Fitzsimmons Patrick N, Hoffman Alex D, Lien Gregory J, Hammermeister Dean E, Nichols John W
U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Boulevard, Duluth, MN 55804, USA.
Aquat Toxicol. 2009 Sep 14;94(3):186-94. doi: 10.1016/j.aquatox.2009.07.001. Epub 2009 Jul 10.
Halogenated acetic acids (HAAs) produced by chlorine disinfection of municipal drinking water represent a potentially important class of environmental contaminants. Little is known, however, about their potential to adversely impact fish and other aquatic life. In this study we examined the kinetics and effects of dichloroacetic acid (DCA) in rainbow trout. Branchial uptake was measured in fish confined to respirometer-metabolism chambers. Branchial uptake efficiency was <5%, suggesting passive diffusion through aqueous channels in the gill epithelium. DCA concentrations in tissues following prolonged (72, 168, or 336 h) waterborne exposures were expressed as tissue:plasma concentration ratios. Concentration ratios for the kidney and muscle at 168 and 336 h were consistent with the suggestion that DCA distributes primarily to tissue water. Reduced concentration ratios for the liver, particularly at 72 h, indicated that DCA was highly metabolized by this tissue. Routes and rates of elimination were characterized by injecting chambered animals with a high (5.0mg/kg) or low (50 microg/kg) bolus dose. DCA was rapidly cleared by naïve animals resulting in elimination half-lives (t(1/2)) of less than 4h. Waterborne pre-treatment of fish with DCA increased the persistence of a subsequently injected dose. In high dose animals, pre-treatment caused a 4-fold decrease in whole-body clearance (CL(B)) and corresponding increases in the area under the plasma concentration-time curve (extrapolated to infinity; AUC(0-->infinity)) and t(1/2). Qualitatively similar results were obtained in low dose fish, although the magnitude of the pre-treatment effect ( approximately 2.5-fold) was reduced. Renal and branchial clearance contributed little (combined, <3% of CL(B)) to the elimination of DCA. Biliary elimination of DCA was also negligible. The steady-state volume of distribution (V(SS)) did not vary among treatment groups and was consistent with results of the tissue distribution study. DCA had no apparent effects on respiratory physiology or acid-base balance; however, the concentration of blood lactate declined progressively during continuous waterborne exposures. A transient effect on blood lactate was also observed in bolus injection experiments. The results of this study suggest that clearance of DCA is due almost entirely to metabolism. The pathway responsible for this activity exhibits characteristics in common with those of mammalian glutathione S-transferase zeta (GSTzeta), including non-linear kinetics and apparent suicide inactivation by DCA. Observed effects on blood lactate are probably due to the inhibition of pyruvate dehydrogenase kinase in aerobic tissues and may require the participation of a monocarboxylase transport protein to move DCA across cell membranes.
城市饮用水氯化消毒产生的卤代乙酸（HAAs）是一类潜在的重要环境污染物。然而，对于它们对鱼类和其他水生生物产生不利影响的可能性却知之甚少。在本研究中，我们检测了二氯乙酸（DCA）在虹鳟鱼体内的动力学及效应。在置于呼吸计 - 代谢室中的鱼体内测量鳃摄取情况。鳃摄取效率小于5%，表明其通过鳃上皮中的水性通道被动扩散。在长时间（72、168或336小时）水暴露后，组织中的DCA浓度以组织：血浆浓度比表示。168和336小时时肾脏和肌肉的浓度比表明DCA主要分布于组织水相中。肝脏的浓度比降低，尤其是在72小时时，表明该组织对DCA进行了高度代谢。通过给置于呼吸计中的动物注射高剂量（5.0mg/kg）或低剂量（50μg/kg）的DCA来表征消除途径和速率。未接触过DCA的动物能迅速清除DCA，消除半衰期（t(1/2)）小于4小时。用DCA对鱼进行水暴露预处理会增加随后注射剂量的持久性。在高剂量动物中，预处理导致全身清除率（CL(B)）降低4倍，同时血浆浓度 - 时间曲线下面积（外推至无穷大；AUC(0-->infinity)）和t(1/2)相应增加。在低剂量鱼中也获得了定性相似的结果，尽管预处理效应的幅度（约2.5倍）有所降低。肾脏和鳃清除对DCA消除的贡献很小（合计占CL(B)的不到3%）。DCA经胆汁的消除也可忽略不计。稳态分布容积（V(SS)）在各处理组之间没有变化，并且与组织分布研究的结果一致。DCA对呼吸生理或酸碱平衡没有明显影响；然而，在持续水暴露期间，血液乳酸浓度逐渐下降。在推注注射实验中也观察到对血液乳酸的短暂影响。本研究结果表明，DCA的清除几乎完全归因于代谢。负责此活性的途径表现出与哺乳动物谷胱甘肽S - 转移酶ζ（GSTzeta）共同的特征，包括非线性动力学以及DCA引起的明显自杀性失活。观察到的对血液乳酸的影响可能是由于需氧组织中丙酮酸脱氢酶激酶的抑制，并且可能需要单羧酸转运蛋白的参与来使DCA穿过细胞膜。
