Kissling Grace E, Malarkey David E, Vallant Molly K, Johnson Jerry D, Hejtmancik Milton R, Herbert Ronald A, Boorman Gary A
Environmental Diseases and Medicine Program, Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709, USA.
Toxicol Sci. 2009 Jan;107(1):19-26. doi: 10.1093/toxsci/kfn228. Epub 2008 Oct 30.
There has been considerable interest in the use of genetically modified mice for detecting potential environmental carcinogens. For this reason, the National Toxicology Program has been evaluating Tg.AC hemizygous and p53 haploinsufficient mice as models to detect potential carcinogens. It was reasoned that these mouse models might also prove more effective than standard rodent models in evaluating the numerous disinfection byproducts that are found in low concentrations in drinking water. Dichloroacetic acid (DCA) is one of the most frequently found disinfection byproducts and DCA has been consistently shown to cause hepatocellular tumors in rats and mice in standard rodent studies. Tg.AC hemizygous and p53 haploinsufficient mice were exposed in the drinking water to DCA for up to 41 weeks. In a second study Tg.AC mice were subjected to dermal DCA exposure for up to 39 weeks. Increased incidences and severity of cytoplasmic vacuolization of hepatocytes were seen in the p53 mice, but there was no evidence of carcinogenic activity at exposures of up to 2000 mg/l in the drinking water. Increased incidences and severity of cytoplasmic vacuolization of hepatocytes were seen in the drinking water study with Tg.AC mice and a modest non-dose-related increase in pulmonary adenomas was observed in males exposed to 1000 mg/l in the drinking water. Dermal exposure up to 500 mg/kg for 39 weeks resulted in increased dermal papillomas at the site of application in Tg.AC mice. No significant increase in papillomas under the same study conditions was seen in the 26-week study. For DCA under these study conditions, the p53 and Tg.AC mice appear less sensitive to hepatocarcinogenesis than standard rodent models. These results suggest caution for the use of Tg.AC and p53 mice to screen unknown chemicals in drinking water for potential carcinogenicity.
利用基因改造小鼠检测潜在环境致癌物已引发了广泛关注。因此，国家毒理学计划一直在评估半合子Tg.AC小鼠和p53单倍体不足小鼠，将其作为检测潜在致癌物的模型。据推测，在评估饮用水中低浓度存在的众多消毒副产物时，这些小鼠模型可能比标准啮齿动物模型更有效。二氯乙酸（DCA）是最常发现的消毒副产物之一，在标准啮齿动物研究中，DCA一直被证明会在大鼠和小鼠中引发肝细胞肿瘤。将半合子Tg.AC小鼠和p53单倍体不足小鼠的饮用水中添加DCA，暴露长达41周。在第二项研究中，对Tg.AC小鼠进行了长达39周的皮肤DCA暴露。在p53小鼠中观察到肝细胞胞质空泡化的发生率和严重程度增加，但在饮用水中暴露浓度高达2000 mg/l时，没有致癌活性的证据。在Tg.AC小鼠的饮用水研究中观察到肝细胞胞质空泡化的发生率和严重程度增加，并且在饮用水中暴露于1000 mg/l的雄性小鼠中观察到肺腺瘤有适度的非剂量相关增加。在Tg.AC小鼠中，皮肤暴露500 mg/kg长达39周导致涂抹部位的皮肤乳头状瘤增加。在26周的研究中，在相同研究条件下未观察到乳头状瘤有显著增加。在这些研究条件下，对于DCA，p53和Tg.AC小鼠似乎比标准啮齿动物模型对肝癌发生的敏感性更低。这些结果表明，在使用Tg.AC和p53小鼠筛查饮用水中未知化学物质的潜在致癌性时应谨慎。
