Latendresse J R, Pereira M A
ManTech Environmental Technology, Toxicology Division, Armstrong Laboratory, Wright-Patterson Air Force Base, Ohio 45433, USA.
Toxicol Pathol. 1997 Sep-Oct;25(5):433-40. doi: 10.1177/019262339702500501.
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 TCA 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 tumor 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 hepatocarcinogenesis 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.
二氯乙酸（DCA）和三氯乙酸（TCA）是工业溶剂及环境污染物三氯乙烯（TCE）的代谢产物，也是氯化饮用水中的污染物。由于这三种物质均已被证明会增加小鼠肝脏肿瘤的发生率，因此人类接触这些化学物质备受关注。剂量-反应曲线、癌症进展以及暴露后病变消退情况的差异表明，TCA和DCA的作用机制不同。本研究的目的是利用肝脏切片中细胞生长、分化和代谢的生物标志物，进一步表征由TCA和DCA促进的增殖性肝细胞病变，以更好地阐明这两种氯乙酸酯在作用机制上的差异。15日龄雌性小鼠经25 mg/kg N-甲基-N-亚硝基脲启动。从49日龄开始，给已启动的小鼠饮用含DCA或TCA（20.0 mmol/L）的水，直至413日龄安乐死。病理评估显示，用DCA促进的动物中出现的肝细胞改变灶和肿瘤为嗜酸性，免疫组化检测TGF-α、c-jun、c-myc、CYP 2E1、CYP 4A1和谷胱甘肽S-转移酶-π（GST-π）呈阳性。DCA病变的c-fos和TGF-β基本为阴性，但非肿瘤肝细胞始终呈TGF-β阳性。相比之下，TCA促进的肿瘤主要为嗜碱性，缺乏GST-π，染色情况不一；通常，超过50%的肿瘤肝细胞对其他生物标志物基本呈阴性。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方面存在一些显著差异。结果还提示了一些可能有助于DCA促进肿瘤的潜在生长信号转导途径，进一步支持了这两种氯乙酸酯以不同方式促进肝癌发生的前提，并为与TCE进行类似比较提供了合理依据。这样的比较应该能让人了解DCA、TCA或两者是否在母体化合物TCE的小鼠肝脏致癌过程中发挥重要作用。
