Dissimilar characteristics of N-methyl-N-nitrosourea-initiated foci and tumors promoted by dichloroacetic acid or trichloroacetic acid in the liver of female B6C3F1 mice
Dissimilar characteristics of N-methyl-N-nitrosourea-initiated foci and tumors promoted by dichloroacetic acid or trichloroacetic acid in the liver of female B6C3F1 mice
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DOI：
10.1177/019262339702500501
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发表时间：
1997-09-01
影响因子：
1.5
通讯作者：
Pereira, MA
中科院分区：
文献类型：
--
作者：
Latendresse, JR;Pereira, MA
二氯乙酸（DCA）和三氯乙酸（TCA）是工业溶剂和环境污染物三氯乙烯（TCE）的代谢物，也是氯化饮用水的污染物。人类接触这些化学物质是值得关注的，因为这三种化学物质都显示会增加小鼠肝脏肿瘤的发病率。剂量-反应曲线、癌症进展和暴露后病变消退的差异表明，TCA和DCA通过不同的机制起作用。本研究的目的是利用肝切片中细胞生长、分化和代谢的生物标志物，进一步表征TCP和DCA促进的增生性肝细胞病变，以更好地描述两种氯乙酸盐作用机制的差异。15日龄雌性小鼠注射25 mg/kg n-甲基-n -亚硝基脲。起始小鼠从49日龄开始在饮用水中给予DCA或TCA (20.0 mmol/L)，直到413日龄安乐死。病理评估显示，DCA促进的动物肝细胞和肿瘤灶发生嗜酸性粒细胞增多，tgf - α、c-jun、c-myc、CYP 2E1、CYP 4A1和谷胱甘肽s -转移酶pi （GST-pi）免疫组化阳性。DCA病变的c-fos和tgf - β基本呈阴性，但非肿瘤肝细胞的tgf - β始终呈阳性。相比之下，TCA促进的肿瘤主要是嗜碱性的，缺乏GST-pi，染色变化；通常，超过50%的特纳肝细胞在其他生物标志物上基本呈阴性。本研究表明DCA和TCA在细胞生长、分化和代谢的某些分子生物标志物上存在显著差异。结果还提示了一些潜在的生长信号转导通路可能参与DCA对肿瘤的促进作用，进一步支持了这两种氯乙酸盐促进肝癌发生的方式不同的前提，并为与TCE的类似比较提供了合理的依据。这样的比较应该能让我们对DCA、TCA或两者是否在母体化合物TCE的小鼠肝癌发生中发挥重要作用有所了解。
Dichloroacetic acid (DCA) and trichloroacetic acid (TCA) are metabolites of the industrial solvent and environmental contaminant trichloroethylene (TCE), as well as contaminants of chlorinated drinking water. Human exposure to these chemicals is of concern as all three have been shown to increase liver tumor incidence in mice. Differences in dose-response curves, progression to cancer, and postexposure regression of lesions suggest that TCA and DCA work through different mechanisms. The purpose of this study was to further characterize the proliferative hepatocellular lesions promoted by TCP, and DCA using biomarkers of cell growth, differentiation, and metabolism in liver sections to better delineate the distinctions in the mechanism of the two chloroacetates. Fifteen-day-old female mice were initiated with 25 mg/kg N-methyl-N-nitrosourea. The initiated mice were administered DCA or TCA (20.0 mmol/L) in drinking water from age 49 days until euthanasia at age 413 days. The pathologic assessment showed that the foci of altered hepatocytes and tumors occurring in the animals promoted with DCA were eosinophilic and positive immunohistochemically for TGF-alpha, c-jun, c-myc, CYP 2E1, CYP 4A1, and glutathione S-transferase-pi (GST-pi). The DCA lesions also were essentially negative for c-fos and TGF-beta, but nontumor hepatocytes were consistently TGF-beta-positive. In contrast, tumors promoted by TCA were predominantly basophilic, lacked GST-pi, and stained variably; usually, more than 50% of the turner hepatocytes were essentially negative for the other biomarkers. This study demonstrates some striking differences in certain molecular biomarkers of cell growth, differentiation, and metabolism between DCA and TCA. The results also suggest some potential growth signal transduction pathways that may contribute to the DCA promotion of tumors, further support the premise that these two chloroacetates promote hepatocarcinogenes is in different ways, and provide a rational basis for a similar comparison with TCE. Such a comparison should give some insight as to whether DCA, TCA, or both are playing a significant role in the murine liver carcinogenesis of the parent compound, TCE.