Fuscoe J C, Afshari A J, George M H, DeAngelo A B, Tice R R, Salman T, Allen J W
Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Environ Mol Mutagen. 1996;27(1):1-9. doi: 10.1002/(SICI)1098-2280(1996)27:1<1::AID-EM1>3.0.CO;2-L.
Chlorination is a widely used method for disinfection of drinking water supplies. Reaction of chlorine with naturally present organic compounds can result in toxic by-products. One major disinfection by-product from the chlorination of drinking water is dichloroacetic acid (DCA). This chemical has been shown to be carcinogenic in rodents, yet little genotoxicity data are available to assess the possible role of DNA and/or chromosomal damage in this process. We have used the peripheral blood erythrocyte micronucleus (MN) assay and the alkaline single cell gel electrophoresis (SCG) technique to investigate the in vivo genotoxicity of DCA in bone marrow and blood leukocytes, respectively. The MN assay detects chromosome breakage and/or malsegregation, while the SCG assay detects DNA damage (e.g., single strand breaks, alkali-labile sites, crosslinking). Mice were exposed to this compound in drinking water, available ad libitum, for up to 31 weeks. Our results show a small but statistically significant dose-related increase in the frequency of micronucleated polychromatic erythrocytes (PCEs) after subchronic exposure to DCA for 9 days. In addition, at the highest dose of DCA tested (3.5 g/l), a small but significant increase in the frequency of micronucleated normochromatic erythrocytes (NCE) was detected following exposure for > or = 10 weeks. Coadministration of the antioxidant vitamin E did not affect the ability of DCA to induce this damage, indicating that the small induction of MN by DCA was probably not due to oxidative damage. Based on the lack of any difference observed in the proportion of kinetochore-positive micronuclei between the treated and control animals, we interpret MN as arising from clastogenic events. The SCG technique suggested the presence of DNA crosslinking in blood leukocytes in mice exposed to 3.5 g/l DCA for 28 days. These data provide evidence that DCA may be an extremely weak inducer of chromosome damage when provided to mice in drinking water under conditions which lead to increased levels of tumors.
氯化是一种广泛用于饮用水供应消毒的方法。氯与天然存在的有机化合物反应会产生有毒的副产物。饮用水氯化产生的一种主要消毒副产物是二氯乙酸（DCA）。这种化学物质已被证明对啮齿动物具有致癌性，但几乎没有遗传毒性数据可用于评估DNA和/或染色体损伤在此过程中可能发挥的作用。我们分别使用外周血红细胞微核（MN）试验和碱性单细胞凝胶电泳（SCG）技术来研究DCA在骨髓和血液白细胞中的体内遗传毒性。MN试验检测染色体断裂和/或错分离，而SCG试验检测DNA损伤（例如，单链断裂、碱不稳定位点、交联）。小鼠在长达31周的时间里自由饮用含有该化合物的水。我们的结果表明，在亚慢性暴露于DCA 9天后，多染性红细胞（PCE）微核频率有小幅但具有统计学意义的剂量相关增加。此外，在测试的最高DCA剂量（3.5 g/l）下，暴露≥10周后，正常染色红细胞（NCE）微核频率有小幅但显著的增加。抗氧化剂维生素E的共同给药并未影响DCA诱导这种损伤的能力，这表明DCA对MN的小幅诱导可能不是由于氧化损伤。基于在处理组和对照组动物之间观察到的动粒阳性微核比例没有任何差异，我们将MN解释为由致断裂事件引起。SCG技术表明，暴露于3.5 g/l DCA 28天的小鼠血液白细胞中存在DNA交联。这些数据提供了证据，表明在导致肿瘤水平升高的条件下，当通过饮用水给予小鼠时，DCA可能是一种极其微弱的染色体损伤诱导剂。
