and 3,4,3',4'-TCB, rats were exposed to a single dose of diethylnitrosamine (DEN) and subsequently to 0.1 p.p.m. 3,4,3',4'-TCB and/or 10 p.p.m. 2,5,2',5'-TCB in the feed for 1 year. The two major targets of PCB toxicity, the liver and the peripheral blood, were examined after these treatments. TCB treatment after DEN exposure caused a predominance of increased placental glutathione S-transferase (PGST) and deficiencies of ATPase as preneoplastic markers in focal hepatic lesions. When 0.05% phenobarbital (PB) was administered after DEN exposure, the distribution of markers in altered hepatic foci (AHF) was essentially equal for increased PGST and gamma-glutamyltranspeptidase (GGT) and for ATPase deficiency. Many of these AHF also exhibited increased P450 b/e expression. Our results demonstrated that the two PCB congeners interacted in vivo to produce an increase in AHF that were PGST positive and ATPase negative. PGST-positive and ATPase-negative AHF correlated best with focal areas of P450 b/e expression. The combination of the two PCBs caused a greater than additive decrease in the total number of lymphocytes and antibody-producing B-cells. Also the thymocyte-dependent T-helper cells isolated from the animals receiving the combination of TCBs demonstrated a morphologically abnormal subpopulation. The results indicate that the interaction of 2,5,2',5'-TCB and 3,4,3',4'-TCB in vivo induced much greater toxicity and mutagenicity in peripheral lymphocytes and hepatocytes than treatment with either congener alone.
多氯联苯（PCBs）是一类广泛分布于环境中的工业化学品。由于这些化合物以混合物形式存在，因此研究它们可能的相互作用对于理解这些混合物的毒性机制至关重要。为了确定2,5,2',5'-四氯联苯（TCB）和3,4,3',4'-TCB在体内的效应是否可能相互作用，将大鼠单次暴露于二乙基亚硝胺（DEN），随后在饲料中给予0.1 ppm的3,4,3',4'-TCB和/或10 ppm的2,5,2',5'-TCB，持续1年。在这些处理后，对PCB毒性的两个主要靶器官肝脏和外周血进行了检查。DEN暴露后进行TCB处理导致胎盘谷胱甘肽S-转移酶（PGST）升高，而作为局灶性肝损伤前肿瘤标志物的ATP酶缺乏占优势。DEN暴露后给予0.05%苯巴比妥（PB）时，改变的肝灶（AHF）中PGST和γ-谷氨酰转肽酶（GGT）升高以及ATP酶缺乏的标志物分布基本相等。许多这些AHF还表现出P450 b/e表达增加。我们的结果表明，这两种PCB同系物在体内相互作用，导致PGST阳性和ATP酶阴性的AHF增加。PGST阳性和ATP酶阴性的AHF与P450 b/e表达的局灶区域相关性最佳。两种PCB的组合导致淋巴细胞和产生抗体的B细胞总数减少幅度大于相加效应。此外，从接受TCB组合处理的动物中分离出的胸腺依赖性T辅助细胞表现出形态异常的亚群。结果表明，2,5,2',5'-TCB和3,4,3',4'-TCB在体内的相互作用在外周淋巴细胞和肝细胞中诱导的毒性和致突变性比单独使用任何一种同系物处理都要大得多。
